Drug Eval uations

Drugs 25: 223-289 (1983)

0012-6667/83/0003-0223/$33.50/0
©ADlS Press Australasia Ply Ltd. All rights reserved.

Cefotaxime
A review of its Antibacterial Activity, Pharmacological
Properties and Therapeutic Use

A.A. Carmine, R.N. Brogden, R.C. Heel, T.M. Speight and

G.S. Avery
ADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: J.P. Fillastre, Faculty of Medicine,
Boisguillaume Hospital, Boisguillaume, France; R. Fujii, Department of Paediatrics,
Teikyo University School of Medicine, Tokyo, Japan; D.A. Kafetzis, Department of
Pediatrics, University of Athens, Greece; S.D.R. Lang, Department of Microbiology,
Middlemore Hospital, Auckland, New Zealand; S. Masuy08hi, Department of
Microbiology, School of Medicine, Gunma University, Gunma, Japan; P.J. McDonald,
Department of Clinical Microbiology, Flinders Medical Centre, Adelaide, Australia; H.C.
Neu, Division of Infectious Diseases, College of Physicians and Surgeons of Columbia
University, New York, USA; M. Richmond, University of Manchester, England; P.M.
Shah, Centre for Internal Medicine, J.W. Goethe University, Frankfurt, Germany; R.C.B.
Slack, Department of Microbiology, University Hospital, Queen's Medical Centre,
Nottingham, England; C.R. Smith, Department of Medicine, The Johns Hopkins
University School of Medicine and The John Hopkins Hospital, Baltimore, Maryland,
USA; A.J. Weinstein, Department of Infectious Disease, Cleveland Clinic, Cleveland,
Ohio, USA; D.H. Wittman, Surgery Department, Altona General Hospital, Hamburg,
Germany.

Contents
Summary .................................................................................................................................... 224
1. Antibacterial Activity ............................................................................................................ 228
l.l In Vitro Inhibitory Activity against Aerobic Bacteria ................................................ 228
1.1.1 Gram-positive Bacteria.......................................................................................... 229
1.1.2 Gram-negative Bacteria ........................................................................................ 230
1.2 In Vitro Inhibitory Activity against Anaerobic Bacteria ............................................ 236
1.3 Activity of Desacetyl-cefotaxime .................................................................................. 237
1.4 fJ-Lactamase Resistance ................................................................................................. 237
1.5 Bactericidal Activity ...................................................................................................... 238
1.6 Effect on Activity of Inoculum, Media, pH and Serum ............................................ 239
1.7 Antibiotic Synergy .......................................................................................................... 240
1.8 Activity In Vivo ............................................................................................................. 241
2. Renal Tolerance .................................................................................................................... 242
3. Toxicity Studies .................................................................................................................... 243
3.1 Acute Toxicity ...............................................................................................................• 243
Cefotaxime: A Review 224

3.2 Subacute and Chronic Toxicity ...................................................................................... 243

3.3 Reproduction Studies ...................................................................................................... 243
4. Pharmacokinetic Studies ........................................................................................................ 244
4.1 Absorption and Serum Concentration ........................................................................... 244
4.2 Distribution ...................................................................................................................... 245
4.2.1 Protein Binding ....................................................................................................... 249
4.3 Elimination ....................................................................................................................... 249
4.3.1 Metabolism and Excretion ..................................................................................... 249
4.3.2 Half-life .................................................................................................................... 251
4.4 Influence of Age on Pharmacokinetics .......................................................................... 251
4.5 Influence of Disease on Pharmacokinetics .................................................................... 252
5. Therapeutic Trials .................................................................................................................. 253
5.1 Treatment of Established Infections ............................................................................... 253
5.1.1 Urinary Tract Infections ......................................................................................... 253
5.1.2 Lower Respiratory Tract Infections ...................................................................... 257
5.1.3 Bacteraemia/Septicaemia and Endocarditis .......................................................... 261
5.1.4 Gonorrhoea .............................................................................................................. 262
5.1.5 Obstetric and Gynaecological Infections ............................................................... 263
5.1.6 Intra-abdominal Infections ..................................................................................... 264
5.1.7 Skin, Soft-tissue, Bone and Joint Infections ......................................................... 265
5.1.8 Infections in Immunologically Compromised Patients ....................................... 266
5.1. 9 Infections caused by Multiresistant Bacteria and Pseudomonas species ............ 266
5.1.10 Meningitis in Children and Adults ...................................................................... 267
5.1.11 Other Paediatric Infections .................................................................................. 269
5.2 Prevention of Infection in Surgery ................................................................................. 270
6. Side Effects .............................................................................................................................. 271
6.1 Local Reactions ................................................................................................................ 271
6.2 Haematological and Hepatic Effects ............................................................................... 271
6.3 Renal Effects .................................................................................................................... 272
6.4 Other Adverse Reactions ................................................................................................. 273
6.5 Adverse Bacteriological Effects ....................................................................................... 273
7. Dosage and Administration ................................................................................................... 274
8. The Place of Cefotaxime in Therapy .................................................................................... 275

Summary Synopsis: Cefotaxime l is a new 'third generation' semisynthetic cephalosporin admin-

istered intravenously or intramuscularly. It has a broad spectrum of activity against Gram-
positive and Gram-negative aerobic and anaerobic bacteria, and is generally more active
against Gram-negative bacteria than the 'first' and 'second generation' cephalosporins. Al-
though cejotaxime has some activity against Pseudomonas aeruginosa, on the basis ofpres-
ent evidence it cannot be recommended as sole antibiotic therapy for pseudomonal infec-
tions. However, cejotaxime has been effective in treating infections due to other 'difficult'
organisms, such as multidrug-resistant Enterobacteriaceae. Like other cephalosporins, cefo-
taxime is effective in treating patients with complicated urinary tract and lower respiratory
tract infections, particularly pneumonia caused by Gram-negative bacilli. High response
rates have also been achieved in patients with Gram-negative bacteraemia. Although fa-
vourable clinical results have been obtained in patients with infections caused by mixed
aerobic/anaerobic organisms (such as peritonitis or soft tissue infections), the relatively low
in vitro activity of cejotaxime against Bacteroides fragilis may restrict its usage in situations
where this organism is the suspected or proven pathogen. In preliminary studies, males and
I 'Claforan' (Hoechst, Roussel).
Cefotaxime: A Review 225

females treated with a single intramuscular dose of cefotaxime for uncomplicated gonor-
rhoea caused by penicillinase-producing strains of Neisseria gonorrhoeae responded very
favourably. Encouraging results have also been reported in open studies in children, in-
cluding neonates, treated with cefotaxime for meningitis and various other serious infec-
tions. In some situations, cefotaxime has been given in combination with another antibiotic
such as an aminoglycoside, but the merits of such a combination have not been clearly
established. Whether cefotaxime alone is appropriate therapy for conditions previously treated
with aminoglycosides (other than pseudomonal infections) also needs additional clarifica-
tion, but if established as equally effective in such conditions cefotaxime offers potentially
important clinical and practical advantages in its apparent lack of serious adverse effects
and freedom from the need to undertake drug plasma concentration monitoring.
Antibacterial Activity: Cefotaxime has a broad spectrum of activity in vitro which in-
cludes Gram-positive and Gram-negative aerobic and anaerobic bacteria. Cefotaxime is as
active as benzyl penicillin against Streptococcus pneumoniae and pyogenes, but is also very
active against penicillin-resistant and multiple drug-resistant strains of Streptococcus pneu-
moniae. Like other cephalosporins, cefotaxime has poor activity against enterococci (in-
cluding Streptococcus faecalis). Penicillin-sensitive and -resistant strains of Staphylococcus
aureus are inhibited by low concentrations of cefotaxime, but cephalothin and cefamandole
are more active against this species. When compared with other 'third generation' cepha-
losporins, cefotaxime tends to be similar in activity to cefoperazone against S. aureus, but
more active than cefoperazone against streptococci in general, and more active than moxa-
lactam against all Gram-positive bacteria.
Cefotaxime exhibits both a wider spectrum and greater activity against Gram-negative
aerobic bacteria than 'first generation' or 'second generation' cephalosporins, is generally
more active than cefoperazone except against Pseudomonas aeruginosa, and similar in
activity to moxalactam. A multicentre study in the USA found that over 91% of 6000
clinical isolates of Enterobacteriaceae were inhibited by 0.5 /Lgfml or less of cefotaxime.
This antibiotic is active against many cephalothin-resistant and gentamicin-resistant En-
terobacteriaceae and against some strains which show multiple drug resistance. Cefotaxime
is also active at very low concentrations (MIC90 :E: 0.06 /Lgfml) against fj-lactamase-pro-
ducing and non-producing strains of Haemophilus influenzae and Neisseria gonorrhoeae.
Although cefotaxime tends to be less active than cefoxitin against Bacteroides fragilis, it
inhibits most other anaerobic bacteria at low concentrations.
Like cefuroxime, cefotaxime is highly stable to degradation by fj-lactamases produced
by S. aureus and various Gram-negative bacteria, but not to that produced by B. fragilis.
Although desacetyl-cefotaxime, the principal metabolite of cefotaxime, is less active in vitro
than the parent compound, it appears to be more active than cefoxitin and cefuroxime
against some Gram-negative bacilli.
A combination of cefotaxime and gentamicin was found to be synergistic for over one-
half of the strains of P. aeruginosa tested, including gentamicin-resistant strains but not
carbenicillin-resistant strains. Similar results were obtained with cefotaxime plus tobra-
mycin against tobramycin-sensitive strains of P. aeruginosa. However, the synergistic ac-
tivity of cefotaxime and amikacin varied widely between studies.
In general, there was usually little difference between minimum bactericidal (MBC) and
minimum inhibitory concentrations (MIC) of cefotaxime for most Gram-negative organ-
isms studied. Although results tended to vary from study to study, larger differences have
been reported for some species such as Enterobacter, indole-positive Proteus and Pseudo-
monas aeruginosa. Little information is available on the MBC to MIC relationship for
Gram-positive organisms.

Renal Tolerance: In studies to date, cefotaxime appeared to be free of adverse effects

on renal function. Thus, a renal tolerance study in rabbits found that subcutaneous cefo-
Cefotaxime: A Review 226

taxime (750 or 1500 mg,/kg/day for 7 days), like moxalactam (same dose), but unlike ce-
phaloridine (100 or 200 mg,/kg/day) did not significantly increase plasma creatinine or
excretion of the lysosomal enzyme N-acetylglucosaminidase.
A study in healthy volunteers which measured urinary excretion of alanine aminopep-
tidase (an early sensitive indicator of renal tubular damage) found that cefotaxime 6 g,/
day alone or given with frusemide 20 mg,/day did not affect proximal renal tubule function.
Similar results were reported in small groups of patients with serious infections (and nor-
mal renal function) treated with cefotaxime 6 g,/day alone or combined with azlocillin 15
gJday. Results from this small study also found that cefotaxime given in combination with
tobramycin 3 mg,/kg/day did not increase the risk of tobramycin nephrotoxicity.
Some patients with impaired renal function have also been treated with cefotaxime,
usually without any deterioration in renal function. However, there is relatively little de-
tailed information available on such patients.

Pharmacokinetics: After a lOOOmg intravenous bolus, mean peak plasma concentrations

of cefotaxime usually range between 81 and 102 ILgJml. Doses of 500mg and 2000mg pro-
duce plasma concentrations of 38 and 200 lLg,/ml, respectively. There is no accumulation
following administration of lOOOmg intravenously or 500mg intramuscularly for 10 or 14
days.
The apparent volume of distribution at steady-state of cefotaxime is 21.6 L/1.73m2
after 19 intravenous 3D-minute infusions. Concentrations of cefotaxime (usually deter-
mined by non-selective assay) have been studied in a wide range of human body tissues
and fluids. Cerebrospinal fluid concentrations are low when the meninges are not inflamed,
but are between 3 and 30 lLg,/ml in children with meningitis. Concentrations (0.2-5.4 1Lg,/
ml) inhibitory for most Gram-negative bacteria, are attained in purulent sputum, bronchial
secretions and pleural fluid after doses of 1 or 2g. Concentrations likely to be effective
against most sensitive organisms are similarly attained in female reproductive organs, otitis
media effusions, prostatic tissue, interstitial fluid, renal tissue, peritoneal fluid and gall-
bladder wall, after usual therapeutic doses. High concentrations of cefotaxime and des-
acetyl-cefotaxime are attained in bile.
Cefotaxime is partially metabolised prior to excretion. The principal metabolite is the
microbiologically active product, desacetyl-cefotaxime. Most of a dose of cefotaxime is
excreted in the urine, about 60% as unchanged drug and a further 24% as desacetyl-cefo-
taxime. Plasma clearance is reported to be between 260 and 390 ml/minute and renal
clearance 145 to 217 ml/minute.
After intravenous administration of cefotaxime to healthy adults, the elimination half-
life of the parent compound is 0.9 to 1.14 hours and that of the deSacetyl metabolite, about
1.3 hours.
In neonates the pharmacokinetics are influenced by gestational and chronological age,
the half-life being prolonged in premature and low birth weight babies relative to that in
term and average birth weight neonates of the same age.
In severe renal dysfunction the elimination half-life of cefotaxime itself is increased
minimally to about 2.5 hours, whereas that of desacetyl-cefotaxime is increased to about
10 hours. Total urinary recovery of cefotaxime and its principal metabolite decreases with
reduction in renal function.

Therapeutic Trials: Published studies on several thousand patients have documented

the efficacy of cefotaxime (usual dosage, 2 to 6 gJdayat 6-, 8- or 12-hourly intervals) in
a wide range of infections caused by Gram-positive and Gram-negative aerobic bacteria
and, occasionally, anaerobic bacteria. Cefotaxime has been used successfully in patients
who had failed to respond to other antibiotics, and in infections caused by organisms
resistant to usual therapy, such as: Enterobacteriaceae resistant to other cephalosporins,
gentamicin and/or carbenicillin; Serratia marcescens and Klebsiella pneumoniae resistant
Cefotaxime: A Review 227

to all commercially available antibiotics; ampicillin-resistant Haemophilus influenzae; and

penicillin-resistant Neisseria gonorrhoeae. Although cefotaxime alone was effective in some
patients with pseudomonal infections, on the basis of present evidence it cannot be rec-
ommended as the sole antibiotic for suspected or confirmed pseudomonal infections.
A large number of patients with urinary tract infections, many of which were compli-
cated by underlying urological abnormalities, have been treated successfully with cefotax-
ime in open or controlled studies. About 70 to 90% of infecting strains of cefotaxime-
sensitive Gram-negative organisms were eradicated from patients with complicated and
uncomplicated urinary tract infections immediately following treatment with cefotaxime
2 gfday. In general, E. coli. Klebsiella species, indole-positive and -negative Proteus. En-
terobacter and Citrobacter species were eradicated more successfully than Pseudomonas
and Serratia species. Although large studies in patients with complicated urinary tract
infections have shown intravenous cefotaxime in a dose of 2 gfday to be significantly (p
< 0.01) superior to cefazolin 4 gfday, ceftezole 4 gfday and sulbenicillin 10 gfday, caution
must be exercised in interpreting these results because of the manner in which response
was assessed. Results from smaller comparative studies suggested that better bacteriological
responses were obtained with cefotaxime 2 gfday, than with cefazolin 2 gfday, cefuroxime
2.25 gfday, cefoxitin 3 gfday, or gentamicin 160 mgfday in various types of urinary tract
infections. However, these results require confirmation in well-controlled studies.
Cefotaxime has been studied in many hospitalised patients with lower respiratory tract
infections, frequently caused by Streptococcus pneumoniae. Haemophilus influenzae. Kleb-
siella species, E. coli and Proteus mirabilis. 75 to 100% of patients with pneumonia showed
complete resolution or improvement in clinical signs and symptoms and chest radiographs.
In a large comparative study in patients with mild to moderate pneumonia complicated
by underlying respiratory disease, or in patients with other lower respiratory tract infec-
tions, cefotaxime 4 gfday was as effective clinically, but more effective bacteriologically,
than intravenous cefazolin 4 gfday. However, only 35% of 218 patients in this study were
bacteriologically assessable.
In the treatment of patients with septicaemia/bacteraemia, cefotaxime-sensitive Gram-
negative bacteria such as E. coli. Klebsiella and Proteus species were isolated most fre-
quently and over 90% of these organisms were eradicated from blood. Bacteraemia caused
by Serratia marcescens. Pseudomonas species and Gram-positive bacteria was also treated
successfully with cefotaxime alone.
Intra-abdominal infections such as peritonitis, and to a lesser extent hepatic and biliary
infections, have also been treated with cefotaxime, often as an adjunct to surgery. Cefo-
taxime 80 mgfkgJday was as effective as a combination of gentamicin 3 mgfkgJday and a
rather lower than usual dose of clindamycin (20 mgfkgJday) in treating patients with per-
itonitis (85% vs 82% cured, respectively) and similar polymicrobial soft-tissue surgical sep-
sis, despite in vitro susceptibility results suggesting superior activity of the combination
therapy.
Satisfactory clinical responses occurred in over 86% of patients treated with cefotaxime
(often in conjunction with surgical procedures) for skin and soft tissue infections (average
dose 4 gfday) or osteomyelitis (average dose 9 g,lday) caused by Gram,positive aerobes
(such as S. aureus), Gram-negative aerobes and by anaerobes.
In general, over 90% of women with a variety of obstetric and gynaecological infections
have responded to cefotaxime, sometimes in conjunction with surgery. Similar response
rates of 96 to 100% have been reported in patients (usually male) treated with a single
intramuscular injection of cefotaxime for uncomplicated gonorrhoea caused by penicilli-
nase-producing or non-penicillinase-producing strains of Neisseria gonorrhoeae.
Encouraging results have been obtained with cefotaxime used alone or in combination
with another antibiotic in the treatment of patients (mainly neonates and infants) with
meningitis caused by the major meningeal pathogens, H. influenzae. S. pneumoniae and
N. meningitidis, and also by Gram-negative bacilli (e.g. E. coli and Klebsiella species),
 Cefotaxime: A Review 228

including strains resistant to traditional therapy. To date, published clinical experience in

other difficult therapeutic areas such as endocarditis, or suspected or proven infections in
granulocytopenic and/or cancer patients is rather limited.
Several hundred children with various other types of serious infections have also been
treated in open studies with cefotaxime alone or in combination with another antibiotic
such as an aminoglycoside or penicillin. In general, clinical response rates varied from
about 90% for children with septicaemia, gastrointestinal or multiple infections, to 100%
for infections of the respiratory and urinary tracts treated with cefotaxime alone. Several
studies in children with bacteriologically confirmed infections found that over 90% of the
pathogens (predominantly cefotaxime-sensitive Gram-negative bacteria) were eradicated
with cefotaxime alone. Dosages usually ranged between 50 and 100 mgjkgjday, given at
6-, 8-, or l2-hourly intervals.
In some countries cefotaxime is approved for perioperative use to reduce the incidence
of postoperative infections in patients undergoing contaminated or potentially contami-
nated surgery, and in women undergoing caesarean section. Favourable results after pro-
phylactic perioperative treatment with cefotaxime have been reported in several branches
of surgery, such as genitourinary, abdominal, gynaecological and obstetric surgery.

Side effects: Cefotaxime has generally been well tolerated by adults and children fol-
lowing intravenous or intramuscular injection. The most commonly reported adverse clinical
effects were reactions at the injection site such as pain on intramuscular injection (similar
in intensity and incidence to that occurring with procaine penicillin G), and phlebitis (5%).
Rash (2%), diarrhoea (1 %) and variations in laboratory test results including transient ele-
vations of renal and liver function tests have occurred with cefotaxime, but symptomatic
drug-related nephrotoxicity or hepatotoxicity have not been reported. Superinfection (1.2%)
and colonisation (1.6%) caused by cefotaxime-resistant Pseudomonas species or other Gram-
negative bacilli, group D streptococci or Candida have occurred in patients treated with
cefotaxime, particularly those who were seriously ill.

Dosage: Cefotaxime can be administered intravenously or intramuscularly. For adults

with uncomplicated infections the usual dosage is Ig 12-hourly, while for those with mod-
erate to severe infections 1 to 2g may be given 6- or 8-hourly, up to a maximum of 12 gj
day. The recommended dose in neonates, infants and children usually varies between 50
and 150 mgjkgjday given 6- to 12-hourly, up to a maximum of 200 mgjkgjday in serious
infections.

1. Antibacterial Activity 1.1 In Vitro Inhibitory Activity against

Cefotaxime (fig. 1) is a 'third generation'·
cephalosporin administered by intravenous or
intramuscular injection. It has a broad spectrum of
activity against Gram-positive and Gram-negative
aerobic and anaerobic bacteria, and is generally
more active against Gram-negative bacteria than
the 'first generation' and 'second generation'
cephalosporins.
Aerobic Bacteria
The antibacterial activity of cefotaxime has been
studied extensively in various parts of the world,
particularly the USA, UK, Europe and Japan. Well-
reported studies in which a relatively large number
of strains (usually clinical isolates) were tested, us-
ing an inoculum of 104 to 106 colony-forming units
(cfu), are reviewed here. In the following discus-

• Although structurally cefoxitin is a cephamycin-derivative as 'second generation' and 'third generation' cephalosporins, re-
and moxalactam (also known as lamoxactam and latamoxef) is spectively, as is common practice because of their spectra of
an oxa-j3-lactam, these antibiotics are referred to in this review antibacterial activity.
 Cefotaxime: A Review 229

sion, the concentration at which 'most' organisms
were inhibited, generally refers to the concentra-
tion which inhibited 90% of the organisms (MIC90),
and the concentration which inhibited 'many'
organisms usually refers to inhibition of 50% of the
organisms (MIC so ). Concentrations of cefotaxime
said to be indicative of 'sensitivity' or 'resistance'
to the drug in vitro have varied from place to place
and as experience with the drug has increased. For
example, bacterial isolates are now considered to
be sensitive in vitro if the MIC is not more than
16 ~gjml, while an MIC of 64 ~gjml or greater is
generally considered to indicate resistance.
1.1.1 Gram-positive Bacteria
Cefotaxime usually inhibits 90% of strains of
Staphylococcus aureus at a concentration of 2 to 4
COON a
N..... OCH 30~ N:-.;::
) CH,OCOCH 3
II I'i
N --rC-CONH---r--t-..
H,N
JlJS
H H S
Cefotaxime
~gjml (Braveny et aI., 1979; Fuchs et aI., .1980;
Hamilton-Miller et aI., 1978; Masuyoshi et aI., 1980;
Neu et aI., 1979a; Sosna et aI., 1978; Wise et aI.,
1980a), and is equally active against penicillin-sen-
sitive and penicillin-resistant strains (Barry et aI.,
1980; Hall et aI., 1980a; King et aI., 1980; Knothe,
1980; Shah et aI., 1978). However, like cefazolin
and cefoxitin, cefotaxime has poor activity against
methicillin-resistant strains of S. aureus, with MIC90
values generally 32 ~gjml or greater (Barry et aI.,
1980; Cherubin et aI., 1981; Kayser 1980a), al-
though in 1 study (Hall et aI., 1980a) all 38 such
isolates were inhibited by 4 ~gjmI.
When the activity of various cephalosporins
against S. aureus was compared, cefotaxime was
found to be less active than cephalothin (Barry et
aI., 1980; Braveny et aI., 1979; Hall et aI., 1980a;
Sosna et aI., 1978) and cefamandole (Barry et aI.,
1980; Counts and Turck, 1979; Kayser, 1980b; Neu
et aI., 1979a), more active than moxalactam (Barry
et aI., 1980; Wasilauskas, 1981; Wise et aI., 1980a),
and generally comparable with cefoperazone (Hall
et aI., 1980; Katsu et aI., 1982; Kayser, 1980b; Tra-
ger et aI., 1981).
Staphylococcus epidermidis tends to be less sen-
sitive to cefotaxime than S. aureus, with most
strains usually being inhibited by 8 ~gjml (Fuchs

