Antimicrobial Drugs

Dr.Mohammad Jadaan
 Antimicrobial drug combination
❖Indication
➢Severe infection of unknown etiology
➢Mixed infection
➢Prevention of resistance
➢Decreased toxicity
➢Enhanced action: penicillin + aminoglycoside = synergism
Disadvantages of antimicrobial combination
➢Increase risk of allergy
➢Antagonism of antimicrobial effect: TTC+ penicillin
➢Increase risk of super infection
➢Increased cost
MOA:
 NARROW SPECTRUM PENICILLINS
❖Natural Penicillins: Penicillin G, Pen.V
❖Active against:
➢G+vecocci & bacilli: except penicillinase producing μbes
➢G-vecocci: N.menigitidis, N.gonorrhea
➢Which have slightly larger porins
➢G-vebacilli: have narrow porins, not effective
➢Spirochetes: T.pallidum, Borrelia, Leptospira
 Therapeutic uses
➢Drug of choice for G+vecocci;
➢Pneumonia or meningitis by Streptococcus pneumonia
➢Pharyngitis by Streptococcus pyogenes
➢Infective endocarditis by Streptococcus viridians
➢Infection caused by G+vebacilli:
➢Gangrene by Cl. perfringes
➢Tetanus by Cl. tetani
➢Anthrax by B. anthracis
 VERY NARROW SPECTRUM:
❖Cloxacillin, Dicloxacillin, Oxacillin, Methicillin,
Nafcillin
➢Also called anti-staphylococcal penicillins
➢They have bulky side chains that protect the β-lactam
ring
➢Use: in S.aureus& Staph.epidermdis infections
 BROAD SPECTRUM
❖AMINOPENICILLINS
❖Ampicillin, Amoxicillin, Bacampicillin, Pivampicillin
➢Antimicrobial spectrum as penicillin G; plus G-ve bacilli:
➢They can enter via porins
➢Spectrum: HELPSto clear enterococci (G-ve)
➢Acid stable: can be administered PO
➢Ineffective against β-lactamase producing bacteria
➢Need to be combined with β -lactamase inhibitors
➢Can’t cover P.aeruginosa: has tight/few porins
 Therapeutic uses
❖Ampicillin: can be given PO & parenterally
➢Meningitis: L.monocytogenes; with 3rdgen
Cephalosporin
➢Pneumonia (G-ve) with gentamycin
➢Hepatic encephalopathy: reducing NH3production
➢Especially in azotemicpatients, since neomycin is not safe
➢Bile (biliary tract infection)
 Amoxicillin:
➢Pharyngitis, otitis media, tonsillitis, bronchitis, sinusitis
➢UTI: cystitis, pyelonephritis
➢PUD (H. pylori): triple/dual therapy
➢Severe dental abscess with spreading cellulitis
➢Anthrax: postexposure inhalational prophylaxis
➢IE prophylaxis: 2 g PO 30-60’ before dental procedure
Amoxicillin-clavulanic acid: augmentin®
➢Available in 4:1 combination.
➢250-750mg amoxicillin & 62.5-125mg clavulinicacid
❖Use:
➢Skin infection: streptococci, staphylococci.
➢Acute otitis media: H.infleunza, M.catarrhalis
➢Sinusitis, Lower RTI
➢Diabetic foot infection: staphylococci, aerobic & anaerobic G-ve
Drug Interactions:
➢Aminoglycosides: synergism
➢Inactive precipitate is formed if mixed in one container
➢Probenecid: inhibits the secretion of penicillins by competing
for active tubular secretion via the organic acid transporter
➢Bacteriostatic antibiotics: due to antagonism
➢Ampicillin and oral contraceptives;
➢Decreased enterohepatic circulation
Adverse effects
• The safest drugs: no monitoring
• Hypersensitivity reaction: pencillioc acid act as a hapten
• Type-I: IgEmediated /immediate hypersensitivity
• IgE-mediated degranulation of mast cells
• Anaphylactic shock is the most dangerous
• Need of skin test for the suspect penicillin
1stGeneration Cephalosporins
➢Relatively narrow spectrum (G+ve bacteria)
➢Selected 1stgeneration Cephalosporins;
2ndGeneration Cephalosporins
➢True Cephalosporins: Cefaclor, Cefamandole, Cefonicid,
Cefuroxime, Cefprozil, Cefpodoxime, Loracarbef &
Ceforanide.
