Infectious Diseases in Clinical Practice:
Stein, Gary E. PharmD
From the Michigan State University, East Lansing, MI.
Correspondence to: Gary E. Stein, PharmD, Michigan State University, East Lansing, MI. E-mail: firstname.lastname@example.org.
The author has no funding or conflicts of interest to disclose.
Ceftriaxone 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) 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 β-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.
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