6¥
OH
et aI., 1980; Hall et aI., 1980a; Sosna et aI., 1978;
COONa CH 3 Wasilauskas, 1981), although a high concentration
r\ O~ N:)CH'SIl~'N (64 ~g/ml) was required to inhibit 90% ofthe pen-
H,C,-N N-CONH--C--CONH--~I'~ N1
- 1I
'-./ I t---f.-. s N icillinase-producing strains studied by Hall et aI.
II \\ H H H
o 0 (l980a). As occurs with S. aureus, cefotaxime is
usually more active than moxalactam (Hall et aI.,
Cefoperazone
1980a; Neu et aI., 1979b; Verbist and Verhaegen,
1981), but less active than cephalothin (Fuchs et
CH 3
COONa I aI., 1980; Neu et aI., 1979b; Sosna et aI., 1978)
0""" N~CH'SlIN'N against S. epidermidis.
HO--{5\ CHCONH-A ) N-~ Streptococcus pneumoniae and Streptococcus
~I CH 30 H 0
pyogenes (group A) are very sensitive to cefotax-
COONa
ime, with most isolates being inhibited by 0.1 and
Moxalactam 0.25 ~gjml or less, respectively (Barry et aI., 1980;
Hall et aI., 1980a; Neu et aI., 1979a; Verbist and
Fig. 1. Structural formulae of cefotaxime sodium, cefoper- Verhaegen, 1980). Concentrations as low as 0.02
azone sodium and moxalactam disodium. ~gjml frequently inhibit these organisms (Hall et
 Cefotaxime: A Review
aI., 1980a; Masuyoshi et aI., 1980; Verbist and Ver-
haegen, 1980). Cefotaxime also inhibits penicillin-
resistant and multidrug-resistant strains of S. pneu-
moniae at low concentrations (e.g. ~ 2 p,gjml;
Cherubin et aI., 1981; Goldstein et aI., 1982; Hans-
man, 1981; Landesman et aI., 1981c). Against pen-
icillin-susceptible strains of S. pneumoniae and S.
pyogenes, cefotaxime is as active as benzyl peni-
cillin, slightly more active than cefoperazone and
more active than moxalactam (Hall et aI., 1980a;
Landesman et aI., 1981c).
Cefotaxime is also active against other strep-
tococcal species such as S. agalactiae and viridans
streptococci. 90% of strains of S. agalactiae (group
B streptococci) were inhibited at very low concen-
trations (e.g. 0.1 p,gjml) [Hamilton-Miller et ai.,
1978; Landesman et ai., 1981a; Neu et ai., 1979a;
Verbist and Verhaegen, 1980], while the concen-
tration required to inhibit 90% of the few strains
tested of viridans streptococci varied from 0.125
p,g/ml (Cherubin et ai., 1981) to 3.1 p,g/ml (Fu and
Neu, 1980).
In general, cefotaxime is more active in vitro
than cefoperazone and moxalactam against strep-
tococci (Hall et ai., 1980a; Kayser, 1980b; landes-
man et aI., 1981c; Neu et ai., 1979b,c). However,
like other cephalosporins, very high concentrations
of cefotaxime (MIC 5o ~ 64 p,gjml) are required to
inhibit enterococci (including S. faecalis) in vitro
(Braveny et ai., 1979; Fuchs et ai., 1980; Hall et
aI., 1980a; Neu et ai., 1979b; Sosna et ai., 1978;
Verbist and Verhaegen, 1981; Wasilauskas, 1981).
1.1.2 Gram-negative Bacteria
As a 'third generation' cephalosporin, cefotax-
ime exhibits a wider spectrum of activity and
greater potency against Gram-negative organisms
than the 'first generation' and 'second generation'
cephalosporins. Indeed, over 91 % of 6083 clinical
isolates of the Enterobacteriaceae (studied in 6 la-
boratories in the USA) were inhibited by ~ 0.5 p,gj
ml of cefotaxime (the minimum concentration
used). Hence, cefotaxime was 8 to 64 times more
active than cephalothin (Fuchs et ai., 1980). Nu-
230
merous in vitro studies (see below) have shown that
E. coli, Klebsiella species, P. mirabilis, Salmonella
and Shigella species, H. injIuenzae, N. gonor-
rhoeae, N. meningitidis and Citrobacter diversus are
very susceptible to inhibition by cefotaxime (MIC9o
values of 1 p,gjml or less).
Providencia species are also susceptible to cefo-
taxime, but activity against indole-positive Proteus
species and Morganella morganii can vary widely
from high to moderate activity (MIC 9o values of
0.2 to 8 p,gjml). Although the concentrations of
cefotaxime required to inhibit most strains (90%)
of Serratia (1 to 16 p,gjml) and Enterobacter spe-
cies (~ 8 p,g/ml or > 32 p,gjml) also varied widely,
many of these organisms (about one-half the strains
tested in each study) were frequently inhibited by
0.5 p,g/ml or less.
In general, many Pseudomonas aeruginosa iso-
lates are moderately sensitive to cefotaxime, but a
proportion are resistant and thus concentrations of
64 p,gjml or more were usually required to inhibit
90% of the strains tested. Cefotaxime appears to be
more active against Acinetobacter calcoaceticus
subspecies lwoffi than against the anitratus subspe-
cies of Acinetobacter calcoaceticus.
The in vitro activity of cefotaxime against vari-
ous Gram-negative organisms is compared with
that of moxalactam, cefoperazone and cefaman-
dole in table I, and with gentamicin, tobramycin,
amikacin, cefoxitin and ticarcillin in table II.
Escherichia coli
E. coli is very susceptible to cefotaxime, with
most strains usually being inhibited by concentra-
tions of 0.12 to 0.5 p,gjml (Braveny et ai., 1979;
Fuchs et ai., 1980; Hall et ai., 1980a; Masuyoshi et
ai., 1980; Neu et ai., 1979c; Shah et ai., 1978; Sosna
et ai., 1978; Verbist, 1981a).
In studies which used very low concentrations
of the drug, 0.06 p,gjml or less often inhibited 50%
of isolates tested (Hall et ai., 1980a; Lang et ai.,
1980; Wise et aI., 1980a; Verbist, 1981a). Cefotax-
ime was active against most cephalothin-resistant
strains of E. coli, but higher concentrations than
Table I. Antibacterial activity in vitro of cefotaxime, moxalactam, cefoperazone and cefamandole against Gram-negative aerobes. Inoculum size was 10s cOlony-
forming units (after Hall et aI., 1980a,b) (')
CD
Organism Antibiotic MIG (ltg/ml) 0'
6i
(no. of isolates) x
cefotaxime moxalactam cefoperazone cefamandole 3'
!'!
range MIGso MIGgo range MIGso MIGgo range MIGso MIGgo range MIG so MIGgo »
:II
CD
E. coli <0.03-64 <0.03 0.12 0.03->128 0.06 0.25 <0.03-32 0.12 0.25-64 0.5 2 <
(ii'
(114) ::e
K. pneumoniae' <0.03-16 0.03 0.12 0.12-128 0.25 0.06->128 4 128 0.25->128 8 128
(62)
K.oxytoca <0.03-0.06 <0.03 <0.03 0.06-1 0.12 0.25 <0.03-8 0.5 0.12-32 0.5 4
(21)
P. mirabilis <0.03-<0.03 <0.03 <0.03 <0.03-0.25 0.06 0.12 <0.03-1 0.12 0.25 0.12-4 0.5 2
(30)
P. vulgaris <0.03-4 <0.03 0.06 0.12->128 0.25 0.5 0.06-8 0.12 0.25 0.5->128 8 8
(29)
M. morganii <0.03->128 <0.03 8 <0.03->128 0.12 0.25 0.12-32 0.5 16 0.5-128 2 32
(27)
P. rettgeri <0.03-4 <0.03 0.06 <0.03-0.25 <0.03 0.25 <0.03-16 0.25 4 <0.03-16 0.12 4
(29)
P. stuartii <0.03-8 0.12 0.06-8 0.12 0.5 0.12-32 2 4 0.12-32 2 8
(27)
S. marcescens' 0.12-16 0.25 4 0.12->128 0.5 4 0.5-128 8 16 4->128 128 >128
(61)
E. cloacae <0.3-128 0.12 0.06-32 0.12 <0.03->128 0.12 32 0.5->128 2 128
(26)
E. aerogenes <0.03-64 0.06 4 0.12-8 0.25 0.06->128 0.25 8 0.5->128 2 32
(20)
P. aeruginosa' 8->128 16 128 2->128 16 64 0.5-64 4 16 >128 >128 >128
(63)
C. diversus <0.03-1 0.06 0.25 0.06-1 0.06 0.25 <0.03-16 0.25 2 0.5-32 8
(18)
C. freundii <0.03-32 0.12 8 0.12->128 0.12 2 0.06-64 0.5 16 0.5->128 32
(30)
N. gonorrhoeae 2 <0.001-0.03 <0.001 0.01 <0.001-0.025 0.03 0.06 <0.001-0.12 0.01 0.06 ... 3 . .. 3
(27)

1 Includes gentamicin-sensitive (MIG ~ 4 Itg/ml) and gentamicin-resistant (MIG", 8 Itg/ml) strains, for which the MIGs of cefotaxime were very similar.
2 Includes penicillinase-producing and non-penicillinase-producing strains, for which the MICs of cefotaxime were very similar.
3 No data for cefamandole, but for penicillin G, range = <0.001->128; MIC so = 0.25 and MIC go = 128. I\)

~
 Cefotaxime: A Review
those required for cephalothin-sensitive strains were
usually needed (Sosna et al., 1978; Verbist; 1981 b).
Similarly, Knothe et al. (1980) reported higher
MICs of cefotaxime for t1-lactamase-positive strains
of E. coli than for t1-lactarnase-negative strains
(MIC 9o of 1.0 and 0.125 #LgJml, respectively). Cefo-
taxime was also very active against a small number
of gentamicin-resistant strains of E. coli (MIC9Q =
0.125 #LgJml) [Jorgensen et al., 1980b].
When compared with other antibiotics, cefotax-
ime was usually slightly more active (a 2-fold dif-
ference in MICs) than moxalactam (Braveny et al.,
1982; Delgado et al., 1979; Hall et al., 1980a) against
E. coli, several-fold more active than cefoperazone
(Braveny et al., 1982; Hall et al., 1980a; Kurtz et
al., 1980), and markedly more active than cefa-
mandole (Neu et al., 1979c), cefoxitin and cefur-
oxime (Braveny et al., 1979; Wise et al., 1980a),
cefazolin (Braveny et al., 1979; Shah et al., 1978),
cephalothin (Shah et al., 1978; Verbist, 1981a), and
the aminoglycosides (Delgado et al., 1979).
Klebsiella species
Cefotaxime is very active against Klebsiella spe-
cies, with most isolates of this genus (Fuchs et al.,
1980; Knothe, 1980; Lang et al., 1980) and of K.
pneumoniae in particular (Delgado et al., 1979;
Masuyoshi et al., 1980; Shah et al., 1978; Sosna et
al., 1978; Verbist, 1981a) usually inhibited by 0.12
to 0.5 #LgJml. Like E. coli, many isolates (50%) of
K. pneumoniae were inhibited at a very low con-
centration of 0.06 #Lg/ml or less (Fu and Neu, 1980;
Masuyoshi et al., 1980; Verbist, 1981a).
Cefotaxime is active against cephalothin-resist-
ant strains of Klebsiella species, usually at concen-
trations only slightly higher than those required for
cephalothin-sensitive isolates (Sosna et al., 1978;
Verbist, 1981 b). Many gentamicin-resistant strains
are also inhibited by low concentrations (e.g. 0.125
#LgJml) of cefotaxime (Braveny and Dickert, 1979;
Hall et al., 1980a; Machka et al., 1980; Stephens et
al., 1979), although some such strains may require
higher concentrations (e.g. 8 to 32 ~ml) for in-
hibition (Drasar et al., 1978; Hall et al., 1980a; Le-
232
gakis et al., 1980).
Compared with other antibiotics, cefotaxime was
generally slightly more active (2- to 4-fold) against
K. pneumoniae than moxalactam (Delgado et al.,
1979; Verbist, 1981a; Verbist and Verhaegen, 1981),
several-fold more active than cefoperazone (Kurtz
et al., 1980), tobramycin and gentamicin (Delgado
et al., 1979), and markedly more active than cefa-
mandole and cefoxitin (Fu and Neu, 1980; Ma-
suyoshi et al., 1980; Wise et al., 1980a).
Proteus and Providencia species
Proteus mirabilis is so susceptible to cefotaxime
that 90% of isolates were frequently inhibited at the
lowest concentration used for in vitro testing,
whether it was 0.5 #LgJml (Fuchs et al., 1980), 0.2
#Lgfml (Sosna et al., 1978), 0.125 #Lgfml (Braveny
et al., 1979), or even 0.03 #Lgfml (Hall et al., 1980a;
Lang et al., 1980). However, Proteus vulgaris, Mor-
ganella morganii (Barry et al., 1980; Hall et al.,
1980a; Knothe, 1980; Masuyoshi et al., 1980) and
indole-positive Proteus species in general (Braveny
et al., 1979; Delgado et al., 1979; Fuchs et al., 1980;
Kurtz et al., 1980; Trager et al., 1981), were less
sensitive to cefotaxime compared with P. mirabi-
lis. MIC90 values for these organisms varied widely
between studies; for example, from less than 0.12
to 8 #Lgfml. However, in most studies 50% of the
strains tested were inhibited by 0.5 #Lgfml or less.
90% of strains of Providencia stuartii (inconstans)
and P. rettgeri were usually inhibited by 0.4 to 4
#Lgfml (Hall et al., 1980a; Knothe, 1980; Masuyoshi
et al., 1980; Neu et al., 1979c; Verbist, 1981a).
Moxalactam is also extremely active against P.
mirabilis (Hall et al., 1980a; Verbist, 1981a; Wise
et al., 1980a), while cefoperazone is slightly less ac-
tive than cefotaxime (Hall et al., 1980a; Lang et
al., 1980). Cefotaxime is more active than the sec-
ond generation cephalosporins (Braveny et al.,
1979) and the aminoglycosides against P. mirabilis
(Delgado et al., 1979). The activity of cefotaxime
against indole-positive Proteus species is generally
comparable with that of moxalactam (Trager et al.,
1981) - although moxalactarn appears to be more
 Cefotaxime: A Review 233

active against M. morganii (Barry et aI., 1980; Hall

et aI., 1980a) - and greater than that of cefoper- ~ JI~1\ ~1\
~
~ ~~~~~~~
1\ 1\ 1\ 1\ 1\
azone (Neu et aI., 1979c; Trager et al., 1981). ~
:;
Cefotaxime aIso has slightly greater activity than
cefoperazone, and similar activity to moxalactam,
i'
c::
E
~~ 21N ~
:;::;
1
~
0

1\
II) • • ~ ~ ~
1\
against Providencia species (Hall et al., 1980a). f!
~
These organisms, and indole-positive Proteus spe- 'Iii illl) • II) • • II) CD • • • CD
c:: U
cies, are less sensitive to cefoxitin, and tend to be 'iii
~ ~
less susceptible to the aminoglycosides, than to c::
:E
cefotaxime (Barry et aI., 1980). Indeed, cefotaxime ~
c::
~
.- u
15lICD N • N NN.NN.N
is often reasonably active against gentamicin-re- !. E -
as ~

It
sistant strains of Proteus mirabilis (Legakis et aI.,
1980) and Providencia species (Drasar et aI., 1978;
JI . . . . . CD ~~.NCD ••
Stephens et aI., 1979), and moderately active against ~
indole-positive Proteus species resistant to genta-
'Ee .g,c::
1\

:II
It) It)
micin (Legakis et aI., 1980). Cefotaxime is very ac-
~ 15lu
as 0
C\lO
NO N ... GO "lit ............
tive against cephalothin-resistant isolates of P. mir-
abilis (Legakis et aI., 1980; Verbist, 1981b) and
-g
as
.. ..
li
o -~

Proteus species in general (Sosna et aI., 1978). ~~..

1!8' c::
J I• • • •
~ II)N.NCD.II)
. - (I") ......

Serratia species
Although there was wide vanatton between
.E
E
as
C')
:~.l9
c::
II
U
It)
5l NON It)
0 ...,.
""" ,....
,.... N
N "I"""
,....
It)
0 ,.... ...
studies in the concentration of cefotaxime required CD -
~
c: Cl
to inhibit 90% of isolates of Serratia species and ~
S. marcescens (e.g. from 1 to 16 "Wml), in most
studies 50% of strains tested were inhibited by 0.5
Ii JICD N . II)
~ C') ...
.~~~~~~
1\ 1\ 1\ 1\ 1\ 1\
.~as
cD
"g/ml or less (Barry et aI., 1980; Delgado et aI., E
.;;c c::

.e~ Iu~
.l9
1979; Fuchs et aI., 1980; Knothe, 1980; Masuyoshi :eo;-
.eo;-
CDI'-
E 5l
IN • • CD NCD~~~.~
et al., 1980; Verbist, 1981a). ()~
00>
... 1\ 1\
When gentamicin-resistant strains of S. marces- 0-' E
~! 0;
cens were studied, about one-haIf the strains tested '>
=0
CD 3
il~ It) ~ ~ It) It)

in each study were inhibited by low concentrations :d't:l U ~ 0 000 ... N 0 0 • II) N
~VI II) ... C')
as ~ CD
V/VI
(e.g. < 2 "g/ml) of cefotaxime (HaIl et al., 1980a; ij.2' E
'c~ ~ 'j(
Markowitz and Sibilla, 1980), but relatively high ~! ~ § o-5lIN N N N
~ .-: "": "'":
11)
NNIt)
..... 'I""" N Lt)
iii
c::
concentrations (e.g. 16 and 25 "wml) were usually ~.!. ~ ~
ie
0000
~V/VIVIv/
O~~OIl)O~
i
required to inhibit 90% of such isolates (Jorgensen
et aI., 1980b; Markowitz and Sibilla, 1980). Cefo-
0"3-
~o
",0 - .~
i
taxime showed similar activity against gentamicin- '-'"
CD>< ! ~ ~!§
resistant and gentamicin-sensitive strains of S. .~It)
_ !!:5 _;"_E
marcescens in the study by HaIl et al. (1980a), but !:I ll)
::!._Il:
2 ._Lt)_
o-~
LOeD
l:::.·o!!!..E
OCD
!.~ !."-Cil-
other authors (Markowitz and Sibilla, 1980; Trager ECD
8'Sj I CDO
call» CD
_ Or: - Eo ca 8 = ~ a ~ .! 6 ",
fIJI::

~ ~ Ul8.eUI ·Iii6 :!0 Iiitil =

CD _
ca~""0tn
0

S .! ~'i -8
et aI., 1981) reported about a 4-fold increase in ·E E~
::::" UI'-
:5
-:::o.Q 0 til 0 0 0 "
MICs for gentamicin-resistant strains. Fu and Neu CD3
:Qg
"c"O
~ci 8 ~ .~ ~.~ ~ ~ i ~ i ~ ~ ~ ~
(1980) studied strains of S. marcescens which ~.E os. LLi 1IC a.: ~ 51- ~ CJ) LLi LLi a.: e5 ~~
 Cefotaxime: A Review
showed multiple resistance to aminoglycosides and
other (j-Iactam antibiotics and found that the ma-
jority of these were also resistant to cefotaxime
(MIC 5o of 25 ~gjml).
When compared with other antibiotics used in
the treatment of Serratia infections, cefotaxime
seems to have similar in vitro activity to genta-
micin against gentamicin-sensitive strains of Ser-
ratia species (Trager et aI., 1981; Wasilauskas,
1981), but is considerably more active than cef-
oxitin (Delgado et aI., 1979). Cefotaxime is also
more active than cefoperazone (Hall et aI., 1980a),
and generally comparable to moxalactam (Barry et
aI., 1980; Delgado et aI., 1979; Hall et aI., 1980a).
Enterobacter species
While many authors found that most of their
isolates of Enterobacter species were inhibited by
8 ~g/ml or less of cefotaxime (Delgado et aI., 1979;
Fuchs et aI., 1980; Hall et aI., 1980a), some re-
ported MIC 90 values of at least 32 ~g/ml (Braveny
et aI., 1979; Masuyoshi et aI., 1980; Wasilauskas,
1981). Nevertheless, 50% of isolates tested were
frequently inhibited by 0.5 ~gjml or less (Braveny
et aI., 1979; Hall et aI., 1980a; Sosna et aI., 1978).
In general, there was little difference in the sus-
ceptibility of E. cloacae and E. aerogenes to cefo-
taxime (Barry et aI., 1980; Delgado et aI., 1979;
Neu et aI., 1979c).
When compared with cefotaxime, cefoperazone
showed similar activity against E. aerogenes, but
was much less active against E. cloacae (Hall et aI.,
1980a; Neu et aI., 1979c). Moxalactam was at least
as active as cefotaxime, or more so, against
Enterobacter species (Barry et aI., 1980; Gentry et
aI., 1980; Hall et aI., 1980a; Verbist, 1981a). Cefo-
taxime is more active than cefamandole (Delgado
et aI., 1979; Hall et aI., 1980a) but usually less ac-
tive than gentamicin against Enterobacter species
(Barry et aI., 1980; Wasilauskas, 1981).
However, the strains tested by Delgado et ai.
(1979) [most of which were gentamicin-sensitive]
were less suceptible to gentamicin than to cefotax-
ime (see table II). In general, most strains of
234
Enterobacter species which are gentamicin-resist-
ant, are also resistant to cefotaxime (Legakis et aI.,
1980; Machka et aI., 1980), although this was not
the case in the study by Drasar et ai. (1978) which
used a low inoculum (10 3 cfu) of gentamicin-
resistant E. cloacae.
Pseudomonas species
Unlike previously available cephalosporins, the
third generation of this class of antibiotics has some
activity against P. aeruginosa. Although cefotax-
ime is active against some strains of this organism,
the extent of the drug's activity in vitro has varied
widely among laboratories; for instance, Kurtz et
ai. (1980) found that only 5% of their 150 isolates
were inhibited by a concentration of 32 ~g/ml, but
elsewhere in the USA Sosna et ai. (1978) reported
that 86% of 155 isolates were inhibited at 12.5
~g/mi.
In numerous studies, at least 50% of P. aeru-
ginosa isolates tested were moderately sensitive to
cefotaxime (MIC ~ 16 ~g/ml) [Barry et aI., 1980;
Braveny et aI., 1979; Delgado et aI., 1979; Fuchs
et aI., 1980; Lang et aI., 1980; Masuyoshi et aI.,
1980; Shah et aI., 1978; Yourassowsky et aI., 1980],
while in other studies, higher concentrations (~ 32
~g/ml) were required for inhibition of one-half the
isolates tested (Knothe, 1980; Kurtz et aI., 1980;
Verbist, 1981a). In general, at least 64 ~gjml of
cefotaxime is required to inhibit 90% of P. aeru-
ginosa isolates (Braveny et aI., 1979; Fuchs et aI.,
1980; Hanslo et aI., 1981; Neu et aI., 1979a).
When compared with other drugs used to treat
infections due to P. aeruginosa, cefotaxime was
usually less active than tobramycin and gentamicin
(Delgado et aI., 1979; Kurtz et aI., 1980; Neu et aI.,
1979a); it tended to be more active than carbeni-
cillin (Neu et aI., 1979a; Shah et aI., 1978), showed
similar activity to ticarcillin and was less active than
piperacillin (Barry et aI., 1980; Delgado et at., 1979).
Strains of P. aeruginosa which were resistant to
gentamicin also tended to be resistant to cefotax-
ime, as shown in the studies by Hall et ai. (1980a),
Machka et ai. (1980), Trager et ai. (1981) and
 Cefotaxime: A Review
Woolfrey et al. (1981 in which at least half of the
gentamicin-resistant isolates required 25 p.g/ml of
cefotaxime or more for inhibition. An even higher
degree of cross-resistance to cefotaxime was ob-
served with carbenicillin-resistant, and ticarcillin-
resistant isolates of P. aeruginosa (Woolfrey et aI.,
1981; Yourassowsky et aI., 1980).
Although the minimum inhibitory concentra-
tions of cefotaxime and moxalactam are usually
several-fold higher than those of cefoperazone for
P. aeruginosa (Fu and Neu, 1980; Hall et aI., 1980a;
Kurtz et aI., 1980; Lang et aI., 1980; Woolfrey et
aI., 1981), the relative in vitro activity of these anti-
biotics can depend on whether activity is assessed
by MIC titration, turbidimetric studies, or the
organism's morphological response (Greenwood
and Eley, 1982).
In general, cefotaxime appears to have rather
greater activity against some pseudomonal species,
such as P. cepacia, but less activity against others
such as P. maltophilia than it has against P. aeru-
ginosa (Applebaum et aI., 1982; Hanslo et aI., 1981;
Jorgensen et aI., 1980b; Masuyoshi et aI., 1980).
Haemophilus species
Haemophilus species are extremely susceptible
to cefotaxime, with most strains of H. influenzae
and H. parainjluenzae being inhibited by 0.06 p.g/
ml or less (Baker et aI., 1980; Braveny et aI., 1980;
Howard et aI., 1979; Khan et aI., 1980; King et aI.,
1980; Masuyoshi et aI., 1980; Wise et aI., 1980a),
although higher concentrations (e.g. 0.8 p.g/ml) are
required occasionally (Neu et aI., 1979c). In addi-
tion to being more active than ampicillin against
tl-lactamase-negative strains of Haemophilus (Baker
et aI., 1980; Braveny et aI., 1980), cefotaxime has
the additional advantage of also being highly active
against tl-Iactamase-producing strains (Baker et aI.,
1980; Howard et aI., 1979; Khan et aI., 1980), and
against multiresistant strains of Haemophilus
species (Braveny and Machka, 1980).
Cefotaxime is considerably more active than
cefamandole and cefuroxime (Braveny et aI., 1980;
Howard et aI., 1979; Khan et aI., 1980), slightly
235
more active than cefoperazone (Baker et aI., 1980),
and at least as active as moxalactam against Hae-
mophilus species in general, but possibly slightly
more active against tl-Iactamase-producing strains
(Braveny and Machka, 1980; Jorgensen et aI.,
198Oc; Khan et aI., 1980; Wise et aI., I 980a).
Neisseria species
Both tl-Iactamase-producing and non-producing
strains of Neisseria gonorrhoeae are highly suscep-
tible to cefotaxime, with most isolates being inhib-
ited by 0.06 p.g/ml or less (Baker et aI., 1980; Hall
et aI., 1980a; Khan et aI., 1981; Piot et aI., 1979;
1980; Sng et al., 1981). Hence, like moxalactam and
cefoperazone, cefotaxime is more active than pen-
icillin, cefuroxime, cefamandole and cefoxitin
against tl-Iactamase-producing and non-producing
strains of N. gonorrhoeae (Baker et aI., 1980; Hall
et al., 1980a; Ng et al., 1981; Piot et aI., 1979; 1980).
Cefotaxime is also extremely active against N.
meningitidis. In 1 non-comparative study 96.5% of
150 strains were inhibited by a concentration of
0.004 p.g/ml, and all isolates were inhibited by ~
0.016 p.g/ml (Brown and Fallon, 1979). In com-
paring the susceptibility of 30 clinical isolates of N.
meningitidis to various tl-lactam antibiotics, Scrib-
ner et al. (l982b) reported MIC90 values of 0.001
p.g/ml for cefotaxime, 0.008 p.g/ml for moxalactam,
0.016 p.g/ml for cefoperazone and 0.12 p.g/ml for
ampicillin and penicillin.
Other Gram-negative Organisms
Many strains of Citrobacter diversus and Citro-
bacter freundii are highly susceptible to cefotaxime
(MIC 5o ~ 0.25 p.g/ml), but the concentration re-
quired to inhibit 90% of strains is usually consid-
erably higher for C. freundii (MIC9o ~ 8 p.g/ml)
than for C. diversus (MIC90 ~ 0.25 p.g/ml). Never-
theless, cefotaxime is markedly more active than
cefoxitin and cefamandole against both these spe-
cies (Barry et aI., 1980; Hall et aI., 1980a).
Salmonella species are highly susceptible to
cefotaxime, with most isolates being inhibited by
0.25 p.g/ml or less (Masuyoshi et aI., 1980; Verbist,
198Ia), a concentration considerably lower than
 Cefotaxime: A Review 236

inhibitory concentrations of ampicillin and cefazo- Table III. Antibacterial activity in vitro of cefotaxime against
lin (Barry et al., 1980). Shigella species are also 10 or more strains of various less commonly encountered path-
ogens. Inoculum sizes were between 1Q4 and 1()8 cfu
inhibited at very low concentrations (~ 0.8 "gfml)
ofcefotaxime (Fu and Neu, 1980; Verbist, 1981a). Organism MIC50 MICgg Refer-
High concentrations of cefotaxime (MIC so = 8 (}tg/ml) IJt9/ml) ence'
"g/ml; MIC90 = 32 "g/ml) are required to inhibit
Bordetella pertussis 0.2 0.4 g
most isolates of Acinetobacter calcoaceticus sub-
species anitratus (Daschner and Nopper, 1980; Campylobacter fetus 3-10 6-40 h, j
subspecies jejuni
Fuchs et al., 1980; Wasilauskas, 1981). However,
it appears from a limited number of isolates that Eikenella corrodens 0.12 0.5 b
cefotaxime is more active against lwoffi and other Listeria monocytogenes 8-25 16-100 a, e
subspecies of Acinetobacter calcoaceticus (Appel- Nocardia asteroides 2 64 c
baum et al., 1982; Jorgensen et al., 1980b).
Yersinia enteroco/itica '::;0.12 .::;0.25 b, d, i, f

Infrequent Pathogens
Cefotaxime is also active in vitro against a num-
ber of less commonly encountered Gram-positive
and -negative organisms (table III).
1 Key to references: a = Ahonkhai et al. (1982); b = Gold-
stein et al. (1982); c = Gombert (1982); d= Martinez-Beltran et
al. (1980); e = Neu et al. (1979c); f = Scribner et al. (1982a);
g = Shishido et al. (1980); h = Van hoof et al. (1980); i = Verbist
(1981a); j = Walder (1979).