➢Have high activity against: H.infleunza, N.meningitidis,
N.gonorhoeae
➢Cephamycins: Cefoxitin, Cefmetazole, Cefotetan.
➢Antibacterial against selected enterobacteriaceae; most active
against B.fragilis.
3rdGeneration Cephalosporins
➢Cefotaxime, Ceftriaxone, Ceftazidime, Cefoperazone,
Cefixime, Ceftizoxime.
➢Less active than 1stgeneration against G+ve cocci.
➢More active against Enterobacteriaceae.
➢Antipseudomonal activity from Cefoperazone & Ceftazidime
➢Ceftriaxone: most potent;t1/2=8hrs/once daily dose
➢High efficacy in bacterial meningitis, multiresistant typhoid
fever, complicated UTI, Abdominal sepsis, Septicaemias
➢Ceftazidime: excellent activity against G-ve: p.aeruginosa
➢Penetrate CSF & DOC in meningitis due to p.aeruginosa;
given parenterally.
➢Cefoperazone: strong against pseudomonas; high ppb
➢Do not reliable penetrate into CSF.
➢Indicated in severe urinary, respiratory, biliary infection and
septicaemia
4thGen. Cephalosporins: Cefepime, Cefpirome
➢Rapidly cross the outer membrane of G-ve.
➢More resistant to hydrolysis [chromosomal β-lactamase:
produced by enterobacter] & lactamases that inactivate
3rdgeneration
➢Active against Enterobacteriaceae, P. aeruginosa, H. influenza &
Neisseria spp.
 Advanced Generation: Ceftaroline
➢Broad spectrum
➢Administered IV as a Prodrug, Ceftaroline fosamil
➢Active against MRSA
➢Used for the tXtof complicated skin & skin structure infections
and CAP
➢The unique structure allows Ceftaroline to bind to PBP2a found
with MRSA and PBP2x found with Streptococcus pneumoniae
Adverse effects
➢Allergic reactions
➢Antibiotic-associated colitis: super infection.
➢Bleeding: hypoprothrombinemia (methylthioterazole/MTT
containing group, 3rdgeneration)
➢Cefoperazone, Cefotetan, Cefamandole, Cefmetazole
➢Local effects: thrombophlebitis from IV injection
 Other β-lactam Antibiotics
➢Carbapenems: Ertapenem, Imipenem, Meropenem, Doripenem
➢Imipenem, with Cilastatin: Primaxin
➢MOA:Inhibit bacterial trans peptidases
• β-lactamase resistant
➢Imipenem (IV)
➢Antimicrobial spectrum: G+ve and G-ve including P.aeruginosa; &
anaerobes
➢Distributed in CSF; metabolized in renal tubule by
dehydropeptidases which can be inhibited by cilastatin
PROTEIN SYNTHESIS
INHIBITORS
 Aminoglycosides
❖Streptomycin, Gentamicin, Kanamycin, Amikacin,
Tobramycin, Sisomycin, Neomycin, Paramomycin,…
❖General properties:
➢Composed of two or more amino sugars connected by a
glycoside linkage
➢At physiological pH, they are polycations
➢Are water soluble, stable in solution
➢Interact chemically with β-lactam antibiotics
❖Antimicrobial spectrum
➢Aerobic, gram-negative organisms
➢Pseudomonas, Klebsiella, E.coli, others
❖Pharmacokinetics
➢Absorbed very poorly from intact GIT: IM & IV
➢Distribution limited to ECF;
➢Bind to renal tissue nephrotoxicity
➢Penetrate to perilymph & endolymph of inner ear ototoxicity
➢Eliminated primarily by kidney
Therapeutic uses
➢Against G-veenteric bacteria in bacterimia & sepsis; TB
➢In combination with β-lactam antibiotic to increase
