Once-Daily Cefazolin and Probenecid for Skin and Soft Tissue Infections

Abstract

Spanish

French

OBJECTIVE

To review the pharmacokinetic and clinical evidence for the use of once-daily cefazolin and probenecid in the treatment of skin and soft tissue infections (SSTI).

DATA SOURCES

MEDLINE (1966–July 2003), EMBASE (1980–July 2003), and PubMed (1966–July 2003) databases for English language, human reports were searched. Search terms included cefazolin, probenecid, cellulitis, and soft tissue infections.

STUDY SELECTION AND DATA EXTRACTION

Studies that described pharmacokinetic and clinical outcomes that evaluated the use of cefazolin in conjunction with probenecid for SSTI were included. All studies were evaluated independently by both authors. For pharmacokinetic studies, the effect of probenecid on the pharmacokinetics of cefazolin was evaluated. For clinical trials, efficacy and safety endpoints were evaluated. For efficacy endpoints, definition of cure was used as defined by each trial.

DATA SYNTHESIS

In all 3 pharmacokinetic studies identified, the addition of probenecid to cefazolin therapy prolonged the half-life and increased serum concentrations of cefazolin. This process allowed serum concentrations to be above the minimal inhibitory concentrations (MIC) for the most likely skin pathogens (Staphylococcus aureus, β-hemolytic streptococci) at the end of the dosing interval. In the first of 2 clinical trials, 7 (7%) of 96 patients receiving intravenous ceftriaxone 2 g and oral probenecid 1 g daily were reported to fail therapy compared with 8 (8%) of 98 patients receiving intravenous cefazolin 2 g and oral probenecid 1 g daily. In the second clinical trial, clinical success was reported in 51 (86%) of 59 patients receiving the same doses of cefazolin and probenecid as above compared with 55 (96%) of 57 patients receiving intravenous ceftriaxone 1 g and oral placebo daily.

CONCLUSIONS

Limited pharmacokinetic and clinical data suggest that intravenous cefazolin 2 g and oral probenecid 1 g daily is an effective regimen in the treatment of SSTI.

Keywords

cefazolin cellulitis probenecid skin and soft tissue infections

Skin and soft tissue infections (SSTI) are commonly diagnosed in the emergency department (ED). The pathogens most frequently isolated are Staphylococcus aureus and β-hemolytic streptococci,¹ although in many cases, no organism is cultured.^1–4 Many patients seen in the ED have SSTI of sufficient severity to warrant administration of intravenous antibiotics, but may not be ill enough to require hospital admission. These patients may be ideal candidates for outpatient administration of intravenous therapy. Traditionally, ceftriaxone has been used to treat SSTI in this setting.^5,6 Ceftriaxone possesses adequate antimicrobial activity against the most likely pathogens and has pharmacokinetic properties permitting once-daily administration.⁷ However, the unnecessary extended spectrum of antimicrobial activity and relatively high cost of ceftriaxone ($34.00/day, $CAN) prompt the need for evaluation of alternative intravenous antimicrobials in the outpatient treatment of SSTI.

Cefazolin, a first-generation parenteral cephalosporin, has been demonstrated to have excellent efficacy in the treatment of SSTI, with clinical cure rates ranging from 77% to 100%.^5,6,8–14 In a review of 5 EDs in Alberta, Canada, cefazolin was reported to be the most frequently used parenteral antibiotic for empiric treatment of SSTI.¹⁵ In patients with normal renal function, cefazolin has a short serum half-life (1.2–2.2 h) and thus is usually administered every 6–8 hours to maintain sufficient serum concentrations to eradicate common infectious organisms in SSTI.¹⁶ Unfortunately, that dosing regimen is not convenient for outpatient management.

Probenecid is a uricosuric agent that has been shown to inhibit the tubular secretion of weak organic acids.¹⁷ This agent demonstrates almost complete absorption when administered by the oral route.¹⁸ Peak probenecid concentrations occur in 1–5 hours, and the half-life of the drug is dose-dependent.¹⁸ After oral doses of 0.5–1.0 g, the half-life may range from 2 to 6 hours; however, after 2-g doses, the half-life is prolonged to 4–12 hours.¹⁹ Probenecid has been shown to inhibit the tubular secretion of penicillins and some cephalosporins, including cefazolin, thereby prolonging the half-life and serum concentrations of these medications.^18,20 Thus, probenecid has the potential to enhance the pharmacokinetics of cefazolin, permitting a less frequent, more convenient, and inexpensive ($2.88/day, $CAN) regimen for outpatient treatment of SSTI in the ED. This article reviews all available published pharmacokinetic and clinical literature evaluating the efficacy and toxicity pertaining to the use of cefazolin and probenecid for the treatment of SSTI.