1.2 In Vitro Inhibitory Activity against

Anaerobic Bacteria
The activity of cefotaxime against Bacteroides
jragilis varied widely among studies, which used a
variety of culture media (Borobio et aI., 1980;
Hamilton-Miller et al., 1978; Jacobus et al., 1980;
Jorgensen et al., 1980a; Neu et al., 1979a; Niederau
et al., 1980a; Phillips et al., 1981; Soussy et al.,
1981; Wise et al., 1980a), and .also within a study
comparing agar and broth dilution methods (Wer-
ner et aI., 1980). However, an MIC of at least 4
"g/ml was usually required to inhibit 50% of the
strains tested, and MIC90 values usually exceeded
16 "g/ml. Hence, in most studies cefotaxime tended
to be less active than cefoxitin and was less active
than moxalactam against B. jragilis (Borobio et al.,
1980; Cuchural et al., 1981;Jacobus et al., 1980;
Jenkins et al., 1982; Neu et al., 1979a; Niederau et
al., 1980a; Wise et al., 1980a). In addition, 11 cef-
oxitin-resistant strains of B. jragilis were also re-
sistant to cefotaxime (Dornbusch et al., 1980).
However, compared with B. jragilis, other spe-
cies of Bacteroides were usually more sensitive to
cefotaxime, cefoxitin and moxalactam (Jacobus et
al., 1980; Niederau et al., 1980b; Phillips et al.,
1981), although again there was a wide variation
in results among these studies (MIC90 of 1 to 25
"g/ml), and within the study by Werner et al. (1980)
which compared the agar and broth dilution
methods.
Most of a few strains of Clostridium perjringens
were inhibited by cefotaxime 4 "g/ml or less (Jor-
gensen et aI., 1980a; Soussy et al., 1981), but many
strains of C. difficile were resistant (MIC90 ~ 64
"g/ml) to the drug (Henry et al., 1980; Greenfield
et al., 1982). Fusobacteria (Jacobus et aI., 1980;
Niederau et aI., 1980a; Phillips et aI., 1981) and
anaerobic Gram-positive cocci (Borobio et al., 1980;
Jorgensen et al., 1980a; Phillips et al., 1981) are
usually susceptible to cefotaxime, with MIC90 val-
ues of ~ 2 "g/ml, and ~ 4 "g/ml, respectively.
Cefotaxime was very active (MIC90 < 1 "gfml)
against propionibacteria (Jorgensen et al., 1980a;
Homer et al., 1980) and Veillonella species (Phil-
lips et al., 1981). For a comparison of the activity
 Cefotaxime: A Review
of cefotaxime, moxalactam, and several other
cephalosporins against anaerobic bacteria (table IV).
1.3 Activity of Desacetyl-cefotaxime
Cefotaxime is partly metabolized to desacetyl-
cefotaxime (see section 4.3.1), which also has some
antibacterial activity. Although not as active as the
parent compound against most species, desacetyl-
cefotaxime inhibited 90% of strains of E. coli, K.
pneumoniae, P. mirabilis, C. diversus, P. rettgeri,
Salmonella and Shigella species, H. influenzae, N.
meningitidis and Streptococcus species other than
S. jaecalis at low concentrations « 1 ~gfml), but
higher concentrations (> 12.5 ~gfml) were gener-
ally required to inhibit 90% of isolates of S. mar-
cescens, M. morganii, P. vulgaris, P. stuartii, En-
terobacter species, P. aeruginosa, B. jragilis and
S. aureus (Jones et aI., 1982; Limbert et aI., 1982;
Neu, et aI., 1982; Wise et aI., 198Oc). Desacetyl-
cefotaxime was also shown to be bactericidal, with
the minimum bactericidal concentration usually the
same or within 1 dilution of the minimum inhib-
itory concentration (Jones et al., 1982).
Comparative studies with a limited number of
isolates (about 10 per species) showed that des-
acetyl-cefotaxime was less active than cefazolin
against staphylococci but more active than cefazo-
lin against all the Enterobacteriaceae (Limbert et
aI., 1982; Wise et aI., 198Oc), and more active than
cefuroxime and cefoxitin against E. coli, P. mira-
bilis and Klebsiella species (Wise et aI., 1980c).
However, cefoxitin was consistently more active
than this metabolite against Bacteroides fragilis
(Wise et aI., 198Oc).
Cefotaxime and desacetyl-cefotaxime exhibited
complete or partial synergy against about 20% and
55%, respectively, of a wide variety of clinical iso-
lates (Jones et aI., 1982; Neu, 1982). This activity
may in part result from the very high (j-Iactamase
stability of the desacetyl metabolite (Limbert et aI.,
1982). Antagonism also occurred (against 4% of
isolates), predominantly with M. morganii and oc-
237
casionally with P. vulgaris (Jones et aI., 1982; Neu,
1982). However, in the former study the 8 strains
of M. morganii affected in this way were still sus-
ceptible to cefotaxime (MICs ~ 2 ~gfml) despite
the addition of up to 256~g of desacetyl-cefotaxime
per mi.
1.4 (j-Lactamase Resistance
Cefotaxime is highly stable against degradation
by penicillinase-producing strains of S. aureus
(O'Callaghan et aI., 1980; Richmond, 1980), and
against most of the chromosomal- or plasmid-me-
diated (j-Iactamases [such as Richmond types I, III
(TEM), IV and V] which are produced by a variety
of Gram-negative species (Fu and Neu, 1978, 1979;
King et aI., 1980; Labia et aI., 1980; Mouton et aI.,
1979; O'Callaghan et aI., 1980; Richmond, 1980).
In general, the (j-Iactamase stability pattern of cefo-
taxime is similar to that of cefuroxime, both being
hydrolysed by fewer (j-Iactamases than cefaman-
dole, cephalothin and cephaloridine (King et aI.,
1980; Mouton et aI., 1979). However, cefotaxime
has been shown to be more susceptible than cef-
oxitin to a number of (j-lactamases (Mouton et aI.,
1979; see below). When hydrolysis occurred, it was
usually at a slower rate for cefotaxime than for ce-
furoxime (Mouton et aI., 1979) but more rapid for
cefotaxime than for cefoxitin.
Unlike cefoxitin, cefotaxime was hydrolysed by
(j-Iactamase isolated from several strains of B. fra-
gilis (Dornbusch et aI., 1980; King et aI., 1980;
Richmond, 1980; Sato et aI., 1980), but less rapidly
than was cefuroxime (King et aI., 1980; Richmond,
1980; Sato et aI., 1980). In general, (j-lactamase ex-
tracted from P. vulgaris also hydrolysed cefotaxime
and cefuroxime (cefuroxime usually more rapidly
than cefotaxime), but not cefoxitin (King et aI.,
1980; Matsubara et aI., 1981; Mouton et aI., 1979).
In some studies, cefotaxime and cefoxitin were
shown to be competitive inhibitors of purified ce-
phalosporinases extracted from E. coli (Minami et
aI., 1980a), P. rettgeri (Matsuura et aI., 1980), and
 Cefotaxime: A Review 238

E. cloacae (Minami et aI., 1980b). At a concentra-

sco J
-
<0 co
<0<0
Ll'l,...
It)
CO N
C\I
C')
CO)
C\I C\I~
tion of 1 to 10 ~g/ml, cefotaxime and cefuroxime
~ N
C\I
0>
showed some propensity to induce fj-Iactamase
0;
J .r.r .r
Ltl
Ll'l
o
It)
Ll'l
O~
o.r production in E. cloacae; this activity was less than
~I~
C\I
~~
co
Q) o N
C\I N
C\I
m "0
~ C')
CO)
.;,
C\I
N C\lC')
NCO) that of cefoxitin and moxalactam, but greater than
:>
.c " COlt)
<OLl'l
co
J, .;,
J, ';'J,

-'"EI"''""
LtlC\l
Ll'lN <0
,...
C\I
N C\I
,...
N NN
C\IC\I
,... ,... that of cefoperazone (Minami et aI., 1980c). Cefo-
~
C\I~
N,... ~ ~ ~ ~ ~

...., '" Cl 1\ 0 .;,

J, oVI ooVI 00
U ~ N VI oci VI VI fj-1actamase production in K.
taxime also induced fj-Iactamase
~ J pneumoniae and C. freundii and was hydrolysed
e co .r co ,...co
~co
by the induced, but not the uninduced, enzyme (Fu
~
C\I
N
:§.
.2 o
Ltl
Ll'l
C\I
N
Ltl
C\I and Neu, 1981).
u c3 ~

o
~

OC\l
o ~
.r~ C\I C\I
VI VI
II CO
,...
<0
,... ~
co
,... <0
,...
~
~ ~

.;, .;, .;,.;,

-:~o I'""
E
:>
co
C\I
J,
C\I
J, &bah 1.5 Bactericidal Activity
"3 1"""(\1 co N
,..... ,...
C\I
N
~
,... ,...
C\IC\I
N
~
N
~
Cl
.;,.;, .;,
to o0 o 00
~ 'U" '" ~ 00 o0 VI VI VI VI
In general, there has been little difference (i.e.
ui
E
m J .r co
Ltl
Ll'l
o
Ltl
Ll'l
OCO @-.-:.
@'.-:. less than or equal to a 2-fold difference) between
~
C\I C\I
'2 C') 'C'!
....:~ minimum bactericidal and inhibitory concentra-
as
c:
e'
o o
Ltl
Ll'l
N
,...
C\I
Ltl
Ll'l
N
,...
C\I "o
oo "c:
;:;, 0 tions of cefotaxime for most Gram-negative organ-
u c3 COlt)
III
~

ci
~

d CD uU
:.;:::;
:c :g I~
<0
,...0 o VI VI,...
VI '"
III CD isms studied (Barry et aI., 1980; Bartmann and
e oN It)
Ll'l Ltl
Ll'l
m
CD
'"
CD
'"
III
m
CD Tarbuc, 1980; King et aI., 1980; Martinez-Beltran
al co
coJ,
co
.;,
to
o.;,
0
an
oco
OCO
';'ab
J,J, '" '"
III
m
~
CD
'"
m
III
"'" ~~
-il'""
C\IC\I
,...,... co ,...
C\I
N N,...
C\I
,... ,...
NN
C\IC\I
m~
1Il~
CD III et aI., 1980; Sosna et aI., 1978; Verbist, 1981a).
Ui o Cl ~

.no
';'0
~
J,
J,
~

oVI
~

o0VI
~

00
~
'"
'6 .!!?
m
.!!1
However, larger differences were occasionally re-
'O"J
:>
'"
u as
~ oVl
oVl o
0 VI VI ::l "0
m _:>
-ti) E
~ ~ IIIm ported for some species, such as Enterobacter (Barry
m
.50 J '" '"
.c
~
CD ~
-~
~
CD
et aI., 1980; Sosna et aI., 1978), indole-positive Pro-
NN co (5£
o -
~
C\IC\I
(; C')
CO) c: 00
a.
m
"
.-
.-
"0
c: "
.-
teus (Barry et aI., 1980), Pseudomonas aeruginosa
o
0;
~
U
~
5l
,...0
~o
It)
Ll'l
C\I
LO
Ll)
o
LO
Ll)
0
LOll)
LOLl)
00 -- '"'"
CD
m "0
_
'" "0
1nS
CD III
(Barry et aI., 1980; Corrado et aI., 1980; Neu et aI.,

-"''"" --"
a. -'" m
CD 1979a), Serratia marcescens (Verbist, 1981a) and
~ E CO
<0 CD -CD
~

~as
Ltl
Ll'l
C\lCO
NCO ,.... T"" ,....,....
,..... T"" oIII
m
cc:
'"
m
III S. aureus (Sosna et aI., 1978), although results
~ .;,.;,
J,J, to .;,
J, .;,.;,
.nab 0

~I'"
co - ~
.c
10
)(
CD
Cl
Ol
NN
,... ,...
C\IC\I
~ ~
,...
<0
~
C\I
,.... C\I
,.... C\lN
,....,.....
,....,.... c:
as -c: tended to vary from study to study despite the use
"0 o
oE " c: 00 .;,
J, oVI 0 00 cc: as
'"
o -.c of similar inoculum sizes (104 or 105 cfu). Unfor-
"as
.~
~

J
VI VI VI VI VI -~
CD -
~'E
" ~'"E
!-o~
- tunately, few authors have specifically mentioned
)(
~
~
'V,.... co co - '"
;.a,
,....co .~
.;(
_ the relationship between the MBC and MIC of
-CD _E
E
~
.E -
~ ~ J
<0
Ltl
Ll'l
N
,...
C\I
~
U,
N
,...
C\I
~
E
U
u -
'"o '"0CDu cefotaxime for Gram-positive organisms.
'0 u ~ ~';.
~~
-
Ltl
Ll'l It)
Ll'l When the bactericidal activity of cefotaxime was
~ 0 - 0
e ~
~O
.ro
~'"
CD -
>
;:; ~
'"
>
's .2 '"
E
coJ,
C\I co
.;,
J,
co
.;,
J,
,...
~

.;,
J,
,...co
~co
.;,.;,
J,';'
'iii
c: III
E compared with that of other antibiotics by means

~i - .~o I'" ';'0

" m of killing-curve studies, cefotaxime killed E. coli at
Cl
It)C\I
C\I~ ,...
C\I
N
~

oVI
,...
C\I
N
~

oVI
,...
C\I
N
~

oVI
NN
,... ,...
C\IC\I
~

00
~ '" "
CD c:
III CD
CD '"
m III

'" "'" o VI VI VI
'" m
m
o~ IIIIIIm a rate similar to that of moxalactam, cefuroxime
~ <
u ~
E ~ and cefoxitin; Klebsiella species at the same rate as
W rn ~-g§: !;p
0;
·c ~ S
~,.....
.~
Q)
:::"ca~
f/JUl._
'"CD 'Q)CD~"
~ ~
moxalactam; P. aeruginosa at least as rapidly as
~ ;:: ~!g
CI)'s
~ a. ·!!?afil
~(,)a.
o "0
0"0
ern ~.em carbenicillin and piperacillin, and S. aureus at a
- '" a·_·o
.c ~
0) 1) (/)
._ m !!! E a. 0m U) U)