coverage(G+ve) & synergism
Adverse Effects
❖Ototoxicity
➢Cochlear toxicity: tinnitus, high frequency hearing loss
✓Neomycin, Kanamycin, Amikacin
➢Vestibular toxicity: vertigo, ataxia, loss of balance
✓Streptomycin & Gentamycine
❖Nephrotoxicity: injure cells of proximal renal tubule
 Tetracyclines
➢Oxytetracycline, Tetracycline, Demeclocycline, Doxycycline,
Minocycline
➢Antimicrobial spectrum: broad
✓G+ve& G-ve aerobic & anaerobic bacteria
✓Spirochetes, Mycoplasma, Rickettsia, Chlamydia & some
protozoa
➢Glycylcyclines (Tigecycline):
✓Related to TTCs in their MOA as well as spectrum
Adverse Effects
✓GI Irritation: oral therapy burning, cramps & NVD
✓Super infection
✓Effect on bone & teeth;
➢Yellow or brown discoloration of teeth
➢Hypoplasia of enamel
➢Suppression of long bone growth in infants
❖Doxycycline bind less with Ca2+ less frequent dental
changes
 Macrolides
➢Macro cyclic lactone ring to which deoxysugar is attached
➢Erythromycin, Clarithromycin, Azithromycin
❖MOA:
➢Binding to 50srRNA inhibitingpeptidyl transfer, ribosomal
translocation (transpeptidation), premature dissociation of peptidyl
t-rRNA from the ribosome inhibition of protein synthesis
➢Usually bacteriostatic, may be -cidal@ high dose
 Erythromycin
❖Pharmacokinetics
➢Decreased by stomach acid enteric coating
➢Stearate & esters: fairly acid resistant better absorbed
➢Estolatesalt best absorbed orally
➢Administration: topical, PO, IM, IV
➢Excretion: primarily bile & faces
Clarithromycin
✓Similar with erythromycin with respect to antibacterial
activity & drug interaction except:
➢More active against M. aviumcomplex
➢Also against M. leprae, H.pylori, Toxoplasma gondii
 Azithromycin
➢Semisynthetic derivative of Erythromycin
➢Have better oral absorption
➢Longer t1/2
➢Fewer GI side effects
➢Are expensive
❑Azithromycinis similar to clarithromycin except:
✍Less active against staphylo-& strepto-cocci
✍Slightly more active against H. influenza
✍Highly active against Chlamydia
✍Long t1/2[3days] permit once daily dosing
✍Free of drug interaction
 Direct Inhibitors of Nucleic Acid Synthesis
❖Quinolones, FQs and Rifamycins
❖Naldixic acid, Ciprofloxacin, Levofloxacin, "-floxacins”
❖MOA:
➢Block DNA replication by inhibit the ligase domains of;
➢Topoisomerase II (DNA gyrase): in G-ve bacteria relaxation of
super coiled DNA DNA strand breakage
➢Topoisomerase IV: G+ve bacteria impacts chromosomal
stabilization during cell division, thus interfering with these
parathion of newly replicated DNA
Antimicrobial Spectrum
➢Norfloxacinis the least active of FQs against G+ve& G-ve
➢Ciprofloxacin, Enoxacin, Lemofloxacin, Ofloxacin,
Pefloxacin,Levo-, Moxi-,Gemi-& Gati-floxacin:
➢Excellent against G-ve: pseudomonas, enterobacteriaceae,
haemophilusspp., Neisseria spp., Campylobacter
➢Moderate to good against G+ve: methicillin susceptible strains
of staph; streptococci & enterococci tend to be less susceptible
➢FQs also have activity against Mycoplasma & Chlamdiae;
Legionella spp. & Mycobacteria