EDITORIAL COMMENT

Should We Use Ceftriaxone to Treat

Staphylococcal Osteoarticular Infections?
Gary E. Stein, PharmD
Written as an editorial commentary regarding Sharff et al. Ceftriaxone for MethicillinSensitive Staphylococcus aureus Osteoarticular Infections: A Survey of Infectious
Disease Physicians Attitudes and Review of the Literature on pages (132140) of
the Journal.

eftriaxone has been an important component in the treatment of serious bacterial infections, such
as pneumonia and meningitis, for the past 3 decades. Although ceftriaxone possesses potent
in vitro activity against a broad range of bacteria, it has only moderate activity against staphylococci.
The potency of ceftriaxone against staphylococci can be further diminished in the presence of serum
proteins and high bacterial inocula. In addition, the high protein binding (approximately 90%) of
ceftriaxone can limit its distribution into body fluids and tissues. These parameters have led to reluctance in the use of this cephalosporin for the treatment of serious staphylococcal infections.
Despite these microbiologic and pharmacokinetic concerns, ceftriaxone has been successful
in the treatment of methicillin-sensitive Staphylococcus aureus (MSSA) infections including cases
of bone and joint infection (BJI).1 In a retrospective review of 22 patients with staphylococcal osteomyelitis, ceftriaxone was found to be effective and safe outpatient treatment after 1 to 2 weeks
of inpatient treatment with nafcillin, cefazolin, or vancomycin.2 In another retrospective study of
110 patients who completed outpatient parenteral antimicrobial therapy (OPAT), Tice et al3 found
that ceftriaxone was effective treatment with osteomyelitis caused by MSSA. The risk of recurrence
with ceftriaxone was low and similar to cefazolin. Comparable findings have also been reported by
Winans et al.4 In a recent retrospective study of 124 patients with osteoarticular infections due to
MSSA, Wieland et al5 found that OPAT treatment with ceftriaxone produced similar treatment success as oxacillin at 3 to 6 months and more than 6 months after completion of therapy. Moreover,
patients receiving ceftriaxone were less likely to discontinue treatment owing to an adverse event.
These studies and other clinical observations support the use of ceftriaxone for OPAT in patients with
osteoarticular infections due to MSSA, albeit none of these findings were from prospective randomized trials.
This clinical evidence has not translated into routine use of ceftriaxone by infectious disease
(ID) physicians for MSSA. In a survey of academic and community physicians in the United States,
Sharff et al6 found that only 71% of ID physicians use ceftriaxone for OPAT of MSSA osteomyelitis
or septic arthritis. Moreover, 40% of positive responders used ceftriaxone less than 20% of the time.
Most ID physicians agree that first-line agents (eg, oxacillin and cefazolin) should be used during
hospitalization before converting to ceftriaxone. This informal survey did not question nonusers
of ceftriaxone about what agents they use and why they did not use this cephalosporin for OPAT
of osteoarticular infections due to MSSA. Furthermore, these ID physicians were not asked what information they required before placing a patient on OPAT. This additional knowledge would be useful to help guide future education and research concerning OPAT with ceftriaxone.
The companion literature review of ceftriaxone in the paper by Sharff et al6 is informative
and does provide some insights into these survey results. One concern in converting patients to
ceftriaxone is the lack of routine susceptibility testing of this cephalosporin against MSSA. In general, ID physicians request this information before treating a serious infection, although more than
50% of ID physicians in this survey who prescribe ceftriaxone do not routinely check its minimal inhibitory concentration (MIC) against MSSA. Knowledge of oxacillin susceptibility, without MIC, is
also not adequate since MSSA strains can have MICs that range up to 2 mg/L (MIC90 = 1 mg/L).
Higher oxacillin MICs correlate to higher ceftriaxone MICs for strains of MSSA. Without MIC data
for these antibiotics, the most effective dosing regimen cannot be determined. The most commonly
used dose of ceftriaxone (2 g/d) for MSSA infections seems to be appropriate for ceftriaxone MICs
4 mg/L or less based on pharmacokinetic/pharmacodynamic considerations (concentration time > MIC)
From the Michigan State University, East Lansing, MI.
Correspondence to: Gary E. Stein, PharmD, Michigan State University, East Lansing, MI. E-mail: steing@msu.edu.
The author has no funding or conflicts of interest to disclose.
Copyright 2014 by Lippincott Williams & Wilkins
ISSN: 1056-9103