'"" ~~-'"
~ -- ~ ~ ~ rn 0 CI) !~ .! rate comparable to that of cephalothin and cefa-
:>
~~&~~~e~
____ o ___ <a (,) ~i8 "c:~ -~"rnc:
--"-0
m
III U)
mandole (Neu et aI., 1979a,b).
i '~o ~~.~~~~.~! ~~8 U5U5 Using the membrane filtration method, Shah et
.Q Cl' oo.!!u·!~~g ~aa
~ 0
LCfJ
~ OS &l&l~&l~o1il-~€(3.t.t ,...N
~C\I ai. (1978, 1979b) also determined the rate and ex-
 Cefotaxime: A Review
tent of the bactericidal activity of cefotaxime against
various Gram-negative bacilli, and showed that as
with penicillin, increasing concentrations of cefo-
taxime did not lead to higher kill rates.
Another group of investigators has measured (by
bioassay) the serum bactericidal activity of cefo-
taxime in healthy volunteers (Bernard et aI., 1980;
Klastersky et al., 1980; Lagast et aI., 1981; Zinner
et ai., 1981). Against E. coli and Klebsiella species
this activity was relatively high at 1 and 6 hours
following infusion of cefotaxime 15 mg/kg com-
pared with the activity against P. aeruginosa or S.
aureus, and was not enhanced significantly by
combination with amikacin. Although serum bac-
tericidal activity against P. aeruginosa was inade-
quate 1 hour after administration of cefotaxime
alone, significant improvement occurred when
cefotaxime and amikacin were given in combina-
tion, but not when cefotaxime and tobramycin were
combined. The negligible serum bactericidal activ-
ity of cefotaxime against S. aureus improved con-
siderably with the addition of either amikacin or
tobramycin, but this improved activity appeared to
be due chiefly to the latter (2) drugs.
1.6 Effect on Activity of Inoculum, Media,
pH and Serum
When the size of the inoculum was increased
100-fold (usually) or 1000-fold to 105 or 106 col-
ony-forming units (cfu) this usually had little effect
on the in vitro activity of cefotaxime (i.e. no more
than a 2-fold increase in MIC) for most strains of
the various Gram-negative and -positive organ-
isms tested (Barry et ai., 1980; Corrado et aI., 1980;
Hamilton-Miller et ai., 1978; Lang et ai., 1980;
Markowitz and Sibilla, 1980; Neu et aI., 1979a;
Wise et aI., 1978; 1980a). However, when B. fra-
gilis (Wise et aI., 1978) and some strains of Gram-
negative bacilli showing multiple drug resistance
(Hall et aI., 1980a) were tested, an inoculum effect
occurred. Similarly, increasing the inoculum size
to 10 7 or 108 cfu usually resulted in a marked de-
239
crease in the inhibitory activity of cefotaxime on
most Gram-negative species (to the extent that
many organisms highly susceptible at low inocula
appearred resistant when over 106 cfu were used),
but activity against Gram-positive organisms was
rarely affected in this way (Barry et aI., 1980; Cor-
rado et aI., 1980; Neu et aI., 1979a).
In contrast to these studies, no important in-
oculum effect was seen by Shah et aI. (1978), but
this may arise from the use of a different culture
media in this study (Diagnostic Sensitest Agar)
compared with most others (Mueller Hinton broth).
Interestingly, Counts and Turck (1979) found that
a greater inoculum effect occurred when cefotax-
ime MICs were determined in Mueller Hinton
broth compared with Mueller Hinton agar.
From limited data on the effect of inoculum size
on the minimum bactericidal concentration (MBC)
of cefotaxime it appears that, as with MICs, larger
increases in MBCs usually occur when inocula of
Gram-negative organisms are increased above 105
cfu than with increases up to 105 cfu (Corrado et
ai., 1980; King et aI., 1980; Kropp et aI., 1980;
Verbist and Verhaegen, 1980).
Conflicting comments have been made regard-
ing the effect on cefotaxime's inhibitory activity of
various culture media (Counts and Turck, 1979;
Neu et aI., 1979a), the form of the media (e.g.
Mueller Hinton broth vs Mueller Hinton agar)
[Counts and Turck, 1979; Marklein and Mattias,
1980; Neu et aI., 1979a; Verbist and Verhaegen,
1981], variations in media calcium and magne-
sium ion content (Neu et ai., 1979a; Yu et al., 1980)
and media pH (Neu et aI., 1979a; Trager et ai.,
1981 ).
It appears that increasing the sodium chloride
content of Mueller-Hinton broth to 4% decreases
MICs of cefotaxime for some genera, particularly
E. coli, Enterobacter and Serratia species, but not
for P. aeruginosa (Trager et al., 1981). In general,
addition of 50% inactivated human serum to
Mueller Hinton broth has little effect on the MIC
and MBC of cefotaxime (Lang et aI., 1980; Neu et
ai., 1979a; Trager et aI., 1981).
 Cefotaxime: A Review
1.7 Antibiotic Synergy
The synergistic activity of cefotaxime in com-
bination with various antibiotics, particularly
aminoglycosides, has been studied using the classic
in vitro checkerboard method. Synergy was usually
defined on the basis of the antibiotics' minimum
inhibitory concentrations (decreased 4-fold) or the
fractional inhibitory concentration index (less
than 1).
In such studies with P. aeruginosa, cefotaxime
in combination with gentamicin was synergistic for
about 60% of strains tested (Murray, 1980; Neu et
al., 1979a; Perea et aI., 1980), including gentami-
cin-resistant strains (Murray, 1980). Synergism be-
tween cefotaxime and gentamicin occurred more
frequently with carbenicillin-sensitive strains of P.
aeruginosa than with strains resistant to carbeni-
cillin (88% vs 48%) in the study by Perea et al.
(1980).
Synergy between cefotaxime and tobramycin
occurred against 34 to 63% of P. aeruginosa iso-
lates (Mintz and Drew, 1981; Murray, 1980; Perea
et aI., 1980); the lower percentage occurred in a
study in which two-thirds ofthe strains tested were
tobramycin-resistant (Murray, 1980), while the
higher percentage resulted from the testing of pre-
dominantly tobramycin-sensitive strains (Mintz and
Drew, 1981).
Results from studies in which cefotaxime and
amikacin were combined varied widely, with syn-
ergy being demonstrated with about 10 to 60% of
P. aeruginosa isolates (Jorgensen et al., 1980b;
Kurtz et aI., 1980; Murray, 1980; Perea et al., 1980;
Zinner et al., 1981). Antagonism between an
aminoglycoside and cefotaxime occurred very
rarely when testing P. aeruginosa (Perea et al.,
1980; Regamey and Lavanchy, 1980; Zinner et
aI., 1981).
In addition to reporting the extent of synergy,
it is also important to consider the actual MICs
obtained when antibiotics are tested in combina-
tion. In one such study (Murray, 1980) using 50
isolates of P. aeruginosa which were selected for
240
resistance to at least 1 aminoglycoside, the MICs
of both drugs in a synergistic combination were re-
duced to clinically achievable concentrations (MIC
~ 8"g of gentamicin or tobramycin per ml, and ~
16"g ofamikacin or cefotaxime per ml) for 18% of
the strains using combinations of gentamicin and
cefotaxime or amikacin and cefotaxime, and for
10% of the strains using a combination of tobra-
mycin and cefotaxime. Clinically relevant syner-
gism occurred mainly with strains moderately reo
sistant to the aminoglycoside (MIC ~ 64 "g/ml),
and only very rarely with highly resistant strains
of P. aeruginosa.
When 22 strains of Serratia marcescens (all of
which were resistant to gentamicin and cepha-
lothin but not to cefotaxime) were studied by the
checkerboard method, 3 criteria for synergy were
met for only 9% of isolates when cefotaxime was
combined with gentamicin or tobramycin and for
about 20% of isolates when combined with ami-
kacin or netilmicin. However, antagonism oc-
curred with 18 to 27% of isolates in each cefo-
taxime-aminoglycoside combination, except
gentamicin plus cefotaxime (Markowitz and Si-
billa, 1980). In contrast, when 1 criterion was con-
sidered indicative of synergy,S of 10 S. marcescens
isolates (which were also resistant to gentamicin,
but susceptible to amikacin) were inhibited
synergistically by amikacin plus cefotaxime, with
MIC90 values of2 and 0.25 "g/ml, respectively. No
antagonism was observed in this study (Kurtz et
al., 1981).
In a study which tested about 100 strains of
Enterobacteriaceae, synergy between amikacin and
cefotaxime was demonstrated for a high propor-
tion (72 to 85%) of E. coli, Klebsiella species and
P. mirabilis isolates, and to a lesser extent (44%)
for strains of S. aureus (Klastersky et al., 1980; Zin-
ner et al., 1981).
These authors also evaluated synergy between
cefotaxime and aminoglycosides by studying in-
fected neutropenic mice, and serum bactericidal
activity in human volunteers (see sections 1.8 and
1.5, respectively).
 Cefotaxime: A Review
1.8 Activity In Vivo
Cefotaxime was shown to be effective in treat-
ing systemic infections in mice inoculated intra-
peritoneally with a wide variety of organisms and
subsequently given I to 3 doses of the drug sub-
cutaneously. In general, the median effective dose
(ED so) of cefotaxime calculated from survival rates
on days 4 or 5 was below 1.5 mg/kg for infections
due to most Enterobacteriaceae (including many fJ-
lactamase-producing strains), and slightly higher (2
to 5 mg/kg) for the limited number of S. aureus
strains tested (Angehrn et aI., 1980; Kamimura et
aI., 1979; O'Callaghan et aI., 1980; Tsuchiya et aI.,
1981 ).
When single doses of cefotaxime or cefuroxime
were given at the time of bacterial inoculation, the
ED so determined for cefotaxime was considerably
lower (around 30 times) than that for cefuroxime
for infections with strains of Enterobacteriaceae
sensitive (MIC ~ 4 J,Lg/ml) to both drugs (Tsuchiya
et aI., 1981). However, cefotaxime (administered
twice) was less effective than gentamicin against
systemic infections in mice caused by 4 strains of
P. aeruginosa; the EDso values ranged from 33 to
over 200 mg/kg for cefotaxime and from 2.6 to 6.3
mg/kg for gentamicin. The MIC of cefotaxime for
each strain was 16 J,Lg/ml, and for gentamicin it was
between 2 and 8 J,Lg/ml, using a rather high inoc-
ulum of 107 cfu (O'Callaghan et aI., 1980).
The effect of cefotaxime on the bacterial con-
tent of particular tissues or fluids has been studied
in various experimental models of infection. In
mice with pneumonia caused by K. pneumoniae,
the 50% clearance dose (CDso) of subcutaneously
administered cefotaxime was 24 mg/kg, while the
50% survival dose was 20 mg/kg (Tsuchiya et aI.,
1981). These authors also treated urinary tract in-
fection in mice with subcutaneous cefotaxime given
4 times daily for 5 days, starting 3 days after in-
jecting P. mirabilis into the ascending route. This
resulted in a 50% clearance dose (8 days after in-
fection) of 0.53 mg/kg for the bladder wall and 0.84
mg/kg for the kidney. In chronic oestrogen-in-
241
duced pyelonephritis in rats subsequently infected
with fJ-lactamase-producing and non-producing
strains of E. coli, treatment with cefotaxime or
cefoxitin 150 mg/kg twice daily for a week (prob-
ably intramuscularly) considerably reduced bacte-
rial counts in the kidneys, compared with un-
treated controls (Marre and Sack, 1979).
In an animal model of intra-abdominal sepsis
designed to simulate sepsis following colonic per-
foration, optimal results were obtained with cefo-
taxime and other antibiotics active against coli-
form and anaerobic bacteria. The incidences of
mortality (3%) and intra-abdominal abscesses (4%)
following 10 days' treatment with intramuscular
cefotaxime 60 mg/day were similar to those oc-
curring with the same dosages of moxalactam or
cefoxitin or with a combination of clindamycin 48
mg/day plus gentamicin 6 mg/day (0 to 7% mor-
tality, 5 to 7% abscess formation). However, mor-
tality (37%) and abscess formation (100%) were sig-
nificantly higher in untreated rats (Bartlett et aI.,
1981 ).
In rabbits with experimental meningitis caused
by E. coli and treated with continuous antibiotic
infusions of 25 mg/kg per hour for 9 hours, either
cefotaxime or moxalactam significantly (p < 0.05)
reduced bacteria in the CSF, compared with netil-
micin 2 mg/kg per hour which had no significant
effect. However, when experimental meningitis was
caused by group B Streptococcus type III, mox-
alactam was significantly (p < 0.01) less effective
than cefotaxime, ampicillin and cefoperazone in
reducing bacterial counts in CSF; moxalactam was
also much less active against this organism than
the other antibiotics when tested in vitro (Schaad
et aI., 1981).
Combined antibiotic therapy was studied using
neutropenic mice injected intraperitoneally with
either E. coli, K. pneumoniae or S. marcescens
(Zinner et aI., 1981). When subeffective doses of
each antibiotic were administered subcutaneously
about I and 4 hours later, significantly enhanced
survival occurred with cefotaxime plus amikacin
compared with either drug alone (p < 0.05).
 Cefotaxime: A Review
The nonspecific influence of cefotaxime on the
immune system has been studied by Gillissen (1981,
1982). Cefotaxime enhanced antibody formation
in mice and also significantly prolonged (p < 0.05)
survival time of immunocompromised mice in-
fected with Candida albicans, although this fungus
is highly resistant to cefotaxime. Thus, cefotaxime
did not have a negative effect on immune response
in vivo.
2. Renal Tolerance
In studies to date cefotaxime appeared to be free
of adverse effects on renal function. Thus, in com-
paring the effects of single daily subcutaneous in-
jections of cefotaxime (750 or 1500 mg/kg),
moxalactam (750 or 1500 mg/kg), cephaloridine
(100 or 200 mg/kg) or saline on rabbit kidneys,
which provide a sensitive model of cephalosporin
nephrotoxicity, excretion of the lysosomal enzyme
N-acetylglucosaminidase, and the concentration of
creatinine in plasma were not significantly in-
creased with either dose of cefotaxime or mox-
alactam given for 7 days. Minor morphological
changes to the glomerular ultrastructure with the
higher dose of these antibiotics were detected by
electron microscopy, but not by light microscopy.
However, cephaloridine caused significant func-
tional and morphological damage to the rabbit kid-
ney (Luft et ai., 1982).
In rats (Marre and Sack, 1979; Sack et ai., 1978),
very high doses (i.e. 5000 mg/kg/day) of cefotax-
ime and cefuroxime were required to increase urin-
ary excretion of renal tubular epithelial cells, com-
pared with cephalothin or cefamandole (3000 mg/
kg/day), cefazolin or cefoxitin (2000 mg/kg/day),
and cephaloridine (500 mg/kg/day). [See also sec-
tion 3.2 for renal effects detected during toxico-
logical studies.]
The effect of cefotaxime on renal tolerance has
been assessed in healthy subjects by measuring
urinary excretion of alanine aminopeptidase (AAP),
an enzyme in the brush border membrane of proxi-
242
mal renal tubules which is considered to be an early
indicator of renal tubular damage. AAP excretion
in urine was not significantly altered during and
after intravenous cefotaxime 3g twice daily for 3
days, or when cefotaxime 6g daily was combined
with frusemide 20mg daily (Mondorf et ai., 1980).
In another study in healthy volunteers (Luthy et
ai., 1979), but using a high rate of infusion of cefo-
taxime (2, 5, or 8g in 3.25 hours), a marked tran-
sient increase in alanine aminopeptidase activity
occurred during infusion (only) of each dose.
However, the activity of alanine aminopep-
tidase remained within the normal range at all
times.
Evidence from a study by Kuhlmann et ai.
(1982a,b) suggests that cefotaxime can be com-
bined with the aminoglycoside tobramycin without
increasing the risk of nephrotoxicity compared with
that with the aminoglycoside alone. Thus, urinary
excretion of alanine aminopeptidase was measured
in 44 patients with normal renal function and se-
rious infections treated with cefotaxime 6 g/day,
tobramycin 3 mg/kg/day, cefotaxime plus tobra-
mycin (at the same dosages), cefotaxime plus azlo-
cillin 15 g/day, or azlocillin plus tobramycin. All
antibiotics were given intravenously at 8-hourly in-
tervals for at least 7 days.
None of the patients treated with cefotaxime
alone or in combination with azlocillin showed an
appreciable rise in AAP excretion or in serum cre-
atinine, or a reduction in creatinine clearance.
However, patients treated with tobramycin alone,
tobramycin plus cefotaxime or tobramycin plus
azlocillin, showed significant (p < 0.05) increases
in AAP excretion during therapy compared with
pre-therapy levels. The magnitude of increases seen
with these antibiotic combinations was similar to
that with tobramycin alone.
In addition, a similar proportion of patients in
each of the 3 treatment groups receiving tobra-
mycin alone or in combination showed patholo-
gical changes in serum creatinine and/or creatinine
clearance. Changes in renal function were revers-
ible in all cases.
 Cefotaxime: A Review
3. Toxicity Studies
3.1 Acute Toxicity
The median lethal dose (LDso) of cefotaxime for
mice is 9.1 g/kg, or> 10.4 g/kg when the drug is
administered intravenously to females and males,
respectively; 12 g/kg when given intraperitoneally
to females, and 18.7 g/kg when given subcu-
taneously to both sexes. In rats the intravenous
LDso of cefotaxime is 9.9 (female) or 10.7 g/kg
(male), while the intramuscular LDso is > 7 g/kg
for both sexes. When administered intravenously
to male and female dogs the LDso of cefotaxime is
> 1. 5 g/kg (Doerr et aI., 1980).
3.2 Subacute and Chronic Toxicity
When repeated doses of cefotaxime were ad-
ministered for 30 days, no pathological changes oc-
curred in rats given up to 238 mg/kg subcu-
taneously or 300 mg/kg intravenously, in dogs given
up to 179 mg/kg intramuscularly or 300 mg/kg
intravenously, and in puppies receiving up to 1500
mg/kg subcutaneously, apart from local reactions
(Doerr et aI., 1980; data on file, Roussel). The high-
est daily dose (3000 mg/kg) of cefotaxime admin-
istered subcutaneously to rats for 30 days, resulted
in haemorrhage at the injection site, dilation of the
caecum, increases in spleen and kidney weights and
histopathological changes to renal tubules (Mo-
rioka et aI., 1980).
Following 90 days' administration of cefotax-
ime 500, 1000 or 1500 mg/kg/day intravenously to
dogs, some animals (especially in the high dose
group) showed slight necrotic lesions of doubtful
significance in the proximal tubules of the kidney.
No lesions were found in any organs of rats given
up to 1600 mg/kg/day subcutaneously over the
same period (Doerr et aI., 1980; data on file,
Roussel).
Chronic toxicity studies conducted for 6 months
with daily cefotaxime doses of up to 250 mg/kg
243
administered subcutaneously and intramuscularly
to rats and dogs respectively, occasionally resulted
in dose-dependent local reactions (Doerr et aI.,
1980; data on file, Roussel). Subcutaneous admin-
istration of cefotaxime 1000 mg/kg/day to rats for
6 months resulted in similar changes to those which
occurred in rats given 3000 mg/kg/day for 90 days
by the same route (see above; Morioka et aI.,
1981b).
Potential toxicological effects on the kidney of
cefotaxime alone and in combination with genta-
micin or frusemide have been studied. A single
intravenous dose of cefotaxime 1 g/kg resulted in
a slight, transient reduction in para-amino hippuric
acid clearance in dogs, but creatinine clearance and
urine output were not affected (data on file, Rous-
sel). When a lower dose (220 mg/kg/day intra-
muscularly) was administered to rabbits for 7 days
no drug-related renal changes occurred (data on file,
Roussel). A longer term study (Morioka et aI.,
1981a) in female rats treated for 28 days with
cefotaxime 1000 mg/kg/day intravenously, or
gentamicin 30 mg/kg/day intramuscularly or fru-
semide 100 mg/kg/day orally, found no signs of
renal toxicity based on urinalysis, excretion of
urinary enzymes and plasma chemical tests. In ad-
dition, cefotaxime given together with gentamicin
or frusemide did not enhance the incidence or ex-
tent of histopathological changes to renal tubules
seen when each drug was given alone. In a study
in rabbits (Doerr et aI., 1980), additive histopath-
ological effects on renal tubules occurred when very
high single doses of cefotaxime (5 g/kg) and genta-
micin (100 mg/kg) were given intravenously in
combination.
3.3 Reproduction Studies
A summary of numerous reproductive studies
conducted in rats and rabbits indicates that cefo-
taxime does not inflence fertility, or fetal and post-
natal development (Doerr et aI., 1980). Similar
conclusions were reached by Sugisaki et al. (1981 b)
 Cefotaxime: A Review
in studying mice given up to 2000 mg/kg/day
intravenously or 6000 mg/kg/day subcutaneously.
The only notable abnormalities (e.g. slight dilation
of the caecum and gallbladder, and haemorrhage
at the site of subcutaneous injection) occurred in
parental mice given doses of 1500 mg/kg/day or
higher. Administration of intravenous cefotaxime
6.25 mg/kg/day to rabbits from days 6 to 18 of
gestation did not affect the dams or offspring.
However, with higher doses (12.5, 25 and 50 mg/
kg/day), a few animals in each group had anorexia
and loose stools, followed by abortion of the fetus
or death of the dam. Reproduction in the remain-
ing dams was similar to that in controls, except for
the number ofresorptions and/or dead fetuses. No
drug-related dysmorphogenic effects occurred in the
live fetuses (Sugisaki et al., 1981 a).
4. Pharmacokinetic Studies
Pharmacokinetic studies of cephalosporins are
usually performed by microbiological determina-
tion of the drug concentration in plasma and urine.
The lack of specificity of the microbiological assay
often does not permit the determination of un-
changed drug in the presence of its metabolites.
Antimicrobially active biotransformation prod-
ucts are produced from cefotaxime, the princIpal
one being desacetyl-cefotaxime (section 4.3.1). In
healthy subjects, this metabolite accounts for about
5 and 14% of the peak plasma drug concentration
after intravenous and intramuscular administra-
tion (15 mg/kg), respectively (Ings et aI., 1982).
Since cefotaxime and its metabolites differ in
antibacterial activity (section 1.3) and in phar-
macokinetic properties (sections 4.3.2 and 4.5), it
is desirable that the assay method used to study
the pharmacokinetics of cefotaxime can distin-
guish between the antimicrobially active products.
Differentiation between cefotaxime and des-
acetyl-cefotaxime can be achieved by using high
performance liquid chromatography (HPLC) or an
indicator strain of a micro-organism that is resist-
244
ant to desacetyl-cefotaxime. Whilst either bioassay
or HPLC may be adequately specific for determin-
ing serum concentrations in healthy subjects (00-
luisio, 1982; Ings et aI., 1982), it is important that
a selective assay be used in patients with renal dys-
function (Doluisio, 1982). In this review, only those
studies which have used HPLC or an indicator
organism stated to be specific for cefotaxime, or
much more susceptible to cefotaxime than to
desacetyl-cefotaxime, will be discussed, except for
distribution data, as the vast majority of body tis-
sue or fluid concentrations were determined by
nonspecific assays.
The one situation in which the use of a non-
selective reference strain is of value, however, is
where the infecting organism is used as the refer-
ence strain; here, the antibacterial activity in plasma
is relevant to the therapeutic activity of cefotaxime
in the individual patient.
4.1 Absorption and Serum Concentration
After an intravenous bolus of 1000mg, mean
peak plasma concentrations of cefotaxime have
usually ranged between 81 and 102 ~g/ml (Ho et
aI., 1980; Luthy et aI., 1981a,b; McKendrick et aI.,
1980a). Mean peak plasma concentrations were 174
to 214 ~g/ml after a 2g intravenous bolus dose (Ho
et aI., 1980; Luthy et aI., 1981a,b; Neu et aI., 1980;)
[table V). At 4 and 6 hours, after a 1000mg dose
mean plasma concentrations were 1.9 and 0.4 ~g/
ml, respectively (Ho et aI., 1980; Luthy et aI.,
1981a). A 1000mg dose administered by intraven-
ous infusion over a period of 30 minutes resulted
in a mean peak plasma concentration of 41 ~g/ml
at the end of the infusion (Fu et aI., 1979).
A cross-over comparison of equal doses of
cefotaxime, moxalactam and ceftazidime resulted
in lower plasma concentrations of cefotaxime than
of the other two drugs (Luthy et aI., 1981a), al-
though such data should be interpreted alongside
data on the relative antibacterial activity of the
drugs being compared. A comparison of some of
 Cefotaxime: A Review 245

Table V. Mean plasma concentrations of cefotaxime after intravenous or intramuscular administration of 0.5 to 2.0g doses to
healthy subjects. All studies used assay methods able to differentiate between cefotaxime and desacetyl-cefotaxime

Reference No. of Dose Route of Peak Cone. at Cone. at AUC

subjects (mg) administration cone. 4 hours 8 hours (ltg/mi. h)
(ltg/ml) (ltg/ml) (ltg/ml)

Fu et al. (1979) 13 500 1M 11.7 1.4 23.2

1000 1M 20.5 3.36 45.7
10 1000 IV 41 1.5 44.3
(30-min infusion)

Ho et al. (1980) 11 500 IV (bolus) 38 1.0 30.6

1000 IV (bolus) 102 1.9 70.4
2000 IV (bolus) 214 3.3 134

Ings et al. (1982) 6 15 mg/kg' 1M 25.5

Luthy et al. 6 500 IV (bolus) 38 <0.1

(1981a,b) 1000 IV (bolus) 81 <0.1
2000 IV (bolus) 174 0.5

1000 + IV 109 0.6

probenecid

Bodyweight was 54 to 72 kg.

the important pharmacokinetic values of cefotax-
ime, cefoperazone, moxalactam, cefuroxime and
cefoxitin, is summarised in table VI.
Bax et ai. (1980) reported a linear increase in
plasma cefotaxime concentrations and in the area
under the plasma concentration-time curve (AVC)
after bolus injections of 0.5, 1.0 and 2.0g. How-
ever, a non-linear increment in AVC was noted by
Luthy et ai. (198Ia,b) and Ho et ai. (1980), who
reported a greater than 4-fold increase in AVC when
the dose was increased from 0.5 to 2.0g.
Concomitant administration of probenecid in-
creases and sustains the plasma concentrations of
cefotaxime (Bax et aI., 1980, Luthy et aI., 1981a,b).
In this respect, cefotaxime is similar to cefuroxime
(Foord, 1976), but unlike cefoperazone (Shimizu,
1980), moxalactam (Luthy et aI., 1981a,b) or cef-
tazidime (Luthy et aI., 1981a,b).
There was no evidence of cefotaxime accumu-
lation when 1.0g every 6 hours was administered
by intravenous infusion for 14 days. The AVC was
57 Ilg/ml • hand 69 Ilg/ml • h on days 1 and 15
respectively (Ho et aI., 1980). Similarly, intramus-
cular administration of O.5g 6-hourly for II days
did not result in any drug accumulation (Ho et aI.,
1980).
Mean peak plasma cefotaxime concentrations
after intramuscular injection of 500 or 1000mg are
about one-quarter to one-third those after intra-
venous administration of the same dose (Fu et aI.,
1979; Ho et aI., 1980; Ings et aI., 1982; Ohkawa
and Kuroda, 1981). Lignocaine (lidocaine) 1%,
which may be included with intramuscular cefo-
taxime to minimize discomfort at the injection site,
has little or no effect on the absorption kinetics of
cefotaxime (Bax et aI., 1980).
4.2 Distribution
The apparent volume of distribution at steady-
state (Vd •• ) of cefotaxime was 21.6 L/1.73m 2 after
Ig intravenous 30-minute infusions. In single-dose
studies with Ig doses of cefotaxime, the apparent
Table VI. Summary of some pharmacokinetic values of cefotaxime. cefoperazone. moxalactam. cefuroxime and cefoxitin
()
CD
Drug Dose Mean peak Half-life (hours) Urinary Protein Reference" §;
(Iv)a serum recovery binding '"3'
)(
normal severe renal
concentration (% in 24h) (%)
failure !'!
(ltg/ml) >
:D
CD
<
CD'
Cefotaxime 19 81-102 0.9-1.14 b 2.3-2.6b 50-65 37-38 8. 13. 18. 19. 20. 21. 33 =:
1.4-1.9c 8-12C
2g 174-214

Cefoperazone 19 140-200 1.6-2.05 2.3-4.2 19-36 87-93 2. 3. 5. 17. 25. 30

2g 250-375

Moxalactam 19 95-147d 1.9-2.7 13.3-20 61-96 52 1.16.17.22.23.29.32

Cefuroxime 19 90-144 1.1-1.4 14.8-15.2 92-96 33 4. 6. 11. 12. 14. 27

Cefoxitin 19 110-125 0.9 13 77-99 65-80 7. 9. 10. 15. 24. 25. 26. 28. 31

a Intravenous bolus.
b Half-life of unchanged cefotaxime.
c Half-life of desacetyl-cefotaxime.
d Higher value is after a dose of15 mg/kg to 5 subjects with a mean bodyweight of 71.7kg.
e 1 = Aronoff et al. (1981); 2 = Bundtzen et al. (1980); 3 = Craig (1980); 4 = Daikos et al. (1977); 5 = Dayer et al. (1980); 6 = Foord (1976); 7 = Fillastre et al.
(1978); 8 = Fu et al. (1979); 9 = Gillett and Wise (1978); 10 = Goodwin et al. (1974); 11 = Gower and Dash (1977); 12 = Gower et al. (1977); 13 = Ho et al. (1980);
14 = Kosmidis et al. (1977); 15 = Leroy et al. (1978); 16 = Leroy et al. (1981); 17 = Lode et al. (1980c); 18 = Luthy et al. (1981b); 19 = Murakawa et al. (1980);
20 = Neu et al. (1979a); 21 = Ohkama and Kuroda (1981); 22 = Parsons et al. (1980); 23 = Peterson et al. (1981); 24 = Reeves et al. (1978); 25 = Reeves et al.
(1980a); 26 = Schwartz et al. (1976); 27 = Simon and Malerezyk (1977); 28 = Sonneville et al. (1976); 29 = Srinivasin et al. (1980); 30 = Swarz et al. (1981);
31 = Trollfors et al. (1978); 32 = Wise et al. (1980b); 33 = Wise et al. (1981). I\)
~
a>
 Cefotaxime: A Review
volume of distribution during the tl-phase (Vdarea)
was 37.2 L/1. 73m2 after intramuscular injection and
33.3 L/1.73m 2 after a 30-minute intravenous in-
fusion (Fu et aI., 1979; Ho et al., 1980; Neu et al.,
1980). In 6 healthy volunteers with a mean body-
weight of 69kg, the apparent volume of distribu-
tion was 0.29,0.24 and 0.21 Lfkg after single intra-
venous bolus doses of 0.5, 1.0 and 2.0g, respectively
(Luthy et aI., 1981a,b). Concentrations of cefotax-
ime (usually determined by non-selective assay)
ha ve been determined in a wide range of human
body tissues and fluids.
In the cerebrospinal fluid of infants, children and
adults, cefotaxime concentrations are low when the
meninges are not inflamed, but are considerably
higher in patients with meningitis (table VII). Cere-
brospinal fluid cefotaxime concentrations in men-
ingitis appear to be higher in patients with im-
paired renal function (plasma creatinine 720-780
~mol/L) than in patients with normal renal func-
tion (Bruckner et aI., 1982). Cherubin et ai. (1982)
mentioned that mean cerebrospinal fluid concen-
trations (measured by HPLC) of the parent drug
and desacetyl-cefotaxime were 5.2 and 5.9 ~g/ml,
respectively, 1 hour after repeated bolus injections
of cefotaxime (dosage not given) to 11 patients.
These concentrations represented about 10 and 55%
of the average serum concentration of the parent
compound and desacetyl-cefotaxime, respectively.
Concentrations (0.2 to 5.4 ~g/ml) inhibitory for
most Gram-negative bacteria are attained in pu-
rulent sputum, bronchial secretions and pleural
fluid in adults given 1 or 2g of cefotaxime paren-
terally (table VII). A parenteral dose of 25 mg/kg
in children produces maximum concentrations of
about 3 to 11 ~g/ml in empyema fluid (Kafetzis,
1980).
Concentrations of cefotaxime likely to be effec-
tive against most sensitive organisms are attained
in the uterus and adnexa after intravenous admin-
istration of 1 or 2g (table VIII). Concentrations of
antimicrobially active drug in amniotic fluid have
varied between studies but are higher after re-
peated doses than after a single dose (Kafetzis et
247
al., 1980). Drug concentrations in human milk are
low, reaching a maximum of 0.32 jLg/ml (mean)
after a Ig intravenous dose (Kafetzis et al., 1980).
Renal tissue concentrations were 1.9 to 7.0 (in-
ner cortex), 1.9 to 10.8 (outer medulla) and 2.3 to
14 ~g/g (inner medulla) after a Ig intramuscular
injection (Grabe et al., 1981). 1.5 hours after a 2g
intravenous bolus, prostatic adenoma contained
22.9 ~g/g, testes 5.4 ~g/g and ureter 9.2 jLg/g
(Schalkhauser and Adam, 1980). A Img intramus-
dar dose produced prostatic tissue concentrations
of 2.6 ~g/g in the deep layer and 3.9 ~g/g in
superficial tissue (Grabe et al., 1981).
Peritoneal fluid contained a mean peak concen-
tration of 28.6 ~g/ml after a 2g intravenous dose
(Wittmann et aI., 1980b) and non-infected ascitic
fluid contained 3.8 to 17.6 ~g/ml 2 hours after a
Ig dose (Moreau et aI., 1980).
High concentrations of cefotaxime and de-
sacetyl-cefotaxime are attained in both common
duct bile (Kees et aI., 1981; McKendrick et al.,
1980a; Pelz et al., 1980; White et aI., 1980), and
gallbladder bile (McKendrick et aI., 1980a; Soussy
et al., 1980). In patients receiving repeated Ig doses,
common duct bile concentrations of cefotaxime and
desacetyl-cefotaxime were 36 and 243 lLg/ml, re-
spectively, 1.3 hours after injection. The corre-
sponding serum concentration of cefotaxime was
19.2 ~g/ml (McKendrick et al., 1980a). Concentra-
tions in gallbladder wall are about one-fifth to one-
tenth those in bile at the same time (Pelz et al.,
1980).
Peak drug concentrations of 32 ~g/g in pericar-
dium and of 22 ~g/g in myocardium occurred 15
minutes after intravenous cefotaxime 50 mg/kg.
After 2 hours, the average concentrations were 10.7
and 3.8 jLg/g in pericardium and myocardium, re-
spectively. The corresponding serum concentra-
tions were 237 and 33 ~g/ml at 15 minutes and 2
hours (Adam and Struck, 1982).
Cefotaxime concentrations in bone are between
3 and 15 ~g/g after a single 2g intravenous dose or
repeated intramuscular 2g doses (table IX). Con-
centrations in interstitial fluid vary according to
 Cefotaxime: A Review 248

Table VII. Antimicrobial activity (cefotaxime plus active metabolites) in cerebrospinal fluid (CSF), sputum and pulmonary fluids
after single or repeated doses of cefotaxime

Population Tissue specimen Time after Drug dose Drug Specimen Reference7
(number) drug (h) cone. !ltg/ml) cone. rati0 1

Infants/children (34) CSF 1-2 50 mg/kg 3-30 0.27-0.62 b, g, i

(meningitis) 100-300 mg/kg/
24 hours

Adults (37) CSF 2-6 19 IV,3 2g IV, 0-0.45 c, h, j, m

(not inflamed) 0.5-1g 1M
30 mg/kg IV

Adults (6) CSF 2-4 2g IV 0-1 c

(slightly inflamed)
(7) CSF meningitis 1-4 2g IV 1.1-7.14 0.1-1.0 c
8.9-17.6; 0.14-0.18 c

Adults (64) Sputum 2-4 19lM 1.3 e

(purulent) 2g 1M 1.8 n
2g IV 2.91-5.4 0.06-0.16 e
19lV 0.22-0.70 0.04 k, I
(4) Sputum 19 inhalation " 150 0
(6) Pleural fluid 3 19lV 7.2 I

Adults (> 13) Bronchial secretions 19lM 1.58-2.46 d, e

2g IV 2.96 0.03 e
(79) Bronchial tissue 19lV 1.66 a
2g IV 5.1 a

Children (6) Empyema fluid 2-4 25 mg/kg 1M 2.9-3.8 0.38-1.6

25 mg/kg IV 2.25-11.2 1-5.6

1 Ratio of specimen/serum concentration at same time.

2 Data from Kafetzis et al. (1982) only.
3 Abbreviations: IV = intravenous; 1M = Intramuscular.
4 Values in patients with normal renal function.
5 Values in patients with impaired renal function.
6 Concentration in ltg/g.
=
7 Key to references: a Blind et al. (1982); b = = =
Borderon et al. (1981b); c Bruckner et al. (1982); d Fraschini et al. (1981);
= = = = =
e Gialdroni et al. (1980); f Kafetzis (1980); 9 Kafetzis et al. (1982); h Karimi et al. (1980); i Kobayashi et al. (1981a,b);
j = Kosmidis et al. (1980); k =Lode at al. (1980a); I =Lode et al. (1980b); m =
McKendrick et al. (1980); n =
Maesen et al.
(1980); 0 = Newsom et al. (1980).

the method used (table IX), but are above 7 ",glml
after a Ig intravenous or intramuscular dose. The
mean extravasal cefotaxime concentration in skin
was 9.9 ",gig 60 minutes after a 2g intravenous in-
jection in 8 patients (Gninder et al., 1980).
Otitis media effusions from children with acute
otitis media who were treated with 50 mg/kg of
intravenous cefotaxime, contained a drug concen-
tration of 2.1 to 3.3 ",glml 1 hour after injection
(Danon, 1980). Intramuscular injections of 50 mgl
kg and 1()(} mg/kg resulted in a mean effusion con-
centration of 1.2 ",glml in 3 patients and 17.5 ",gI
ml in 2 patients, respectively. Non-infected aqueous
humour contained low concentrations (0 to 2.3 ",gI
ml) I hour after a single 2g intravenous injection
(Busse et aI., 1980).
 Cefotaxime: A Review 249

Table VIII. Antimicrobial activity (cefotaxime plus active metabolites) in female reproductive organs, milk, amniotic fluid, cord
blood and fetal tissue after parEjnteral cefotaxime

Specimen Time after Drug dose Drug Specimen/serum References

(no. of patients) drug concentration 1 concentration
(h) ratio

Ovary, oviduct, cervix uteri, 0.5-2 19lV 0.5-2.9 p.g/g a, b, e, f

corpus uteri, endometrium (25)

Portio vaginalis (17) 0.5-1 19 IV 3.3-3.4 p.g/g a, b

Ovary, oviduct, endometrium, :s; 0.75 2g IV 3.5-4.8 p.g/g

myometrium (17)

Cervix uteri, portio vaginalis (17) :s; 0.75 2g IV 5.3-5.8 p.g/g

Ovary, oviduct, uterus 2-4 2g IV 0.26-5.6 p.g/g e, g

Ovary, uterus, fallopian tubes (29) 0.3-1.15 2g IV 1.3-6.4 p.g/g d

Cord blood (19) 1.0 19lM 3.8p.g/ml 0.23,20.57, 1.0 h

at 1, 2, 3 hours

Amniotic fluid (19) 1-4 19lM 3.6p.g/ml 0.09, 0.3, 0.8 h

at 1, 2, 3 hours
1-4 19 IV 0.47-13 c
19lV 1.8-3.3

Milk (12) 2 19 IV 0.32 0.09 c

Fetal tissue
kidney; lung; serum (10) 1-4 19 IV 1.0-6.3; 0.5-6.3; c
0.9-6.53 c
kidney; lung; serum (4) 1.8-5 19lV 1.1-3.5; 0.8-1.5;
0.8-6.74

1 Concentration of cefotaxime and its active metabolites in nearly all instances.

2 Cord blood/maternal plasma concentration ratio.
3 Single dose.
4 Repeated doses.
5 Key to references: a = Ikeuchi et al. (1981); b = Ishii et al. (1981); c = Kafetzis et al. (1980); d = Kleinstein and Neubiiser
(1980); e = Ludwig et al. (1980); f = Miyamoto et al. (1981); g = Motomura et al. (1981); h = Pierre et al. (1981); i = Saito et
al. (1981).

4.2.1 Protein Binding 4.3 Elimination

When determined by ultracentrifugation and di-
alysis, protein binding of cefotaxime at therapeutic
concentrations is about 38% (Murakawa et al., 1980;
Neu et aI., 1979a). A value of 27% was reported
when agar diffusion was used to determine binding
(Neu et aI., 1979a).
4.3.1 Metabolism and Excretion
Cefotaxime is partially metabolized prior to ex-
cretion. The principal metabolite is the microbio-
logically active product, desacetyl-cefotaxime (Bax
et aI., 1980; Chamberlain et aI., 1980; Reeves et
 Cefotaxime: A Review 250

al., 1980b, White et al., 1980). Two other (inactive)
metabolites, M2 and M3 (isomers of desacetyl-
cefotaxime lactone in which the ,B-lactam ring has
been opened) [Coombes, 1982] are generally un-
detectable in serum of healthy subjects, but are
found in higher concentrations in patients with
renal failure (Reeves et al., 1980b). These metab-
olites are present in significant concentrations in
the urine of healthy subjects (Chamberlain et al.,
1980; Coombes, 1982; Ings et al., 1982; Reeves et
al., 1980b). At 15 minutes after an intravenous in-
jection of a single 800mg dose of 14C-cefotaxime,
81 % of plasma radioactivity represented un-
changed drug and 6%, desacetyl-cefotaxime. One
hour after injection, 42% of plasma radioactivity
was present as cefotaxime and 28% as desacetyl-
cefotaxime (Chamberlain et al., 1980).
Most of a dose of cefotaxime is excreted in the
urine. About 50 to 60% of an intravenous dose of
I or 2g is excreted as unchanged cefotaxime over

Table IX. Antimicrobial activity (cefotaxime plus active metabolites) in uninfected bone and interstitial (extravascular) fluid in
humans after single or repeated doses of cefotaxime

Specimen Time after Drug dose1 Drug concentration Reference

drug (h)

Bone
Spongy bone 0.5-1 2g IV (bolus) 5.41'9/g Wittmann et al. (198Oc)
1-2 2g IV (bolus) 4.41'9/g Wittman et al. (l98Oc)
2-4 19 x 41M < 0.5-1.8 "gIg Papathanassiou et al. (1980)
2g x 31M 3.3-15.4 "gIg
Cortical bone 0.5-1 2g IV (bolus) 5.4 "gIg Wittmann et al. (1980c)
1-2 2g IV (bolus) 2.1 "gIg Wittmann et al. (198Oc)

Cortical and spongy 0.5-3 2g IV 7.64 "g/ml3 Wittmann (1980a)

Compact bone 2g IV '" 3 "9/9 2 Rosin and Uphaus (1980)

Interstitial fluid (obtained by indicated method)

Suction blister 1 19lM 25 "g/ml4 Frongillo et al. (1981)
2 19lV 4 "g/ml 5 Bergan et al. (1982a)
4 1.6 "g/ml6 Bergan et al. (1982a)
Skin window 3 19lM 9 "g/ml Frongilla et al. (1980)
Skin chamber 19lM 11 "g/ml Frongillo et al. (1980)

Subcutaneously implanted 2g IV (infusion) 16.8 "g/ml

cotton threads

Blister fluid 19 IV (bolus) 7.2 "g/ml Wise et al. (1980b)

Tissue fluid secreted in 2-3 2g IV (bolus) 20.8 "g/ml Wittmann et al. (1980b)
postsurgical wounds

1 19 x 4 indicates that 19 was administered 4 times daily.

2 Absolute value.
3 Geometric mean.
4 All values for extravascular fluid are peak concentrations.
5 Concentration of cefotaxime itself at peak (determined by HPLC).
6 Concentration of desacetyl-cefotaxime at peak (determined by HPLC).
 Cefotaxime: A Review
a 24-hour period (Bax et al., 1980; Ho et at, 1980;
Luthy et at, 1981a,b; Neu et al., 1980). In addition,
about 24% of a dose is excreted in the urine as
desacetyl-cefotaxime. Most of the drug recovered
in the urine is excreted in the first 2 hours after
drug administration.
Total plasma clearance is reported to be be-
tween 260 and 390 ml/minute after intravenous or
intramuscular injection, and renal clearance be-
tween 145 and 217 ml/minute (Bax et at, 1980;
Luthy et at, 1981a,b). Renal clearance values re-
lated to body area varied from 104 to 122 ml/minj
1. 73m 2 after intramuscular administration of 500
or 1000mg (Fu et at, 1979), and from 130 to 154
ml/minjl. 73m 2 after intravenous administration
of 1000mg (Fu et at, 1979; Ho et at, 1980; Neu
et at, 1980). A significant decrease in total plasma
and renal clearance was noted by Luthy et at
(1981a,b) as the dose was increased from 500mg
to 2000mg, but this was not reported by Ho et at
(1980). The plasma clearance after the first dose of
intravenous cefotaxime was not significantly dif-
ferent from that after 14 days' treatment with Ig
6-hourly (Ho et at, 1980), but a significantly de-
creased fractional serum and renal clearance oc-
curred after 10 days' treatment with an intramus-
cular dose of 500mg 8-hourly (Neu et at, 1980).
Renal clearance is significantly decreased by the
concomitant administration of oral probenecid,
with a consequent increase in AVC (Bax et at,
1980; Luthy et at, 1981a,b).
4.3.2 Half-life
The mean elimination half-life of cefotaxime is
0.9 to 1.14 hours after intravenous administration
of single doses of 500 to 2000mg to healthy adults
(Bax et at, 1980; Fu et at, 1979; Ho et at, 1980;
Ings et at, 1982; Luthy et at, 1981a,b) and is not
altered after repeated doses (Ho et at, 1980). The
mean half-life is 1.2 and 1.34 hours following single
intramuscular doses of 500 and 1000mg, respec-
tively (Fu et at, 1979). Following administra-
tion of cefotaxime, the elimination half-life of des-
acetyl-cefotaxime in healthy subjects is reported to
251
be about 1.3 hours after bolus injection of 15 mgj
kg or 2000mg (Ings et al., 1982; Luthy et al., 1981 b).
However, after intravenous administration of the
metabolite itself, the half-life is less than 1 hour
(data on file, Hoechst). The half-life of desacetyl-
cefotaxime is markedly increased in patients with
severe renal dysfunction (section 4.5).
4.4 Influence of Age on Pharmacokinetics
The pharmacokinetics of cefotaxime have been
studied in neonates, infants and children and to a
limited extent, in elderly patients.
In neonates, the pharmacokinetics of cefotax-
ime are significantly influenced by gestational and
chronological age (Hashira et at, 1982; Hattingberg
et at, 1980; Heimann et at, 1980; Helwig, 1980a;
Kafetzis et at, 1982; Kobayashi et at, 1982) as well
as by birth weight (McCracken et at, 1982). In pre-
term and low birth weight neonates, the elimina-
tion half-life is prolonged relative to that of full
term (Hashira et at, 1982; Kafetzis et at, 1982) or
average birth weight neonates of the same age (table
X). The plasma clearance is decreased in preterm
and low birth weight neonates compared with full
term and average birth weight babies and infants,
and children (Heimann et at, 1980; Helwig, 1980a;
Kafetzis et at, 1982). High performance liquid
chromatography studies indicate that the plasma
concentration of desacetyl-cefotaxime varies con-
siderably between subjects, but in some instances
is equal to or exceeds that of cefotaxime 2 to 4
hours after intravenous injection (Kobayashi et at,
1982; Nishimura et at, 1982). The elimination of
the metabolite is somewhat slower than that of the
parent drug (Kobayashi et at, 1982).
The volume of distribution of cefotaxime under
steady-state conditions, is higher in the newborn
(0.31 to 0.35 Ljkg) than in adults (Luthy et at,
1981b).
In elderly patients (72 to 95 years) given 2g
cefotaxime by intravenous and intramuscular in-
jection, the elimination half-life of 2 to 2.5 hours
 Cefotaxime: A Review
Table X. Pharmacokinetics of cefotaxime in neonates according to gestational age and birthweight after intravenous admin-
istration of 25 to 50 mg/kg (data from Kafetzis et al.. 1982; McCracken et al.. 1982)
Population Elimination
half-life (h)
Preterm < 1 week 5.7
1-4 weeks 3.5
Full term < 1 week 3.4
1-4 weeks 2.0
low birthweight < 1 week 4.S
(1103 ± 216g)
Average birthweight < 1 week 3.3
(2561 ± S07g)
was longer than in younger adults (section 4.3.2).
The plasma clearance was 114 to 161 ml/minute
after intravenous injection (Miihlberg and Platt,
1982; Naber and Adam, 1980) and 148 ml/minute
after an equal intramuscular dose (Naber and
Adam, 1980). The mean plasma creatinine con-
centration in these patients was 140 ~mol/L.
4.5 Influence of Disease on
Pharmacokinetics
The pharmacokinetics of cefotaxime have been
studied in patients with varying degrees of renal
dysfunction, in patients with severe renal dysfunc-
tion and coexisting acute illness and in patients with
hepatic dysfunction.
As the pharmacokinetics of cefotaxime and its
principal metabolite desacetyl-cefotaxime differ to
a greater extent in patients with renal dysfunction
than in those with normal renal function, it is par-
ticularly important that pharmacokinetic studies in
patients with renal dysfunction employ assay
methods that provide data on both cefotaxime and
desacetyl-cefotaxime. Thus, only studies which have
used HPLC are discussed in this section.
In patients with severe renal dysfunction (cre-
atinine clearance < 10 ml/minute), the total plasma
clearance, renal clearance, and the urinary recov-
ery of unchanged cefotaxime is decreased. The
252
Volume of Plasma
distribution clearance
0.61l 1.37 ml/min
0.53l 1.79 ml/min
0.S8l 2.30 ml/min
0.S9l 4.45 ml/min
0.51 l/kg 23 ml/min/1.73m 2
0.44 l/kg 43.9 ml/min/1.73m 2
maximum plasma concentration is slightly or
moderately increased and the half-life increased to
about 2.5 hours (Ings et aI., 1982; Ohkawa and Ku-
roda, 1981; Usuda et aI., 1980, 1981; Wise et aI.,
1981). The extent of the increase in the half-life of
unchanged cefotaxime is slight compared with that
of cephalosporins such as cefuroxime, which is not
metabolised (Foord, 1976). The volume of distri-
bution of cefotaxime is not significantly altered in
severe renal dysfunction (Bergan et aI., 1982b; Fil-
lastre et aI., 1981; Ings et aI., 1982; Ohkawa and
Kuroda, 1981; Wise et aI., 1981).
Changes in the pharmacokinetics of desacetyl-
cefotaxime are more marked (table XI), with the
elimination half-life increasing to about 10 to 15
hours (Fillastre et aI., 1981; Ings et aI., 1982; Wise
et aI., 1981). A more marked increase in the elim-
ination half-life of both cefotaxime and desacetyl-
cefotaxime occurs in patients who have acute ill-
ness (e.g. heart failure, pulmonary oedema and
septicaemia) in addition to severe renal dysfunc-
tion (table 'XI) [Wise et aI., 1981].
Total urinary recovery of cefotaxime and des-
acetyl-cefotaxime decreases with reduction in renal
function. However, the ratio of urinary recovery of
desacetyl-cefotaxime to that of cefotaxime in-
creases with declining renal function. Thus, the
percentage of a dose recovered in the urine as the
metabolite exceeds that excreted unchanged in
patients whose creatinine clearance is below about
 Cefotaxime: A Review
10 mljminute (Ohkawa and Kuroda, 1981; Usuda
et aI., 1980, 1981).
The elimination of cefotaxime in severe renal
dysfunction is improved by haemodialysis, the half-
life decreasing from 2.5-3.4 to about 1.5 hours (Ings
et aI., 1982; Ohkawa and Kuroda, 1981; Usuda et
aI., 1980, 1981). The decrease in the half-life of des-
acetyl-cefotaxime (from 14 hours to 3 hours) is
more marked, however (Ings et aI., 1982). Al-
though cefotaxime is absorbed into serum when
given by the peritoneal route to patients under-
going peritoneal dialysis (Shurig, 1981), this is of
little value in increasing the elimination of the drug
(Wise et aI., 1981; Wright and Wise, 1980).
There is slight accumulation of cefotaxime fol-
lowing intravenous administration of Ig twice daily
to patients with creatinine clearances below lOmlj
minute (Wise et aI., 1981). However, desacetyl-
cefotaxime, M2 and M3 accumulated to a greater
extent than the unchanged drug (Ings et aI., 1982;
Wise et aI., 1981). Thus, the frequency of admin-
istration should probably be reduced in patients
with severe renal impairment.
The half-life of unchanged cefotaxime is not ap-
preciably influenced by the presence of liver dam-
age (Wise et aI., 1981). However, desacetyl-cefo-
taxime formation is markedly decreased in severe
liver damage (Wright and Wise, 1980).
5. Therapeutic Trials
Published studies on several thousand patients
worldwide have documented the efficacy of cefo-
taxime in treating a wide range of infections caused
by Gram-positive and Gram-negative aerobic bac-
teria, and occasionally anaerobic bacteria. Cefotax-
ime has been used in the treatment of urinary tract
infections, lower respiratory tract infections, bac-
teraemia/septicaemia, intra-abdominal, obstetric
and gynaecological infections, and in uncompli-
cated gonorrhoea, and in soft tissue infections.
Open studies have also been conducted in a smaller
number of adults with bone and joint infections,
253
endocarditis, meningitis, and in immunologically
compromised patients with suspected or proven
infection. Neonates, infants and children with vari-
ous bacteriologically confirmed infections - in-
cluding septicaemia, urinary tract, respiratory tract
and gastrointestinal infections, peritonitis and
meningitis - were treated with cefotaxime alone or
in combination with another antibiotic.
In published studies in adults, cefotaxime has
been compared with other cephalosporins, genta-
micin and sulbenicillin in treating urinary tract in-
fections, with cefazolin and cefoperazone in lower
respiratory tract infections, and with a combina-
tion of gentamicin plus clindamycin in peritonitis
and other similar soft-tissue infections. In addi-
tion, a single intramuscular dose of cefotaxime
alone or with oral probenecid has been compared
with procaine penicillin G plus probenecid in males
and females with uncomplicated gonorrhoea caused
by penicillinase-producing and non-producing
strains of Neisseria gonorrhoeae. In controlled
studies of perioperative prophylactic use of cefo-
taxime to reduce the incidence of infection in
patients undergoing various types of surgery, cefo-
taxime was compared with untreated controls and
with cefazolin. The usual total daily doses of cefo-
taxime studied in the treatment of established in-
fections were 2 to 6g in adults and 50 to 100 mg/
kg in children. The drug was given by intravenous
or intramuscular injection at 6-, 8-, or 12-hourly
intervals.
5.1 Treatment of Established Infections
5.1.1 Urinary Tract Infections
A large number of patients with urinary tract
infections, many of which were complicated by un-
derlying urological abnormalities, have been treated
with cefotaxime in open or controlled studies. Re-
sponse rates varied widely between studies, as did
the types of infection, presence of predisposing fac-
tors, definition of response, and time of assess-
ment. Hence, it is difficult to establish a 'usual'
 Cefotaxime: A Review
Table XI. Mean half-lives of cefotaxime and desacetyl-cefotaxime in patients with varying degrees of renal dysfunction following
single intravenous bolus injection of 19 or 0.5g of cefotaxime (after Wise et aI., 1981; Wright and Wise, 1980)
Renal function No. of Cefotaxime serum
(creatinine clearance; patients half-life
ml/min) (h)
> 100 4 1.0 (0.72-1.3)
30-100 3 1.3 (1.27-1.34)
10-30 6 1.9 (1.26-2.4)
3-10 9 2.6 (1.4-3.6)
Severe impairment 7 5.6 (2.2-11.5)
« 5) plus acute illness
response rate, even in patients with specific bac-
terial infections. Patients were usually treated with
between 1.5 and 6 gJday of cefotaxime alone, the
most common dosage being 19 l2-hourly for 5 to
10 days. Studies in a relatively small number of
patients with uncomplicated urinary tract infec-
tions gave bacteriological response rates of 87 to
100% after treatment with cefotaxime 2 gJday
(Graninger et al., 1981; Ludwig and Knebel, 1980).
Not unexpectedly, in patients with complicated
urinary tract infections the bacteriological response
to cefotaxime varied according to when patients
were assessed. On the last day of treatment urine
cultures were negative in 93 to 100% of73 patients
treated for 5 to 10 days with either 1.5 or 3 gJday
of intramuscular cefotaxime. One week later, ster-
ile urine was observed in about 60 to 70% of
patients; the original organism was re-isolated in
14 to 29%, and/or a different organism in 4 to 21 %
of cases (Madsen and Iversen, 1981). In this study,
complicated urinary tract infections were usually
due to a single pathogen, and a relatively high pro-
portion (28%) were Gram-positive. In another study
(Casellas et al., 1980), in which about half of the
patients had renal or ureteric obstruction, urine
from 97% of 30 patients was sterile 7 days follow-
ing the end of treatment (2 gJday for 5 days). Four
weeks later 59% of patients had no bacteriuria and
90% remained asymptomatic.
Overall, 70 to 90% of infecting strains of cefo-
taxime-sensitive Gram-negative organisms were
254
No. of Desacetyl-cefotaxime
patients half-life
(h)
3 1.5 (1.1-1.8)
2 6.6 (2-9.9)
6 10 (8.2-11.8)
4 30 (19.2-56.8)
eradicated from patients with complicated or un-
complicated urinary tract infections at the end of
treatment (Homer and Piper, 1981; Kawada et al.,
1980; Ludwig and Knebel, 1980) [tables XII and
XIV]. In general, E. coli, Klebsiella species, indole-
positive and -negative Proteus, Enterobacter and
Citrobacter species were eradicated more success-
fully than Pseudomonas and Serratia species (table
XII). Interestingly, in the study by Kawada et al.
(1980) in patients with complicated infections,
eradication rates were similar for bacteria (both
Gram-positive and -negative) with cefotaxime
MICs less than or equal to 25 ~gJml (76% eradi-
cated) and those bacteria resistant to cefotaxime
(MIC > 25 ~gJml) on in vitro testing (68%). No-
tably, 12 of 14 (86%) 'resistant' strains of Strepto-
coccus faecalis were eradicated by the end of 5 days'
treatment with cefotaxime. These responses pre-
sumably result from the high urinary excretion of
cefotaxime.
Although cefotaxime is active in vitro against fJ-
lactamase-producing strains of Gram-negative
organisms, little information is available on the
drug's clinical activity against these strains. How-
ever, in one small study (Portier et al., 1981), 8 of
10 patients with urinary tract infections caused by
fJ-lactamase-producing strains of Klebsiella species
(4), Proteus mirabilis (4), or E. coli (3), and who
also had underlying diseases, were successfully
treated with up to 50 mgJkgJday of intramuscular
cefotaxime.
 Cefotaxime: A Review
In a few studies which specifically reported
patients' clinical response to cefotaxime, about 90
to 97% of those treated with cefotaxime alone for
complicated or uncomplicated infections became
asymptomatic (Cassellas et aI., 1980; Ludwig and
Knebel, 1980) and/or showed improvement (Cox
and Simmons, 1982). Similar results (84 to 95% of
patients clinically cured) were reported in several
large reviews of data collated by the manufacturers
from studies conducted in Europe (including the
UK) and Latin America (Bax and Young, 1981;
Connelly, 1982; Young et aI., 1980). However, a
small proportion of these patients probably re-
ceived other antibiotics as well as cefotaxime.
The response of specific types of urinary tract
infection to cefotaxime has been reported in small
open studies. Paradisi et ai. (1982) used cefotaxime
to treat 30 hospitalised patients with urinary tract
infections which had not responded to prior anti-
biotics. Some patients also had underlying urinary
tract abnormalities. Those 'cured' clinically and
bacteriologically 2 weeks after the end of treatment
included 11 of 12 patients with acute cystitis, 4 of
5 with chronic or recurrent cystitis, all 9 with acute
pyelonephritis, but none of 3 patients with chronic
pyelonephritis. Daily doses of cefotaxime ranged
between 2 and 6g given 6- or 8-hourly, usually
intramuscularly, for 7 to 11 days. Ofthe 6 patients
with infections caused by cefotaxime-sensitive
Pseudomonas aeruginosa, 3 were cured, 1 relapsed
and 2 failed. The strains of P. aeruginosa isolated
from post-therapy specimens from the 2 failures
were apparently the same as the pre-therapy strains,
but were shown to be resistant to cefotaxime (by
the disc diffusion method).
Guibert et ai. (1981) reported negative follow-
up cultures 4 weeks after the end of treatment in
10 of23 patients (44%) with chronic pyelonephritis
and underlying urological pathology, in 8 of 12 cases
(67%) with uncomplicated cystitis and 11 of 18
cases (61 %) with cystitis associated with urological
abnormalities. Doses administered were 1.5 or 2 g/
day (range, 1 to 4 g/day) given intramuscularly. The
duration of treatment was longer than usual, rang-
255
ing from 7 to 28 days with a median of 18 days.
It is well known that catheterised patients with
urinary tract infections are more difficult to treat
than those without catheters, and this was also
shown to be the case with cefotaxime (Kawada et
aI., 1980; Ohkawa and Kuroda, 1980). Although
urinary catheters were used in some patients in
several other studies, rarely was the extent of such
usage and the response of these patients specifically
reported (Mogabgab et aI., 1982).
Some studies in urinary tract infection included
patients with impaired renal function, but response
to cefotaxime in this subgroup of patients was rarely
reported. However, Daikos et ai. (1980) reported
eradication of urinary pathogens (many of which
were multidrug-resistant) from 5 of 6 patients with
'renal failure' (not defined), 6 of 7 with kidney
stones, and from 3 patients requiring haemodialy-
sis. No side effects or toxicity were reported in these
patients, most of whom received 0.5g of cefotax-
ime 8-hourly (range 0.5 to 3 g/day).
Controlled Studies
Cefotaxime has been compared with various
other antibiotics used to treat urinary tract infec-
tions, in blinded and non-blinded studies. In 3 large
Japanese trials in complicated urinary tract infec-
tion (summarised in table XIII), response was based
on the assessment of bacteriuria and pyuria, prob-
ably at the end of treatment. Elimination of both
signs was classed as 'excellent', but a 'moderate'
response was very broadly defined (see footnotes
to table XIII). Significantly (p < 0.01) more patients
given intravenous cefotaxime 2 g/day, usually for
5 days, had excellent plus moderate responses
compared with those on cefazolin 4 g/day, ceftez-
ole 4 g/day or sulbenicillin 10 g/day (table XIII).
However, in patients assigned at random to treat-
ment with sulbenicillin, 55% of urinary organisms
were resistant to the drug (MIC > 200 ~gfml) and,
not unexpectedly, these organisms were less fre-
quently eradicated than were sulbenicillin-sensi-
tive organisms (Kawada et aI., 1980). Unfortu-
nately, the sensitivity (or resistance) of organisms
 Cefotaxime: A Review 256