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Infectious Diseases in Clinical Practice Volume 22, Number 3, May 2014

and clinical outcome data. This dosage regimen would not be sufficient for isolates with MICs = 8 mg/L, which are common
in many medical centers.7 Additional concerns include obese
patients and those with vascular insufficiency. Standard doses of
-lactam antibiotics often provide inadequate drug exposure in
obese (body mass index > 30 kg/m2) patients and those with vascular insufficiency.8,9 This is especially a concern with highly
protein-bound drugs.10
Bone and joint infections are commonly treated with OPAT
with varying success rates. A retrospective review of 198 patients
with BJI found that factors associated with poorer outcomes included older age, MSSA infection, and osteomyelitis related to
diabetic foot infection.11 A lack of test results has also been independently associated with readmissions in patients receiving
OPAT.12 The most appropriate antibiotic for OPAT depends on several factors, which include microbial susceptibility, frequency of administration, tissue penetration, patient response, adverse effects,
and cost.13 Ceftriaxone is attractive for OPAT of osteomyelitis for
a number of reasons. Most (98%) MSSA strains are susceptible
to ceftriaxone, it penetrates cancellous and cortical bone, it is safe
and inexpensive, and can often be given once daily. Moreover, the
results from various studies suggest that ceftriaxone is an effective
agent for the treatment of osteoarticular MSSA infections.
An appropriate dosing regimen of ceftriaxone is critical
to provide optimal treatment. Although uncommonly used by
ID physicians, in the survey by Sharff et al, a dosage regimen
of 2 g every 12 hours seems warranted in many cases of osteomyelitis including patients who are obese, have vascular insufficiency, or are infected with a less susceptible strain (MIC = 8 mg/L)
of MSSA. An improved understanding of this cephalosporin and
the requisite for varied dosing regimens of ceftriaxone for OPAT
of BJI should increase physician comfort with this antibiotic and
enhance patient success rates.

REFERENCES
1. McCloskey RV. Clinical and bacteriologic efficacy of ceftriaxone in
the United States. Am J Med. 1984;77(suppl 4C):97103.
2. Guglielmo BJ, Luber AD, Paletta D, et al. Ceftriaxone therapy for
staphylococcal osteomyelitis: a review. Clin Infect Dis. 2000;
30:205207.

2014 Lippincott Williams & Wilkins

Editorial Comment

3. Tice AD, Hoaglund PA, Shoultz DA. Outcomes of osteomyelitis

among patients treated with outpatient parenteral antimicrobial therapy.
Am J Med. 2005;114:723728.
4. Winans SA, Luce AM, Hasbun R. Outpatient parenteral antimicrobial
therapy for the treatment of methicillin-susceptible Staphylococcus
aureus: a comparison of cefazolin and ceftriaxone. Infection.
2013;41:769774.
5. Wieland BW, Marcantoni JR, Bommarito KM, et al. A retrospective
comparison of ceftriaxone versus oxacillin for osteoarticular infections
due to methicillin-susceptible Staphylococcus aureus. Clin Infect Dis.
2012;54:585590.
6. Sharff KA, Graber CJ, Spindel SJ, et al. Ceftriaxone for
methicillin-sensitive Staphylococcus aureus (MSSA) osteoarticular
infections: a survey of infectious disease physicians attitudes and
review of the literature. Infect Dis Clin Pract. 2014;22:132140.
7. Richter SS, Heilmann KP, Dohrn CL, et al. Activity of ceftaroline and
epidemiologic trends in Staphylococcus aureus isolates collected from
43 medical centers in the United States in 2009. Antimicrob Agents
Chemother. 2011;55:41544160.
8. Hites M, Taccone FS, Wolff F, et al. Case-control study of drug
monitoring of -lactams in obese critically ill patients. Antimicrob
Agents Chemother. 2013;57:708715.
9. Brill MJE, Houwink API, Schmidt S, et al. Reduced subcutaneous tissue
distribution of cefazolin in mobidly obese versus non-obese patients
determined using clinical microdialysis. J Antimicrob Chemother.
2014;69:715723.
10. Chen M, Nafzigen AN, Drusano GL, et al. Comparative
pharmacokinetics and pharmacodynamics target attainment of
ertapenem in normal-weight, obese and extremely obese adults.
Antimicrob Agents Chemother. 2006;50:12221227.
11. Mackintosh CL, White HA, Seaton RA. Outpatient parenteral
antibiotic therapy (OPAT) for bone and joint infections: experience
from a UK teaching hospital-based service. J Antimicrob Chemother.
2011;66:408415.
12. Huck D, Ginsberg JP, Gordon SM, et al. Association of laboratory test
result availability and rehospitalizations in an outpatient parenteral
antimicrobial therapy programme. J Antimicrob Chemother.
2014;69:228233.
13. Chapman ACN, Seaton RA, Cooper MA, et al. Good practice
recommendations for outpatient parenteral antimicrobial therapy
(OPAT) in adults in the UK: a consensus statement. J Antimicrob
Chemother. 2012;67:10531062.

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