Table XII. Frequency of eradication of bacteria during treat- urinary tract infection are summarised in table XIV.
ment of complicated urinary tract infections with cefotaxime Although the study by Madsen and Iversen (1981)
Bacteria No. of bacteria eradicated/
did not show a statistically significant difference
no. isolated (% eradicated) between cefotaxime and cefazolin in the treatment
in studies by of complicated urinary tract infections, this could
Kumazawa Kawada et al.
well be due to the small number of patients
et al. (1981)' (1980)2 studied.
Unpublished reports of small single- or double-
Gram-positive
blind studies mainly in hospitalised patients with
Staphylococcus epidermidis 4/4
Streptococcus faecalis / 3/5
acute cystitis or pyelonephritis indicated that cefo-
enterococcus taxime 2 to 4 gjday was more effective bacterio-
Streptococcus pyogenes 3/3 logically than the same dose of cefazolin, although
Other Gram-positive cocci 5/6 6/6 pathogens were sensitive in vitro to each drug
(Drennan, 1982; Mogabgab et aI., 1982). Similar
Gram-negative
Escherichia coli 17/17 28/34
results from large groups of patients were reviewed
Klebsiella species 2/2 12/14 by Madsen (1982), but unfortunately insufficient
Proteus mirabilis 4/4 information was provided to permit meaningful
Indole-positive Proteus 6/7 } 11/12 assessment of these results (e.g. dosage of cefazolin,
Enterobacter species 6/8 4/4 types of urinary tract infection treated and com-
Serratia species 13/21 7/15
Citrobacter species 9/10 3/4
parability of treatment groups were not specified).
Pseudomonas aeruginosa 10/17 4/11 Thus, although such studies suggest that cefotax-
Other Pseudomonas 4/6 ime may be more effective than cefazolin in the
Acinetobacter species 2/3 treatment of urinary tract infections, this needs
Total Gram-negatives 73/95 (77) 69/94 (73) confirming in a large well-designed and well-re-
ported study using appropriate dosages.
1 Patients had chronic complicated urinary tract infections
and were treated with cefotaxime 2 g/day intravenously for 5 or
In the study by Homer and Piper (1981), the
more days. Response was assessed on day 5. Sensitivity of initial pathogen was eradicated from bladder punc-
organisms to cefotaxime unknown. ture specimens in significantly more (p = 0.05)
2 Patients had complicated urinary tract infections, were patients treated with cefotaxime 2 g/day (83%) for
treated with cefotaxime 2 g/day intravenously for 5 days, and 3 days than with cefuroxime 2.25 g/day (56.5%).
assessed 'after treatment'. Results are presented for organisms
(isolated from midstream or catheter specimens) with cefotax-
However, a change in pathogen occurred during
ime MICs .. 25 ltg/mi. therapy in 2 patients in each group thus resulting
in 74% of cefotaxime patients and 48% of cefur-
oxime patients having sterile urine at the end of
to the antibiotics used in the other 2 studies (Ku- therapy. The statistical significance of this differ-
mazawa et aI., 1981; Ohkawa and Kuroda, 1980) ence was not reported. Regrettably, there was no
was not reported. Hence, in view of this, and the late follow-up in this study, nor in the studies by
manner in which response was assessed, results of Ludwig and Knebel (1980).
these studies should be interpreted with caution. These latter authors consider the bacteriological
Cefotaxime has also been compared with cef- response of urinary pathogens to cefotaxime 2 g/
azolin (Madsen and Iversen, 1981), cefuroxime day superior to that achieved with a relatively low
(Homer and Piper, 1981), cefoxitin and gentamicin dose of gentamicin (160 mgjday) in acute recurrent
(Ludwig and Knebel, 1980). Bacteriological re- and acute on chronic urinary tract infections, and
sponse rates in these studies in various types of superior to that with cefoxitin 3 g/day in uncom-
 Cefotaxime: A Review 257

Table XIII. Summary of controlled studies conducted in Japan in patients with complicated urinary tract infections treated with
intravenous cefotaxime (cefot). sulbenicillin (sulb). ceftezole (ceftz). or cefazolin (cefaz)

Reference Study design' Drug and No. of Response3 (% of patients)

(duration in daily dose patients
excellent moderate poor
days) (g) assessed 2

Kawada et al. (1980) Db. r. mc (5) Cefot 2 128 24 41 35

Sulb 10 133 20 24 56

Kumazawa et al. (1981) Mc (~5) Cefot 2 85 14 53 33

Ceftz 4 87 13 27 60
Ohkawa and Kuroda (1980) Db. r. mc (5) Cefot 2 131 27 40 33
Cefaz 4 133 16 26 58

Db = double-blind; r = randomised; mc = multicentre.

2 Presumably assessed on day 5 in all studies.
3 Response based on the assessment of bacteriuria and pyuria. Excellent = elimination of both signs; moderate = bacteriuria
eliminated and pyuria decreased or unchanged. or bacteriuria decreased and pyuria cleared. decreased or unchanged. or bacteriuria
replaced and pyuria cleared or decreased.

plicated, symptomatic urinary tract infections.
However, there was no information concerning
comparability of treatment groups in these 2 single-
blind, randomised studies and the results were not
analysed statistically.
5.1.2 Lower Respiratory Tract Infections
Cefotaxime has been studied in a considerable
number of patients with lower respiratory tract in-
fections, particularly pneumonia. Many patients
also had other conditions, some were elderly, and
some seriously ill. While most studies were con-
ducted in hospitalised patients, few indicated
whether respiratory infection was hospital- or com-
munity-acquired. Usually a daily dose between 2
and 6g of cefotaxime (alone) was given intramus-
cularly or intravenously in 2 to 4 divided doses for
7 to 14 days. In open and comparative studies, 75
to 100% of patients with pnemonia showed com-
plete resolution or improvement in clinical signs
and symptoms and chest radiographs at the end of
therapy (see below).
In open studies in 'difficult' patients (e.g. those
with underlying diseases such as chronic lung dis-
ease, alcoholism, ischaemic heart disease, or in the
elderly), some of whom were seriously ill, response
rates of 85 to 100% have been reported (Hanninen
et aI., 1980; Mullaney and John, 1982; Schleupner
and Engle, 1982). Most of such patients received a
dose of 4 to 6g daily given intramuscularly or intra-
venously for about 7 to 10 days. S. pneumoniae,
H. injluenzae and K. pneumoniae were isolated
most frequently from appropriate specimens (e.g.
transtracheal aspirates) and were readily eradicated
(Mullaney and John, 1982), but pulmonary super-
infection due to Pseudomonas species occurred in
4 patients who were being mechanically ventilated,
3 of whom died (Schleupner and Engle, 1982).
A few patients with empyema (Dolmann et al.,
1981; Goullon, 1980; Kemmerich, and Lode, 1981;
Mullaney and John, 1982) or a lung abscess (Dol-
mann et aI., 1981; Kemmerich and Lode, 1981;
Mullaney and John, 1982; Newsom et aI., 1981)
have been treated with cefotaxime in daily doses
of 3 to 8g. Most showed clinical improvement or
resolution.
In summarising results from studies conducted
in Europe and LatinAmerica, Younget al. (980)
reported that 81 % of 410 patients with various res-
piratory tract infections were cured clinically, 5%
relapsed and 14% failed. Over 80% of patients were
treated with 2 to 4 gfday of cefotaxime, but some
Table XIV. Summary of some controlled studies in patients with various types of urinary tract infections (UTI). Also see text (section 5.1.1) for discussion of additional
controlled studies ()

Reference Type of infection' Study Response Urine Drug,3 usual No. of Bacteriological response (% of bacteria) i3'
x
(no. of patients) design2 assessed specimen daily dose (g), bacteria
eradicated' relapsed persisted reinfected !1!
(duration (days and route isolated >
(original (different :Il
in days) post-
therapy)
pathogen) pathogen) '"ar<
~
Hoffler and UTI5 (18) + R Bladder Cefot 2 23 74 17 9
Piper (1981) uncomp. pyelon (25) + (3) puncture Cefur 2.25 23 48 43 9
compo pyelon (3)

Ludwig and Acute recurrent or Sb, r Midstream Cefot 21M 36 81 5.5 5.5 8
Knebel (1980) acute on chronic (10) or catheter Gent 0.16 1M 40 55 12.5 17.5 15
UTI (58)

Uncomp., Sb, r Not stated Cefot 2 1M 47 87 6.5 6.5

symptomatic (... )' Cefox 3 IV 43 72 14 14
UTI (69)

Madsen and Compo UTI (43) R8 79 Midstream Cefot 1.5 1M 28 71 25'0 '0 4
Iversen (1981) (5 to 7) Cefaz 3.0 1M 15 60 13'0 '0 27

1 Compo = complicated; uncomp. = uncomplicated; pyelon = pyelonephritis.

2 R = randomised; SB = single-blind (observer unaware of antibiotic used).
3 Cefot = cefotaxime, cefur = cefuroxime, gent = gentamicin, cefox = cefoxitin, cefaz = cefazolin.
4 Original organism(s) eradicated and urine remained sterile until post treatment assessment.
5 No renal parenchymal involvement.
6 Response assessed 'after treatment'; no other details given.
7 Not given.
8 Patients randomised to cefotaxime or cefazolin group in a ratio of 2 : 1.
9 Patients also assessed on the last day of treatment (urine sterile in 100% of cefotaxime and 93% of cefazolin patients).
10 Combined results for relapse and persistence of infection. I\)
C11
0>
 Cefotaxime: A Review
may have also received other antibiotics. Similarly,
in 2 multicentre studies in the UK, 82% of 103
patients (Bax and Young, 1981) and 90% of 103
patients (Connelly, 1982) with lower respiratory
tract infections were cured with cefotaxime alone
or in combination with other unspecified antibi-
otics.
Understandably, bacteriological response by
organism was reported only occasionally in patients
with respiratory tract infections. In the largest single
report (Perkins, 1982) which contained this infor-
mation (for 328 organisms), a satisfactory bacte-
riological response (organism eradicated or speci-
men unobtainable) occurred with over 95% of S.
pneumoniae and H. injluenzae isolates, about 90%
of S. aureus and E. coli and 70 to 80% of P. mir-
abilis, Enterobacter and Klebsiella species. Similar
results were reported by Young et ai. (1980).
Although Pseudomonas species have been iso-
lated from a few patients with respiratory tract in-
fections treated with cefotaxime (e.g. Dolmann et
ai., 1981; KrUger et ai., 1980; Maesen et ai., 1980;
McKendrick et ai., 1981; Miki and Shiota, 1980;
Mullaney and John, 1982; Okubadejo and Bax,
1982; Schleupner and Engle, 1982), there are in-
sufficient data on which to base conclusions, par-
ticularly regarding bacteriological response rates of
pseudomonal infections. Perkins (1982) reported
satisfactory bacteriological and clinical responses
in 5 and 9 patients, respectively, of 13 patients
treated with cefotaxime for lower respiratory tract
infections involving P. aeruginosa. Many, but not
all of these isolates were sensitive in vitro (MIC
range 0.08 to 200 ~g/ml, MIC 50 10 ~gfml).
In a brief report, Newsom et al. (1981) com-
mented that 4 patients with severe chronic bron-
chitis/bronchopneumonia due to ampicillin-resist-
ant (MIC ~ 16 ~g/ml) H. injluenzae were treated
successfully with intravenous cefotaxime Ig thrice
daily for at least 7 days.
Controlled Studies
Cefotaxime has been compared with cefazolin
(Jenkinson et ai., 1980; Miki and Shiota, 1980; Per-
259
kins, 1982) and cefoperazone (Kemmerich and
Lode, 1981) in lower respiratory tract infections.
In randomised controlled multicentre trials (Per-
kins, 1982) in hospitalised patients with bacterio-
logically confirmed lower respiratory tract infec-
tions, clinical response rates (by patient) with
cefotaxime (95%) and cefazolin (92.5%) were sim-
ilar in a 79-patient observer-blind study, but dif-
fered significantly (99% vs 92%, respectively; p =
0.03) in a single-blind study in about 200 patients,
two-thirds of whom received cefotaxime. Bacteri-
ological response rates were similar with each anti-
biotic in both studies (bacteria eradicated in about
96% of patients or sputum production resolved).
The specific types of infection treated in these
studies were not clearly specified. A summary of
dosage data from these patients plus 210 patients
treated with cefotaxime in an open study was pro-
vided and showed the mean dosage of cefotaxime
ranged from 4 to 6 gfday depending on the patient's
initial condition, and of cefazolin from 3 to 4 g/
day. The route of administration differed between
treatment groups in the single-blind triai.
In another comparative study, clinical response
with intravenous cefotaxime 4 g/day was similar
to that with the same intravenous dose of cefazolin
in 128 patients with mild to moderate pneumonia
complicated by underlying respiratory disease, and
in 90 patients with other respiratory tract infec-
tions such as infected bronchiectasis, 'infected lung
cancer', lung abscess, and infection associated with
chronic obstructive pulmonary diseases (fig. 2).
Bacteria (mainly Gram-negative bacilli) were iso-
lated from sputum in only 92 (42%) of all 218
patients in this multicentre randomised, non-
blinded, Japanese study (Miki and Shiota, 1980);
the bacteriological response was assessable in just
76 patients. At the end of treatment the putative
pathogen was eradicated from significantly more
patients in the cefotaxime group than in the cef-
azolin group (65% vs 39%).
Results from a small non-blinded study in
patients with uncomplicated pneumococcal pneu-
monia suggested cefotaxime 2 g/day intramuscu-
 Cefotaxime: A Review
larly was as effective clinically as cefazolin 1 gjday
intramuscularly; bacteriological response was not
assessed (Jenkinson et aI., 1980, 1982).
In a non-blinded, non-randomised study, intra-
venous cefotaxime 6 gjday appeared comparable
to intravenous cefoperazone 4 to 8 gjday (mean, 5
gjday) in patients with serious bronchopulmonary
and pleural infections such as pneumonia, acute
exacerbations of chronic bronchitis, and pleural
empyema. Complete resolution or clinical im-
provement occurred in 14 of 19 (74%) patients
treated with cefotaxime for an average of 12 days,
and in 16 of22 (73%) cefoperazone patients treated
for a similar period. Although most pre-treatment
bacterial isolates were Gram-negative bacilli,
organisms differed between the 2 groups: K. pneu-
Cefotaxime Cefazohn
Pneumonia (28 patients)
Fig. 2. Clinical response to intravenously administered cefotaxime 4 g/day or cefazolin 4 g/day by patients with pneumonia or
other lower respiratory tract infections (after Miki and Shiota, 1980).
260
moniae and E. coli predominated in cefotaxime-
treated patients, while P. aeruginosa, H. injluenzae
and Gram-positive cocci were isolated more fre-
quently from cefoperazone patients. Unfortu-
nately, bacteriological assessment was not reported
(Kemmerich and Lode, 1981; Lode et aI., 1980b).
Cefotaxime has been used successfully in treat-
ing acute purulent exacerbations of chronic bron-
chitis. In an inpatient study by Maesen et ai. (1980),
cefotaxime-sensitive H. injluenzae (43%) and S.
pneumoniae (22%) were the most common isolates
from sputum. Clinical and bacteriological response
in 27 patients treated with intramuscular cefotax-
ime 19 twice daily was excellent (78%) or good
(22%) at the end of 10 days' treatment; however,
22% of patients were reinfected 7 days later. In
• = excellent (rapid and complete remission)
o- good (complete remIssion)
o = faIr (partial remiSsion)
= poor (no improvement)
Cefotaxime Cefazolin
Other respiratClrf tract infectJ()(ls
(90 patients)
 Cefotaxime: A Review
similar groups of patients previously treated by
these investigators, clinical response rates (with
orally administered drugs) were lower with ampi-
cillin 3 gjday, and similar with amoxycillin 2.25 gj
day and bacampicillin 2.4 gjday, while recurrence
rates were higher with ampicillin and amoxycillin
and similar with bacampicillin to results achieved
with cefotaxime 2 gjday. Excellent results, with no
reinfections within 10 days, occurred in all 10
patients treated with 4 gjday of cefotaxime.
5.1.3 Bacteraemia/Septicaemia and
Endocarditis
Published reports on several hundred patients
indicate that cefotaxime has been used successfully
in the treatment of bacteraemia/septicaemia over
a wide dosage range (2 to 12 gjday). However, in
patients with normal renal function, the usual dose
was 3 or 6g daily for about 8 to 17 days. Many
patients had concomitant disease in addition to
septicaemia, which usually originated from the
urinary, respiratory or gastrointestinal tracts. Blood
samples from most patients grew a single species
of a cefotaxime-sensitive Gram-negative organism.
Cefotaxime was used alone in the treatment of most
patients, although a few also received another anti-
biotic, mainly on aminoglycoside, and such patients
usually responded favourably (Armengaud et aI.,
1980; Bastin et aI., 1981; Goulon et al., 1981; Le-
peu et aI., 1981; Portier et al., 1981). Occasionally,
patients who had not responded to other antibi-
otics were treated successfully with cefotaxime
(Bastin et al., 1981; Bruch and Blomer, 1980; Gou-
Ion et aI., 1981; Motin et aI., 1981), as were a few
patients with bacteraemia caused by organisms re-
sistant to other ~-lactam antibiotics (Neu and
Francke, 1982).
Reviews of data from bacteraemic/septicaemic
patients treated with cefotaxime alone in the USA
(Meyers, 1982; Neu, 1981), or the UK and Ireland
(Bax, 1982) reported very similar results. In patients
assessed according to strict criteria, Neu (1981) re-
ported that 91 % of 79 pathogens were eradicated
with cefotaxime (mean dose, 6 gjday), including 47
261
of 54 (87%) Gram-negative aerobes, all 16 Gram-
positive aerobes and the 2 anaerobic isolates. Single-
pathogen bacteraemias were eradicated in 94% of
65 assessable patients and multiple pathogen bac-
teraemias in 5 of 7 patients (79%). Bax (1982) re-
ported an overall bacteriological eradication rate of
83%, comprised of 51 of 58 (88%) Gram-negative
aerobes, 6 of 8 Gram-positive aerobes and 1 of 2
anaerobes. The response of those organisms iso-
lated most often from patients in these 2 reports
are presented in table XV. Bax (1982) also reported
that 85% of 78 assessable patients were cured
clinically, 4% relapsed and 11% failed. However,
some of the 7 patients classified as 'unassessab1e'
by the individual investigators could also have been
considered to be 'failures'. The commonest dosage
used was 19 8-hourly, although some severely ill
patients required double that dose.
In small individual studies in which patients
with bacteraemia were treated with cefotaxime
alone, bacteriological response rates between 80 and
100% were reported (McKendrick et aI., 1980b,
1981, 1982; Motin et al., 1981). Clinical response
rates in these studies tended to be lower than bac-
teriological response rates. For instance, 71 % of 17
patients in intensive care with severe Gram-nega-
tive infections (and other conditions) were clinic-
ally cured with 2 to 6 gjday of cefotaxime (Motin
et aI., 1981), as were 60% of 25 patients treated
with 3 or 4 gjday of cefotaxime (in most cases)
[McKendrick et aI., 1980b). In the latter study, the
clinical response in patients infected with Gram-
negative organisms (e.g. E. coli, Klebsiella aero-
genes, P. mirabi/is) was better than in those in-
fected with staphylococcal and streptococcal spe-
cies, although all organisms were eradicated from
the blood. It should be noted, however, that this
study included patients with endocarditis (4), ty-
phoid fever (2), osteomyelitis (1), and agranulo-
cytosis (1), who did not respond as well as those
in whom the primary diagnosis was intra-abdom-
inal sepsis (12) or renal tract infection (5).
The 4 patients with endocarditis in the above
study were treated with 1.5 to 3g daily of cefotax-
 Cefotaxime: A Review
ime alone. Blood cultures became sterile soon after
starting therapy in all patients; one (infected with
/1-haemolytic streptococci, Group G) was cured
clinically, one (with S. aureus) improved, and 2
(with E. coli or /1-haemolytic streptococci, Group
C) required urgent cardiac surgery. In other stud-
ies, a few patients with endocarditis due to E. coli,
P. aeruginosa, Branhamella catarrhalis (Neisseria
catarrhalis), S. aureus, Streptococcus durans (Ar-
mengaud et aI., 1980), viridans streptococci (Dai-
kos et aI., 1980; Niebel and Rinke, 1980), Serratia
liquefaciens (Bastin et aI., 1981), Serratia marces-
cens (Hyams et aI., 1981), Proteus mirabilis (Aznar
et aI., 1981), or Actinobacillis actinomycetemcom-
itans (Shah et aI., 1980) have been treated with 4
to 8 g/day or cefotaxime for prolonged periods,
often in conjunction with an aminoglycoside. Most
patients were cured clinically and/or bacterio-
logically.
5.1.4 Gonorrhoea
The excellent in vitro activity of cefotaxime
against penicillinase-producing and non-producing
strains of Neisseria gonorrhoeae has been corrob-
orated clinically in patients with uncomplicated
gonorrhoea. Although clinical efficacy against pen-
icillinase-producing strains is of greater interest with
a drug such as cefotaxime, most of the data avail-
able, particularly concerning comparative efficacy
and in the treatment of non-genital gonorrhoea,
pertain to non-penicillinase-producing strains.
Non-penicillinase-producing
Neisseria gonorrhoeae
A single intramuscular injection of cefotaxime
(0.5 to Ig) given to patients (most of whom were
male) infected with non-penicillinase-producing
strains usually yielded cure rates of 96 to 100%
(Backhaus and Myer-Rohn, 1980; Belli et aI., 1980;
Handsfield, 1982; Hard et aI., 1980; Hubrechts et
aI., 1980b; Lee and Ngeow, 1982; Panikabutra et
aI., 1982; Rajan et aI., 1980; Simpson et aI., 1981).
The most frequently used dosage was a single
intramuscular injection of Ig, but some patients re-
262
Table XV. Bacteriological response of the more common
organisms causing bacteraemia in patients treated with cefo-
taxi me (data after Bax, 1982; Neu, 1981)
Pathogen No. eradicated/
no. isolated (%)
Staphylococcus aureus 7/8 (88)
Streptococcus pneumoniae 5/5 (100)
Other streptOCOCCi 9/10 (90)
Escherichia coli 48/52 (92)
Klebsiella species 20/21 (95)
Proteus species 12/13 (92)
(indole-positive and -negative)
Serratia marcescens 8/9 (89)
Pseudomonas species 8/10 (80)
ceived a smaller dose plus probenecid Ig (Back-
haus and Meyer-Rohn, 1980; Panikabutra et aI.,
1982; Rajan et aI., 1980).
A single Ig dose of cefotaxime was as effective
as aqueous procaine penicillin G 4.8 million units
given in 2 intramuscular injections plus probene-
cid (1g orally) in treating patients with genital or
rectal infections caused by /1-lactamase-negative N.
gonorrhoeae (Handsfield, 1982; Handsfield and
Holmes, 1981; Lutz et aI., 1982; Simpson et aI.,
1981). In a non-blinded multicentre study con-
ducted in the USA (Handsfield, 1982), cefotaxime
and penicillin plus probenecid each cured 98% of
287 urethral or endocervical infections, and 96%
or 94%, respectively, of 41 rectal infections. Al-
though cefotaxime cured 8 of 11 (73%) pharyngeal
infections while penicillin plus probenecid cured
all 4 such infections, further studies are needed to
determine clearly the relative efficacy of cefotax-
ime in pharyngeal gonococcal infection. In most
centres, cefotaxime and aqueous procaine penicil-
lin G caused similar degrees of pain following in-
jection, but as only 1 dose of cefotaxime was re-
quired, this drug appeared to be better accepted by
patients and easier to administer. Similar efficacy
and tolerance data were reported from individual
centres in the USA (Handsfield and Holmes, 1981;
Simpson et aI., 1981).
 Cefotaxime: A Review
In one of the few studies which determined the
incidence of post-gonococcal urethritis following
cefotaxime therapy, Handsfield and Holmes (1981)
diagnosed this condition in 10 (43%) of23 men re-
examined 11 to 30 days following treatment; in 5
of these patients Chlamydia trachomatis was iso-
lated from the urethra. When seen within a week
of treatment, 2 of 50 patients given cefotaxime in
the study by Simpson et ai. (1981) had post-
gonococcal urethritis.
Penicillinase-producing Neisseria gonorrhoeae
Since other effective oral and parenteral anti-
biotics are available for the treatment of gonor-
rhoea caused by non-penicillinase-producing strains
of N. gonorrhoeae, the use of cefotaxime in treating
penicillinase-producing strains is of greater poten-
tial importance. From published data available so
far on a relatively small number of patients (about
150 in total), a single dose of cefotaxime (0.5 to Ig)
appears to be highly effective (98 to 100% re-
sponse) in the treatment of uncomplicated genital
gonorrhoea due to penicillinase-producing gono-
cocci (Boakes et aI., 1981; Egere et aI., 1982; Hard
et aI., 1980; Handsfield, 1982; Lancaster et aI., 1980,
1982; Lee and Ngeow, 1982; Panikabutra et aI.,
1982; Slack et aI., 1980).
A 98% cure rate was achieved by Rajan et ai.
(1980) in treating 13 males and 42 females (mainly
prostitutes in Singapore) who had genital or rectal
gonorrhoea, with a single 0.5g intramuscular dose
of cefotaxime plus Ig of probenecid orally. The only
failure was a female prostitute; the MIC of cefo-
taxime for her original infecting strain of N.
gonorrhoeae was ~ 0.016 ~g/mi.
In a Nigerian study, all 19 males with gonococ-
cal urethritis caused by penicillinase-producing
strains were cured with a single Ig dose of cefo-
taxime (Egere et aI., 1982). Similarly, a brief com-
munication from the UK indicated that all 33
patients treated with a single 0.5g dose of cefotax-
ime were cured, including 2 with oropharyngeal as
well as genital infections and one patient who had
not responded to treatment with spectinomycin
263
despite in vitro sensitivity of the strain to spec-
tinomycin (Boakes et aI., 1981).
Two studies compared the efficacy of cefotax-
ime, in a dose of Ig (Lancaster et aI., 1980) or 0.5g
plus oral probenecid (Panikabutra et aI., 1982), with
that of aqueous procaine penicillin G 4.8 million
units and probenecid Ig in the treatment of gono-
coccal urethritis in males. Because a mixture of
patients infected with penicillinase-producing and
non-producing strains of N. gonorrhoeae partici-
pated in these studies, cefotaxime was markedly
more effective than penicillin (overall response rates
of 94 to 100% vs 40 to 62%). All 41 patients (in
both studies) with penicillinase-positive strains were
cured with cefotaxime, compared with about 22%
of 60 who were treated with penicillin.
5.1.5 Obstetric and Gynaecological
Infections
In several studies in the treatment of obstetric
and gynaecological infections, cefotaxime 2 to 6 g/
day has been used successfully, with response rates
generally greater than 90% (Hemsell and Cun-
ningham, 1981; Hemsell et aI., 1982; Soutoul et aI.,
1980; Takase, 1981). In a summary of results from
172 evaluable cases studied at 31 institutions in
Japan, Takase (1981) reported clinical resolution
in 98% of 43 uterine infections, 94% of 51 cases of
adnexitis, 93% of 14 infections on external geni-
talia, 91 % of 57 pelvic infections and in all cases
of mastitis (4) and panperitonitis (3) treated with
cefotaxime (no data on dosage and duration given).
Patients who also underwent surgery (as part of
therapy) were included in these results, but no de-
tails were provided. 158 organisms were isolated
from 98 (57%) of the patients studied, and con-
sisted of Gram-negative (42%) and Gram-positive
(28%) aerobes or anaerobes (30%).
A retrospective analysis of 7 different antimi-
crobial regimens studied in various protocols by
the same group of investigators in more than 600
women with serious pelvic infections suggests that
cefotaxime 3 or 6g daily given intravenously is more
effective than parenterally administered penicillin
 Cefotaxime: A Review
G plus an aminoglycoside, and that cefotaxime 6g
daily is as effective as intravenously administered
clindamycin 2400mg daily plus gentamicin 3 mgf
kg/day in women with endomyometritis following
caesarean section (Hemsell and Cunningham, 1981;
Hemsell et ai., 1982). However, such findings have
not been confirmed in well-controlled studies.
In a small study in women with bacteriologi-
cally confirmed pelvic inflammatory disease, N.
gonorrhoeae was isolated from the cervix of 5
patients (2 of whom also had E. coli in culdocen-
tesis aspirates). Non-gonococcal aerobic and an-
aerobic bacteria were isolated from culdocentesis
aspirates taken from 11 others. Signs and symp-
toms completely resolved with 5 days of intraven-
ous cefotaxime therapy (3 or 6 gfday) in all 5
patients with gonococcal pelvic inflammatory dis-
ease and in 7 (64%) of those with non-gonococcal
pelvic infection. Two of the remaining patients im-
proved with cefotaxime 6 gfday, but were changed
after 5 days of therapy to another antibiotic. De-
spite a daily dose of 6g, 1 patient developed tubo-
ovarian abscesses following the end of therapy, and
the fourth remained febrile throughout the course.
The identity and sensitivity of organisms isolated
from these patients with partial or unsatisfactory
responses were similar to those treated success-
fully, as were serum concentrations 1 hour after the
first dose. Unfortunately, cultures were not done
for Chlamydia, which can playa role in pelvic in-
flammatory disease (Monson et ai., 1981).
5.1.6 Intra-Abdominal Injections
Cefotaxime has been used alone in the treat-
ment of patients with peritonitis and, to a lesser
extent, in treating biliary and hepatic infections.
Most patients with peritonitis, treated in a large
comparative study (Stone et ai., 1981) or in small
open studies (Berndt et ai., 1980; Goullan, 1980;
Wittmann et ai., 1980a), were cured clinically with
cefotaxime given intravenously in total daily doses
of about 4 to 6g. In many cases this was accom-
plished in conjunction with surgical treatment.
A non-blinded comparative study by Stone et
264
ai. (1981) demonstrated that cefotaxime 80 mg/kgf
day (i.e. usually about 6g daily) was as effective as
gentamicin (3 mgjkgfday) given in combination
with a relatively low dose of clindamycin (20 mg/
kg/day) to patients with peritonitis. Of 77 assess-
able patients given cefotaxime for 5 to 10 days,
85% were cured clinically, infection recurred in 10%
and in 5% treatment failed. Corresponding results
in 76 patients treated with gentamicin plus clin-
damycin were 82% cured, 14% recurred and 4%
failed. In addition to receiving antimicrobial
therapy, about 80% of all patients studied also
underwent an operative procedure. On analysing
clinical response by operative procedure, the
authors postulated that late or inadequate surgery,
rather than inferior antibiotic therapy, probably
contributed to many of the treatment failures. This
study also included another 75 patients with
polymicrobial soft-tissue surgical sepsis (see sec-
tion 5.1.7). The overall incidence and severity of
adverse reactions other than nephrotoxicity (see
section 6.3) was similar for both treatment groups.
The difference in mortality rates between treat-
ment groups was not statistically significant: 4 (3%)
cefotaxime-treated patients died (2 from uncon-
trolled sepsis) compared with 9 (7%) control
patients (including 3 from uncontrolled sepsis and
2 from superinfection).
In a review of chemotherapeutic principles of
the treatment of peritonitis, Wittmann (1980b)
commented that cefotaxime should be combined
with another antibiotic such as metronidazole,
clindamycin or piperacillin, in view of the rela-
tively few isolates of Bacteroides species inhibited
by achievable intraperitoneal drug concentrations.
Interestingly, in vitro sensitivity data from the study
by Stone et ai., (1981) suggested the antibiotic com-
bination of gentamicin and clindamycin was more
active than. cefotaxime alone, but both regimens
were equally effective clinically, as described above.
Although cefotaxime has been used in a small
number of patients with biliary, hepatic or pan-
creatic infections (Kasai et ai., 1981; McKendrick
et ai., 1981; Paris et ai., 1981; Wittmann et ai.,
 Cefotaxime: A Review
1980a), further data are required in order to assess
clearly the efficacy of the drug in treating these
conditions. Interestingly, Paris et al. (1981) re-
ported that cefotaxime 2 to 3g daily was tolerated
well, without adversely affecting liver function tests
in 8 patients with cirrhosis.
Results from a few patients treated with cefo-
taxime for typhoid fever (McKendrick et al., 1980b,
1981; Papadatos et aI., 1980; Shah et aI., 1980),
enteric fever (Rimmer, 1981) and enterocolitis
(Kalager et al., 1982), suggest that this drug is usu-
ally not effective in treating these infections caused
by Salmonella species, despite its good in vitro ac-
tivity in general against this genera. It has been
postulated that this situation, which has occurred
with other antibiotics, may be due to inadequate
intracellular penetration of the drug.
5.1.7 Skin, Soft-Tissue, Bone and Joint
Infections
Favourable results have been reported following
the use of cefotaxime in large (LeFrock and
McOoskey, 1982; McCloskey et al., 1982) and small
groups (Aznar et aI., 1981; Chandler et aI., 1982;
Clumeck et aI., 1981, 1982; Daikos et al., 1980;
Kalager et al., 1982; Karakusis et aI., 1982; Keaney
et al., 1982; Wittmann et al., 1980a) of patients
with infections of skin and subcutaneous tissues,
and in comparison with a· combination of genta-
micin and clindamycin (Stone et aI., 1981). A sat-
isfactory clinical response (cure and improvement)
occurred in 86 to 100% of those patients, many of
whom also underwent surgical procedures.
In summarising manufacturer's data on up to
260 hospitalised patients treated in the USA with
cefotaxime for bacteriologically confirmed wound
infections of the skin and subcutaneous tissue such
as cellulitis, abscess or necrotising ulcers, Mc-
Closkey et al. (1982) found the mean daily dose
used was 4g (range 1.4 to 12g). Cefotaxime was
usually given by intravenous infusion 3 or 4 times
daily for a minimum of 5 days and surgical pro-
cedures (mainly debridement and drainage) were
performed whenever indicated. Infection in 94% of
265
260 clinically evaluable patients improved or com-
pletely cleared, while treatment was successful bac-
teriologically (pathogen eradicated or wound/le-
sion healed with no follow-up cultures possible) in
84% of 225 evaluable patients. Bacteriological suc-
cess rates for the more frequently reported patho-
gens (single and mUltiple combined) were about
70% for P. aeruginosa and enterococci, about
85% for Enterobacter species and indole-positive
Proteus species and over 90% for S. aureus, S. ep-
idermidis, Groups A and B' streptococci, E. coli, P.
mirabilis, Klebsiella and Bacteroides species.
Clinical success rates by organism tended to be
higher.
A comparative study by Stone et al.(1981) in-
cluded 75 patients with polymicrobial soft tissue
surgical sepsis in addition to a large group of
patients with peritonitis (previously discussed in
section 5.1.6). Similar clinical response rates were
achieved with intravenous cefotaxime 20 mg/kg 6-
hourly and with a combination of gentamicin 1 mgf
kg 8-hourly and a relatively low dose of clinda-
mycin (5 mgfkg 6-hourly) in 45 patients with deep
soft-tissue sepsis (86% vs 83% cured), and in 30
patients with perirectal abscess (100% vs 89%
cured). Interestingly, each of the 4 'failures' had
sites of infection that had only been drained or de-
brided, whereas radical excision (when possible)
consistently provided either a permanent cure or a
more easily controlled recurrent sepsis.
Clinical experience with cefotaxime in the treat-
ment of 55 patients with serious bone and joint
infections such as osteomyelitis, septic arthritis and
bursitis has been summarised from manufacturer's
data by LeFrock and Carr (1982). Additionally, a
number of individual reports on studies with cefo-
taxime have included a few patients with postop-
erative or post-traumatic bone and joint infections
(Berndt et al., 1980; Dutoy and Wauters, 1980), or
osteomyelitis caused by Enterobacteriaceae (Clu-
meck et aI., 1982; Daikos et al., 1980; Fabricus and
Riegel, 1980; Francke and Neu, 1981; Harle, 1980;
KrUger et aI., 1980; McKendrick et aI., 1981; Witt-
mann et aI., 1980a), Pseudomonas aeruginosa (Ka-
 Cefotaxime: A Review
rakusis et aI., 1982; McKendrick et aI., 1981), or
Gram-positive aerobes (Fabricus and Riegel, 1980;
Wittmann et aI., 1980a). However, in view of the
limited data often available for such patients in
these studies, results reported by Mader et ai. (1982)
are of particular interest.
Their open study in 43 evaluable patients with
osteomyelitis found that high doses of cefotaxime
plus aggressive debridement surgery yielded fa-
vourable results. Osteomyelitis was arrested (ac-
cording to clinical criteria) on completion of therapy
and on follow-up examination about 6 months later
(range 0 to 17 months) in 15 of 16 patients (94%)
with acute infection and in 24 of27 patients (89%)
with chronic infection unsuccessfully treated with
other antibiotics. Similar clinical response rates
were achieved in patients with chronic osteomye-
litis from whom 1 aerobic species was isolated (9
of 10 arrested), more than 1 aerobic species was
isolated (8 of 9 arrested) or mixed aerobic and an-
aerobic pathogens were isolated (7 of 8 arrested),
usually by bone biopsy. Acute or chronic osteo-
myelitis was arrested in 20 of 22 (91 %) of patients
infected with the predominant pathogen, S. aureus,
12 of 13 (92%) infected with other Gram-positive
bacteria, all 15 with Enterobacteriaceae, 6 of 7 with
Pseudomonas species (MICs of 0.1 to 25 ~g/ml)
and all 13 infected with anaerobes. The usual dose
of intravenous cefotaxime was 2g given 4- or 6-
hourly (average dose, 9 g/day) for about 5 weeks
(range, 3 to 8 weeks). Most patients with chronic
osteomyelitis subsequently took oral antibiotics for
1 to 3 months. Some patients also received hyper-
baric oxygen therapy.
5.1.8 Infections in Immunologically
Compromised Patients
Cefotaxime has been used to treat suspected or
proven infections in granulocytopenic patients (Bint
et aI., 1980; Guy et aI., 1981; Karakusis et aI., 1982;
Preiss, 1980) and in cancer patients whose hae-
matological profile was not reported (Cone et aI.,
1.981). In the latter study, 28 of 40 patients (70%)
with pneumonia (16), fever of unknown origin (8),
266
bacteraemia (7), urinary tract infections (6), or soft-
tissue infections (3), were cured with cefotaxime
given alone in 1 to 2g doses every 4 to 6 hours.
Treatment was successful in 8 of 10 patients in-
fected with Gram-positive cocci, 10 of 16 with
Gram-negative bacilli and 10 of 13 from whom no
pathogen was isolated.
A slightly higher response rate (80%) was ob-
tained in 30 acute leukaemic patients with thera-
peutically induced bone marrow aplasia who were
treated with cefotaxime 240 mg/kg/day plus ami-
kacin 15 mg/kg/day (given 6-hourly by intraven-
ous infusion) for fever of unknown origin (13), sep-
ticaemia (11), perianal abscesses (4) or lung disease
(2). The predominant pathogens were S. epider-
midis (4), s. aureus (2), E. cloacae (4) and P. aeru-
ginosa (2), most of which were eradicated. How-
ever, 9 (37.5%) of 24 patients treated successfully
developed new infections during treatment with
cefotaxime for a mean period of 14 days. Group
D streptococci (7) and P. aeruginosa (2) were iso-
lated from stool specimens of such patients and B.
fragilis (1) from a perianal fistula (Guy et aI., 1981).
5.1.9 Infections Caused by Multiresistant
Bacteria and Pseudomonas species
Cefotaxime has been used successfully in the
treatment of serious infections due to multiresist-
ant Gram-negative organisms (Oumeck et al., 1981,
1982; Daikos et al., 1980; Dureux et aI., 1981;
Francke and Neu, 1981; Shah et aI., 1979c, 1980;
Van Laethem et aI., 1981). A few patients with in-
fections (usually bacteraemia or urinary tract in-
fections) caused by Klebsiella species (Daikos et aI.,
1980; Dureux et aI., 1981; Francke and Neu, 1981),
E. coli (Daikos et aI., 1980), Serratia (Dureux et
aI., 1981), Enterobacter and Proteus species (Dai-
kos et aI., 1980), Francke and Neu, 1981) resistant
to one or more of cephalothin, cefuroxime, genta-
micin or carbenicillin, were usually cured with
cefotaxime (alone) in dosages of 1.5 to 6 g/day. Of
particular importance, Karakusis et ai. (1982) re-
ported that 10 of 13 patients infected with strains
of Serratia marcescens resistant to all commer-
 Cefotaxime: A Review
cially available antibiotics, including amikacin, re-
sponded favourably to high doses (8 to 12 g/day)
of cefotaxime.
Because cefotaxime has shown some in vitro ac-
tivity against P. aeruginosa (see section 1.1.2), its
clinical efficacy against this pathogen is of partic-
ular interest. However, from published data it is
difficult to determine clearly the effect of adequate
doses of cefotaxime, given alone or in combination
with other antibiotics, on patients infected with this
organism. Results from a small number of patients
treated with cefotaxime alone for various infec-
tions caused by P. aeruginosa (Aguirre et ai., 1981;
Karakusis et ai., 1982; McKendrick et ai., 1981;
Wittmann et ai., 1980a,b) or Pseudomonas species
(Francke and Neu, 1981; Lepeu et ai., 1981) tend
to suggest that treatment was effective clinically and
bacteriologically in only about half of these patients.
However, many received daily doses less than the
6g minimum recommended for cefotaxime-sensi-
tive Pseudomonas species. In addition, some
organisms were not sensitive on in vitro testing,
while for others sensitivity data was not provided.
Interestingly, higher response rates (70% bacterio-
logical success, 87% clinical success) were reported
following treatment with cefotaxime (dosage not
specified) in 23 patients with infections of skin or
subcutaneous tissue attributed to P. aeruginosa
alone or in combination with other organisms
(McCloskey et ai., 1982).
In a review by the manufacturer of a large num-
ber of patients, 52% of 147 isolates of Pseudomo-
nas species were eliminated. However, these re-
sults included 'a small number of patients' who
were receiving other antibiotics in addition to cefo-
taxime (Young et ai., 1980). Hence, the efficacy of
cefotaxime for the treatment of pseudomonal in-
fections has not been clearly established, and thus
at this stage cetofaxime could not be recommended
as the sole therapy for such infections.
5.1.10 Meningitis in Children and Adults
Cefotaxime can be considered for the treatment
of meningitis because in addition to entering cere-
267
brospinal fluid of adults and children with in-
flamed meninges (see section 4.2), low concentra-
tions of this antibiotic are bactericidal for most
organisms which cause this condition, such as H.
influenzae, N. meningitidis, S. pneumoniae, group
B streptococci, E. coli and Klebsiella species. Hence,
patients of all ages have been treated with cefotax-
ime for meningitis, although most experience to
date has been in neonates and infants up to 2 years
old.
Several papers have summarised clinical expe-
rience in children with meningitis (Belohradsky et
ai., 1980; Roos et ai., 1980), and in patients of all
ages, particularly those with Gram-negative bacil-
lary meningitis (Cherubin et ai., 1982; Landesman
et ai., 1981 b). Results from the largest group of
patients reported to date (l00 children and 27
adults) indicated that cefotaxime alone or in com-
bination with other unspecified antibiotics was
highly successful in the treatment of meningitis
caused by the 3 major meningeal pathogens, N.
meningitidis, H. injluenzae and S. pneumoniae
(98% of 55 patients cured), and by E. coli and Kleb-
siella species (96% of 37 patients cured). Although
one-quarter of these patients (mainly those who
entered early in the study) received concomitant
antibiotics, their response rates are said not to have
differed from those receiving cefotaxime alone.
Neonatal meningitis, caused predominantly by
Enterobacteriaceae, was usually treated success-
fully with cefotaxime alone (Borderon et ai., 1981 a;
Kobayashi et ai., 1981b) or in combination with
other antibiotics such as amikacin (Belohradsky et
ai., 1980; Kafetzis et ai., 1982). The dosage of cefo-
taxime used in this relatively small group of patients
varied widely from 70 to 300 mg/kg/day given at
4-,6-, or 8-hourly intervals. Borderon et ai. (l981a)
reported curing 4 cases of neonatal meningitis, due
to cefotaxime-sensitive E. coli, P. mirabilis, En-
terobacter cloacae and S. marcescens, with cefotax-
ime 200 mg/kg/day given 6 hourly for 3 weeks.
Drainage was also used in 2 of these patients, who
had ventriculitis and either hydrocephalus or cere-
bral abscesses.
 Cefotaxime: A Review 268

Table XVI. Summary of results of treating meningitis in children (including neonates and infants), according to the causative
organism, with cefotaxime alone (monotherapy) or combined with another antibiotic such as an aminoglycoside, chloramphenicol
or ampicillin (data after Belohradskey et aI., 1980; Borderon et al., 1981 a; Kobayashi et al., 1981 b)

Pathogen Monotherapy Combination therapy

no. successful/no. treated no. successful/no. treated

Gram-positive
Streptococcus pneumoniae 1/2
Group B streptococcus 1/1
a-Haemolytic streptococcus 0/1
Staphylococcus epidermidis 2/3

Gram-negative
Haemophilus influenzae 10/10 2/2
Haemophilus parainfluenzae 1/1
Escherichia coli 5/5 1/1
Klebsiella species 1/1 1/2
Enterobacter species 1/1 0/1
Proteus mirabilis 1/1
Serratia marcescens 1/1
Salmonella panama 1/1
Pseudomonas aeruginosa 0/1 1/1
Neisseria meningitidis 1/1

In another study (Kafetzis et aI., 1982), 5 of 7
cases of neonatal meningitis (2 E. coli, I S. mar-
cescens, I P. aeruginosa, I group B streptococci)
treated with cefotaxime 80 to 200 mg/kg/day plus
amikacin or penicillin were cured. Treatment with
cefotaxime and gentamicin failed in I neonate with
meningitis and ventriculitis due to P. mirabilis.
Another neonate with ventriculitis improved
clinically with cefotaxime alone, and Klebsiella
species was eradicated. All 7 of these neonates had
been treated unsuccessfully with gentamicin plus
ampicillin or penicillin.
A small number of infants and children with
bacteriologically confirmed meningitis have also
been treated successfully with cefotaxime alone
(Belohradsky et aI., 1980; Borderon et aI., 1981a;
Helwig and Daschner, 1982; Kobayashi et aI.,
1981b) or in combination with an aminoglycoside,
ampicillin, penicillin or chloramphenicol (Beloh-
radsky et aI., 1980; Papadatos et aI., 1980). Dosages
used were similar to those in neonates. Haemo-
philus influenzae, the predominant pathogen, was
successfully eradicated from cerebrospinal fluid
with cefotaxime alone in all of 10 patients studied
by Borderon et ai. (198Ia) and Kobayashi et ai.
(198Ib), including 1 infant infected with an am-
piciiIin-resistant strain. Treatment was also effec-
tive against various other pathogens (table XVI)
[Roos et aI., 1980].
Although some children with meningitis plus
complicating factors such as the presence of shunts
or ventriculitis and hydrocephalus did not respond
to treatment with cefotaxime, alone or in combin-
ation, others made a complete recovery (Borderon
et aI., 1981 a; Kafetzis et aI., 1982; Kobayashi et aI.,
1981 b; Ludwig and Wille, 1980). If sequelae oc-
curred following treatment, these tended to be in
patients with underlying conditions or in some of
those in whom the use of effective treatment was
delayed, e.g. through the use of other antibiotics
(Belohradsky et aI., 1980; Borderon et aI., 1981a;
Kobayashi et aI., 198Ia,b). Indeed, many of the
 Cefotaxime: A Review
children successfully treated with cefotaxime plus
another antibiotic had failed to respond to prior
treatment with 2 or more antibiotics (Belohradsky
et al., 1980; Kafetzis et al., 1982). In addition, a
few organisms (such as H. influenzae and Staph-
ylococcus epidermidis) shown to be resistant to
other antimicrobial agents were successfully treated
with cefotaxime (Belohradsky et aI., 1980; Borde-
ron et al., 1981a).
Treatment of a few adults with bacterial men-
ingitis has nearly always been successful using cefo-
taxime alone or combined with various other anti-
biotics (Bruckner et al., 1982; Dureux et al., 1981;
Fernandez-Guerrero et al., 1982; Francke and Neu,
1981; Landesman et aI., 1981b; Motin et al., 1981;
Shah et aI., 1980), although an occasional relapse
has been described (Bradsher, 1982; Iannini and
Kunkel, 1982). The drug has sometimes been used
to treat pneumococcal meningitis, e.g. in penicil-
lin-allergic patients (Bruckner et al., 1982; Shah et
al., 1980), but in most cases adults treated with
cefotaxime had cerebrospinal fluid infected with
Gram-negative enteric bacilli, particularly Klebsi-
ella species.
Some of the adults treated with cefotaxime had
meningitis due to drug-resistant organisms. For in-
stance, Francke and Neu (1981) reported curing 2
adults with meningitis caused by multiresistant
Klebsiella pneumoniae using cefotaxime alone in
an initial daily dose of9 or 12g, given 4-hourly for
21 or 28 days. A case of postoperative meningitis
due to carbenicillin-resistant P. aeruginosa plus a
multiresistant strain of K. pneumoniae was suc-
cessfully treated with a combination of cefotaxime,
azlocillin and gentamicin (Shah et al., 1979a; 1980).
Dureux et ai. (1981) also reported curing a patient
with meningitis and septicaemia caused by a multi-
resistant strain of Klebsiella species, using cefotax-
ime plus tobramycin.
5.1.11 Other Paediatric Infections
Cefotaxime is very active in vitro against most
bacteria which commonly cause infections in
children, such as the Enterobacteriaceae, H. influ-
269
enzae (ampicillin-sensitive and -resistant strains),
S. pneumoniae and group B streptococci. Hence,
this drug has been used in open studies to treat a
variety of infections in several hundred children
(including infants and neonates), but no controlled
studies have been reported to date. Most patients
suffered from serious infections, many of which had
not responded to prior antibiotic treatment (Bruch
and Blomer, 1980; Kafetzis et al., 1981, 1982). The
dosage of cefotaxime was usually between 50 and
100 mg/kgJday, although occasionally total daily
doses of 150 to 300 mg/kg have been administered
without untoward clinical or biochemical effects
(Gamier and Giraud, 1981; Gekle et al., 1980; Ka-
fetzis et aI., 1982; Ramirez et al., 1982). The fre-
quency of administration varied from 1 to 4 times
daily.
Following analysis of case reports on 129 child-
ren treated with cefotaxime alone in trials in Euro-
pean and Latin American countries, Young et ai.
(1980) reported that 95% were cured clinically, 1%
had a relapse and 4% were considered to be fail-
ures. Response rates varied from about 90% for
those with septicaemia (26 assessable cases), gas-
trointestinal (29) or multiple (15) infections, to
100% for infections of the respiratory (26) and
urinary (13) tracts, or other sites (20).
Similar results from smaller groups of patients
were reported in more detail by Aufrant et ai.
(1981), Kafetzis et ai. (1981, 1982) plus co-worker
Papadatos et al. (1980). All but 1 patient treated
in these studies had bacteriologically confirmed in-
fections caused by organisms sensitive to cefotax-
ime, predominantly Gram-negative bacilli. Thus,
Kafetzis et al. (1981) administered cefotaxime 25
mg/kg 6-hourly, usually by intravenous injection,
to 33 seriously ill infants and children (aged 5
months to 12 years) with peritonitis (11), pneu-
monia (5), urinary tract infection (4), septicaemia
(2), osteomyelitis (2), infected bums (2), liver ab-
scess (2), infected hydatid cyst (3) and other infec-
tions (2), usually due to Gram-negative bacilli. Al-
though most patients (70%) had been treated
unsuccessfully with other antibiotics, 85% were
 Cefotaxime: A Review
cured clinically with cefotaxime alone and 12% im-
proved. Bacteria were eradicated from all but 2 of
the patients (94%), both of whom were infected with
P. aeruginosa and Proteus species.
Kafetzis et al. (1982) also treated 32 neonates
(l8 of whom were preterm) with cefotaxime alone
(75 to 100 mg/kg/day), or in combination with an
aminoglycoside or penicillin, and followed them
up for at least 1 month. 16 of 18 patients (89%)
treated with cefotaxime alone for septicaemia (10),
urinary tract infection (2), pneumonia with cystic
fibrosis (1), omphalitis (2) or cellulitis (1) were
cured; the other 2 patients improved (I with men-
ingitis plus ventriculitis due to Klebsiella species
and 1 with septicaemia). All pathogens were erad-
icated, most of which were Gram-negative bacilli
(e.g. E. coli, Klebsiella species, P. aeruginosa and
S. marcescens). Prior to receiving cefotaxime many
of these neonates had been treated unsuccessfully
with a combination of antibiotics such as genta-
micin and ampicillin.
In another study in infants and children with
severe Gram-negative infections and associated
conditions (Aufrant et al., 1981), treatment with
cefotaxime 50 to 100 mg/kgfday given 8-hourly was
effective clinically and bacteriologically in 4 in-
fants with respiratory tract infection who were being
ventilated, 2 with otitis media plus renal failure
and 3 children with severe urinary tract infections.
In this study the predominant pathogen, H. influ-
enzae, was isolated by tracheal aspiration or lung
puncture.
Cefotaxime combined with an aminoglycoside
has also been used to treat a small number of pae-
diatric infections in several other studies (Aufrant
et al., 1981; Blomer et al., 1981; Kafetzis et al.,
1982; Marget et al., 1978), some of which included
children with leukaemia (LOpez et al., 1980; Peters
et al., 1980). Such treatment has usually been well
tolerated, as was cefotaxime used alone in paedia-
tric patients.
Similar response rates to those above (i.e. over
85% of patients clinically cured) have been achieved
in studies in which many infections in children,
270
particularly those of the respiratory tract, were not
confirmed bacteriologically (Gamier and Giraud,
1981; Gekle et al., 1980; Helwig, 1980a,b).
5.2 Prevention of Infection in Surgery
In some countries cefotaxime is approved for
perioperative use to reduce the incidence of post-
operative infections in patients undergoing con-
taminated or potentially contaminated surgical
procedures (e.g. vaginal and abdominal hysterect-
omy, gastrointestinal and genitourinary surgery),
and in women undergoing caesarean section (when
the drug is administered after the umbilical cord
is clamped). Studies in cardiac surgery (Adam and
Struck, 1982; Regensburger and Podszus, 1982) and
controlled studies comparing the prophylactic ef-
ficacy of cefotaxime with untreated controls in gen-
itourinary (Hargreave et al., 1982; Schalkhauser and
Fegg, 1981) and colonic surgery (Germann and
Hottenrott, 1982; J ostamdt et al., 1981), with cef-
oxitin in colonic surgery (Anders et al., 1982) and
with cefazolin in genitourinary surgery (Childs et
al., 1981, 1982; Iversen and Madsen, 1982), co-
lonic or rectal surgery (Jagelman et al., 1982), sur-
gery for penetrating abdominal trauma (Fabian et
al., 1982), vaginal or abdominal hysterectomy (Roy
and Wilkins, 1982; Wideman and Matthijssen,
1982) or emergency caesarean section (Louie et al.,
1982) have been reported.
Cefotaxime was usually administered in Ig doses
perioperatively (e.g. within 90 minutes before sur-
gery, 2-hourly during surgery and once immedi-
ately following surgery), or perioperatively (as
above) and for 24 hours postoperatively (lg 6- or
8-hourly). Used in this way, cefotaxime was re-
ported to have a favourable effect on postoperative
infection rates following various types of surgery
(Fabian et al., 1982; Iverson and Madsen, 1982;
Jagelman et al., 1982; Wideman and Matthijssen,
1982).
One study, in patients undergoing prostatec-
tomy by transurethral resection (Hargreave et al.,
 Cefotaxime: A Review
1982), reported a significant reduction in postop-
erative sepsis and other complications with cefo-
taxime (four 0.5g doses within a 48-hour period)
compared with untreated controls. As might be ex-
pected considering the small treatment groups
studied (usually about 30 patients per regimen),
none of the studies which compared cefotaxime
given perioperatively and/or for 24 hours postop-
eratively with an equal dose of cefazolin given peri-
and postoperatively showed a statistically signifi-
cant difference in postoperative infection rates. Re-
sults of the study by Anders et ai. (1982) which
compared cefotaxime with cefoxitin in patients
undergoing colonic surgery were not analysed sta-
tistically.
6. Side Effects
Cefotaxime has generally been well tolerated by
adults and children (including neonates and in-
fants) following intravenous or intramuscular
administration. The drug's side effect profile, which
closely resembles that of other cephalosporins
(Smith, 1981, 1982), includes in particular, local
reactions at the injection site, rash and diarrhoea.
Occasional variations in laboratory test results have
occurred with cefotaxime but significant deterior-
ation in renal function directly attributable to cefo-
taxime has not been reported. As with other broad
spectrum antibiotics, superinfection has occurred,
particularly in seriously ill patients.
Reviews of the safety and efficacy of cefotax-
ime, sometimes in combination with other anti-
biotics, in large groups of patients (from 300 to
4000) have been reported (Bax and Young, 1981;
Bruch and Blomer 1980; Childs and Kosola; Con-
nelly, 1982; Smith, 1982; Yakabow and Wood,
1982; Young et aI., 1980). The overall incidence of
adverse effects in over 2000 patients was 10%
(Childs and Kosola; Yakabow and Wood, 1982),
while the incidence of side effects considered to be
drug-related was stated as 5 to 8% in other series
of patients (Connelly, 1982; Young et al., 1980).
271
Cefotaxime was discontinued in 1 to 2% of patients
(Childs and Kosola; Connelly, 1982; Smith, 1982;
Yakabow and Wood, 1982).
6.1 Local Reactions
Thrombophlebitis has occurred in about 5% of
patients treated with intravenous cefotaxime (Bax
and Young, 1981; Smith, 1982; Wittmann et aI.,
1980a,b). Although this is a relatively low inci-
dence for a cephalosporin, there is some evidence
to suggest that it may be higher than that which
occurs with cefazolin (Smith, 1982). However,
cefotaxime was rarely discontinued for this reason
(e.g. in less than 0.1% of patients) [Smith, 1982].
The incidence and severity of pain on intramus-
cular injection of cefotaxime was mild in 27%,
moderate in 4.5% and severe in 0.4% of889 patients
(Smith, 1982). In controlled studies, pain with
intramuscular cefotaxime 1.0g was similar in in-
tensity and incidence to that occurring after intra-
muscular procaine penicillin G (4.8 million units)
[Handsfield and Holmes, 1981; Simpson, et aI.,
1981] but worse than with intramuscular genta-
micin 80mg (Ludwig and Knebel, 1980). Pain is
minimised when cefotaxime is diluted with 0.5%
or 1% lignocaine (lidocaine) solution instead of
sterile water (Hanninen et aI., 1980; Hubrechts et
aI., 1980a,b; Ludwig and Knebel, 1980).
6.2 Haematological and Hepatic Effects
Haematological effects of cefotaxime noted in
reviewing a large number of patient reports in-
cluded a positive Coombs' reaction (6.4%),
thrombocytopenia (3.8%), eosinophilia (1.3%), leu-
copenia (0.5%), and a single case of reversible
agranulocystosis (Smith, 1982). Few studies have
included serial determinations of prothrombin time,
but the review by Smith (1982) reported that none
of 26 patients developed a prolongation of pro-
thrombin time. In a study of coagulation disorders
 Cefotaxime: A Review 272

in intensive care patients treated with cefotaxime, ors did not mention that the gentamicin dosage was
moxalactam or cefoperazone for bronchopulmon- adjusted for age, sex or renal function, or that
ary infections, marked changes in prothrombin time gentamicin serum concentrations were obtained.
occurred with cefoperazone and moxalactam in Thus, it is difficult to determine the clinical rele-
patients receiving parenteral nutrition. Although vance of their results.
changes also occurred with cefotaxime, prothrom- Patients with impaired renal function have been
bin time remained within the normal range treated with cefotaxime (Bax, 1980; Bax and Young,
(Schwigon and Barckow, 1982). 1981; Connelly, 1982; Daikos et al., 1980; Motin
Transient increases in liver enzymes have been et aI., 1981; Schulz, 1980; Young et al., 1980), al-
reported occasionally (Bax and Young, 1981; Con- though wide experience in this patient group has
nelly, 1982; Smith, 1982; Yakabow and Wood, not been reported in detail. While the dose in such
1982). The incidence of elevated transaminase and patients was often said to be 'reduced', little infor-
alkaline phosphatase concentrations with cefotax- mation is available on the actual dosages used.
ime was similar to that occurring with cefazolin Nevertheless, renal function did not worsen in most
(Miki and Shiota, 1980; Ohkawa and Kuroda, cases, and in many it improved as the infection
1980). resolved. In· particular, Ninane (1979) and
Clumeck et al. (1979, 1982) found no evidence
of direct tubular toxicity by measuring urinary
6.3 Renal EtTects excretion of alanine aminopeptidase, ~-N-acetyl­
glucosamidase or serum creatinine in a few patients
Cefotaxime did not adversely affect renal func- with impaired renal function who were treated with
tion in the majority of patients studied, including cefotaxime 0.5 to 4 g/day. Published summaries of
the seriously ill. Changes in blood urea or creatin- data collated by the manufacturer from multi-
ine concentrations which occurred occasionally in centre studies (Bax, 1980; Bax and Young, 1981;
patients with normal renal function were usually Connelly, 1982; Young et al., 1980) reported a fur-
transient and were not reported to be of signifi- ther deterioration in renal function in a few cases.
cance in managing the patient (Connelly, 1982; This was usually attributed to the patient's wors-
Francke and Neu, 1981; Graninger et aI., 1981; ening clinical condition, leaving only a minimal
Keaney et al., 1982; Kumazawa et al., 1981; Miki number of cases of uncertain aetiology. Unfortu-
and Shiota, 1980). Smith (1982) reported a 1.4% nately, in some studies it was unclear whether these
incidence of glomerulotubular dysfunction in 1250 particular patients were receiving cefotaxime alone.
patients receiving cefotaxime who had normal In numerous patients, particularly those sutTer-
baseline values. ing from septicaemia, cefotaxime has been given
In a comparative study by Stone et al. (1981), together with an aminoglycoside, usually without
none of the 125 patients treated with cefotaxime . major adverse etTects on the kidney. Results from
(80 mg/kgJday) for peritonitis or soft-tissue sepsis a study by Kuhlmannet al. (1982a,b) in about 30
developed signs of nephrotoxicity (serum creatin- patients suggested that cefotaxime in combination
ine increased by more than 1.5 mg/l00m1 over pre- with tobramycin did not increase the risk of tobra-
treatment levels) compared with 8 of 124 patients mycin nephrotoxicity in patients with serious in-
(7%) receiving a combination of gentamicin (3 mg/ fections and normal renal function (see section 2).
kg/day) and clindamycin (20 mg/kgJday). Patients In a review, by the manufacturer, of 22 adults and
were assigned at random to the treatment groups 48 children, some of whom had impaired renal
but no details were given on the comparability of function before being treated with cefotaxime and
pretreatment renal function. In addition, the auth- an aminoglycoside, blood urea and creatinine con-
 Cefotaxime: A Review
centrations remained unchanged or abnormal lev-
els improved in 94% of patients. The deterioration
in renal function of the remaining 4 patients was
attributed to their severe progressive fatal diseases
(Blomer et aI., 1981). There was a suggestion of
renal impairment occurring in another 5 patients
treated in other studies with cefotaxime and genta-
micin, but the role of cefotaxime in these findings
is unclear (Bastin et aI., 1981; Keaney et aI., 1982;
Portier et aI., 1981). Definitive data from a well-
designed and well-controlled study on the safety of
cefotaxime in combination with an aminoglycos-
ide would clarify this matter.
6.4 Other Adverse Reactions
Hypersensitivity in the form of rash or pruritus
occurred in about 2% of patients and was the most
common reason for discontinuing cefotaxime (Bax
and Young, 1981; Smith, 1982; Young et aI., 1980).
Most rashes (95%) were maculopapular. Rashes
ha ve developed in some of the patients with a past
history of penicillin allergy who were treated with
cefotaxime (Jenkinson et aI., 1980; Shah et aI.,
1980). Drug fever has also been observed in cefo-
taxime-treated patients (0.4%), but anaphylaxis has
not (Smith, 1982).
Gastrointestinal effects such as diarrhoea, coli-
tis, nausea and vomiting have occurred in 1.7% of
patients treated with cefotaxime (Yakabow and
Wood, 1982). Diarrhoea, which was the most fre-
quently reported gastrointestinal reaction, devel-
oped in 0.4 to 1.2% of patients but rarely resulted
in cessation of treatment (Connelly, 1982; Smith,
1982; Young et aI., 1980). On rare occasions, pseu-
domembranous colitis has occurred in patients re-
ceiving cefotaxime (Cone et aI., 1981; Gineston and
Henry, 1982; Karakusis et aI., 1982; Mader et aI.,
1982; Wittmann et aI., 1980b; Yakabow and Wood,
1982).
Central nervous system reactions (including
hallucinations, vertigo or disorientation have oc-
curred in about 0.3% of patients (Smith, 1982).
273
Because cefotaxime possesses the cephalospor-
anic acid nucleus it may interfere with oxidation
reduction methods for determining the presence of
urine glucose, thus producing a false-positive result
(Kennedy and Lauffer, 1982; Kowalsky and Wish-
noff, 1982). It appears that desacetyl-cefotaxime
present in serum can affect the bioassay of genta-
micin unless specifically inactivated by an appro-
priate i3-lactamase preparation (Johnston and Grif-
fiths, 1982). However, neither cefotaxime nor
desacetyl-cefotaxime interfere with creatinine as-
says of serum and urine by the Jaffe (alkaline pi-
crate) reaction (McKendrick and Legg, 1981).
A disulfiram-like reaction, which has occurred
in patients drinking alcohol while being treated with
cefoperazone, cefamandole or moxalactam (which
have a common side chain) has not occurred dur-
ing clinical studies with cefotaxime, or in a special
study in healthy volunteers (Smith, 1982).
6.5 Adverse Bacteriological Effects
Colonisation and superinfection, which occur
with other broad spectrum antibiotics, have also
been reported in patients treated with cefotaxime,
particularly those who were seriously ill. On re-
viewing results from 1650 patients treated with
cefotaxime, Smith (1981) reported the incidence of
colonisation (defined as isolation of a new organ-
ism during therapy without signs of infection) as
1.6%, and of superinfection (isolation of a new
organism plus signs or symptoms of infection) as
1.2%. Usually cefotaxime-resistant Pseudomonas
species or group D streptococci were isolated, but
occasionally other resistant Gram-negative bacilli,
or Candida, were involved (Clumeck et aI., 1981,
1982; Guy et aI., 1981; Keaney et aI., 1982;
McKendrick et aI., 1980b; Motin et aI., 1981;
Schleupner and Engle, 1982; Smith, 1981).
Development of resistance to cefotaxime during
treatment has been very rarely documented. In 1
such case (Karakusis et aI., 1982), the MIC of cefo-
taxime for a strain of Pseudomonas aeruginosa iso-
 Cefotaxime: A Review 274

Table XVII. Examples of some dosage schedules (dose x frequency) recommended by the manufacturer for cefotaxime given
intramuscularly or intravenously. Maximum dose in adults is 12 g/day and in children 200 mg/kg/day

Type of infection/patient USA UK Germany France

Uncomplicated 19 12-hourly 19 12-hourly 19 12-hourly

Moderate 19 12-hourly

Moderate to severe 1-2g 6- or 8-hourly 2g 12-hourly

Severe/serious 2g 6- or 8-hourly up to 2g 2g 12-hourly 19 6- or 8-hourly

6- or 8-hourly

Life-threatening 2g 4-hourly 2-3g 6- or 8-hourly 2g 4-hourly

Gonorrhoea 19 stat 19 stat

Neonates 100-150 mg/kg/day' 50 mg/kg/dayb 50-100 mg/kg/dayb 50-100 mg/kg/dayb

Infants + children
usual dose 50-180 mg/kg/day<' 100-150 mg/kg/dayb 50-100 mg/kg/dayb 50-100 mg/kg/dayb
very severe infections 180 mg/kg/day<' 200 mg/kg/dayb

a Administered 8- to 12-hourly.
b Administered 6- to 12-hourly.
c Administered 4- to 6-hourly.

lated from bone biopsies was 25 ~gjml before
therapy and greater than 100 ~gjml during therapy
(no dosage data given). Selection of resistant bac-
teria (e.g. P. aeruginosa) [Livermore et aI., 1982]
may also be possible with cefotaxime.
7. Dosage and Administration
In many countries, cefotaxime is now approved
by regulatory agencies for the treatment of bacter-
aemia/septicaemia, lower respiratory, genitouri-
nary (including gonorrhoea), obstetric, gynaecol-
ogical, intra-abdominal, soft-tissue, bone and joint
infections presumed or shown to be caused by sus-
ceptible organisms. Cefotaxime is also approved in
some countries for the treatment of meningitis,
ventriculitis or endocarditis and for use perioper-
atively to reduce the incidence of postoperative in-
fections in patients undergoing contaminated or
potentially contaminated procedures (e.g. vaginal
hysterectomy, genitourinary surgery) or caesarean
section. Approval has also been given in some
countries for the treatment of neonatal and pae-
diatric infections with cefotaxime.
Examples of some recommended dosage sched-
ules for cefotaxime are shown in table XVII. Ob-
viously, the dosage, route and frequency of admin-
istration are determined by the severity of the
infection, sensitivity of causative organisms and
condition of the patient. The maximum daily dose
should not exceed 12g in adults and 200 mg/kg in
children. The manufacturer also states that for in-
fections caused by sensitive Pseudomonas species,
doses of more than 6 g/day are required. However,
on the basis of in vitro data and clinical experience
reported to date, it would appear that cefotaxime
alone may not be a suitable choice for treatment
of suspected or proven pseudomonal infections. In
severe infections caused by Pseudomonas the con-
current use of cefotaxime and an aminoglycoside
may be appropriate.
Although there is no clinical evidence support-
ing the necessity of changing the dosage of cefo-
taxime in patients with even severe renal dysfunc-
tion, a significant portion of a dose of cefotaxime
 Cefotaxime: A Review
is excreted in the urine, either unchanged or as an
active metabolite. Hence, until further data are ob-
tained the dose of cefotaxime should be reduced
by 50% in patients with severe renal impairment.
As with antibiotic therapy in general, adminis-
tration of cefotaxime should usually be continued
for a minimum of 48 to 72 hours after fever abates
or after evidence of bacterial eradication has been
obtained.
When cefotaxime is being used to prevent post-
operative infection in contaminated or potentially
contaminated surgery, Ig should be administered
intravenously or intramuscularly 30 to 90 minutes
before the start of surgery and again 30 to 120 min-
utes later. Another 19 dose should also be admin-
istered within 2 hours following surgery. In women
undergoing caesarean section the first dose of Ig is
administered intravenously as soon as the umbil-
ical cord is clamped; the second and third doses of
19 each should be given 6 and 12 hours later. Al-
though cefotaxime is contraindicated in patients
with a known allergy to cefotaxime or other cepha-
losporins, the drug may be given with caution to
patients who are hypersensitive to penicillins.
However, special care is indicated in patients who
ha ve had an anaphylactic response to penicillin.
8. The Place of Cefotaxime in Therapy
The specific infections for which an injectable
antibiotic of this type would normally be consid-
ered as 'appropriate therapy' vary widely according
to local medical custom, decisions of regulatory
agencies, and geographical patterns of bacteriolog-
ical susceptibilities. The wide in vitro antibacterial
activity of cefotaxime has been reflected in good
clinical efficacy in a variety of infections. Its effi-
cacy has been demonstrated in adults with com-
plicated urinary tract infections, lower respiratory
tract infections, such as pneumonia caused by
Gram-negative bacilli, and in the treatment of
Gram-negative bacteraemia. Less extensive studies
in adults with uncomplicated gonorrhoea caused
275
by penicillinase-producing gonococci, and in child-
ren with meningitis or other serious infections, in-
dicate potential usefulness of cefotaxime in such
patients.
Unfortunately, only limited controlled studies
with this drug have been published, making it dif-
ficult to determine clearly its relative efficacy com-
pared with drugs such as the aminoglycosides and
other cephalosporins. The comparative studies
which have been conducted suggest cefotaxime is
at least as effective as several 'first generation' and
'second generation' cephalosporins in treating
patients with urinary tract infections, and as clinic-
ally effective as cefazolin in the treatment of lower
respiratory tract infections. Cefotaxime appears to
be as effective as a combination of gentamicin plus
a lower than usual dose of clindamycin in the
medical management of peritonitis. However, the
relatively low in vitro activity of cefotaxime against
Bacteriodes jragilis may temper its usage in situ-
ations where this organism is the suspected or
proven pathogen.
It has been suggested that cefotaxime may
sometimes be used instead of an aminoglycoside.
On the basis of in vitro activity studies and existing
clinical data, this would seem to be a reasonable
supposition and may be particularly relevant in
Gram-negative bacilliary meningitis. If equivalent
efficacy of cefotaxime and aminoglycoside antibi-
otics is clearly established, cefotaxime may offer
potentially important clinical and practical advan-
tages since it appears to be relatively free of ad-
verse effects and it does not require drug plasma
concentration monitoring. However, unlike the
aminoglycosides, the efficacy of cefotaxime in in-
fections due to Pseudomonas species has not been
convincingly demonstrated.
In summary, the particular situations in which
use of cefotaxime is worthy of consideration are in
the initial treatment of seriously ill patients with
infections of undetermined aetiology, especially
when Gram-negative aerobes (other than Pseudo-
monas species) are the suspected pathogens, when
resistance of Gram-negative organisms to usual
 Cefotaxime: A Review
therapy is suspected or has been demonstrated, and
when patients are not responding as expected to
other antibiotics. However, the most appropriate
'niche' in therapy for cefotaxime, compared with
other antibiotics such as the aminoglycosides or
other 'third generation' cephalosporins with a sim-
ilar spectrum of activity, has yet to be clearly
established.
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Author's address: Anne Carmine, ADIS Drug Information
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Zealand).