Data Sources

A systematic search of MEDLINE (1966–July 2003), EMBASE (1980–July 2003), and PubMed (1966–July 2003) was performed to identify English-language publications pertaining to concomitant use of cefazolin and probenecid for treatment of SSTI in humans. Search terms included cefazolin, probenecid, cellulitis, and soft tissue infections. A manual search through references of identified articles was also performed to identify papers not located in the electronic database search.

Citations identified following the literature review were evaluated independently by both authors for inclusion using title and abstract. Where questions remained regarding eligibility for inclusion, full text was reviewed. Both pharmacokinetic and clinical studies that evaluated the use of cefazolin in conjunction with probenecid for SSTI were included. All studies, regardless of design, were reviewed for inclusion. Review articles, abstracts and unpublished reports, animal data, and literature published in languages other than English were excluded.

All studies were evaluated independently by both authors. For pharmacokinetic studies, the effect of probenecid on the pharmacokinetics of cefazolin was evaluated. For clinical trials, efficacy and safety endpoints were evaluated. For efficacy endpoints, definition of cure was used as defined by each trial.

The search yielded one abstract²¹ and one review article²⁰ that were excluded. One trial was excluded due to a lack of reported data.²² Two trials pertaining to the use of cefazolin and probenecid for the treatment of gonorrhea were excluded.^23,24 Three pharmacokinetic studies^25–27 and 2 clinical trials^12,13 evaluating the use of cefazolin with probenecid for the treatment of SSTI were included in this review.

Pharmacokinetic Studies

Cefazolin 500 mg was administered intramuscularly to 5 healthy volunteers with normal hepatic and renal function.²⁵ After an undefined washout period, 3 of the volunteers ingested 500 mg of probenecid, and the same dose of cefazolin was given one hour later. Probenecid doses were repeated every 6 hours for 24 hours. In the patients receiving cefazolin alone, the peak serum concentrations of cefazolin occurred between 30 and 60 minutes after injection and ranged from 44.0 to 70.0 μg/mL. The mean half-life was 1.60 hours (range 1.37–1.96). In the 3 patients receiving oral probenecid in addition to cefazolin, peak serum concentrations of cefazolin were higher (47.0–82.5 μg/mL; p value not reported [NR]), and the mean serum half-life of cefazolin was prolonged by 20–40% (2.23 h, range 1.96–2.38; p value NR) compared with patients receiving cefazolin alone. The serum concentrations of cefazolin in all patients 24 hours after either dosing regimen was <5.0 μg/mL, the lower limit of quantitation for the assay.

A prospective, randomized, unblinded crossover study was conducted in 6 healthy male volunteers with normal renal function and compared the pharmacokinetics of a single dose of cefazolin 2 g with a single dose of probenecid 1 g followed in 10 minutes by cefazolin 2 g.²⁶ After a one-week washout period, volunteers received the alternate treatment. Ten blood samples were obtained, commencing immediately prior to administration of cefazolin, with the last sample drawn at 24 hours. The investigators found that probenecid reduced the elimination rate and prolonged the half-life of cefazolin (mean 2.7 h, cefazolin and probenecid vs 1.6 h, cefazolin alone; p value NR). The mean ± SD serum concentration of cefazolin after 24 hours was higher in the group receiving probenecid (2.0 ± 0.9 vs 1.1 ± 0.1 μg/mL; p < 0.05). Four of the subjects receiving cefazolin alone did not have measurable serum concentrations at 24 hours, whereas all of those receiving probenecid prior to cefazolin administration had detectable cefazolin serum concentrations at 24 hours.

Spina and Dillon²⁷ performed a prospective, nonrandomized, unblinded study comparing the serum concentrations attained following administration of cefazolin 2 g every 24 hours in conjunction with probenecid 500 mg 4 times daily (n = 21) with serum concentrations attained from administration of cefazolin 2 g every 8 hours (n = 5). Inpatients received the 8-hourly regimen, while outpatients received the once-daily regimen. The first dose of probenecid was given 60 minutes prior to cefazolin in the outpatient group. Serum cefazolin concentrations were monitored on days 1 and 5 of treatment. For both groups, a peak serum concentration was drawn one hour after the initial infusion was started. A trough cefazolin concentration was measured 23 hours after the initial infusion was started, just prior to the next scheduled dose. In patients receiving once-daily cefazolin with probenecid, the mean ± SD peak and trough cefazolin concentrations reported after the first dose of therapy were 146.53 ± 42.35 and 2.02 ± 1.66 μg/mL, respectively. In 4 evaluable patients receiving cefazolin 2 g every 8 hours, peak and trough concentrations reported after the first dose were 122.15 ± 45.31 and 18.65 ± 13.90 μg/mL, respectively. Peak and trough concentrations reported in evaluable patients receiving once-daily cefazolin with probenecid on day 5 were 148.30 ± 40.50 μg/mL (n = 13) and 2.67 ± 2.17 μg/mL compared with 136.51 ± 52.52 and 16.98 ± 6.67 μg/mL in the patients receiving cefazolin every 8 hours. Treatment success, defined as step-down to oral antibiotic therapy, occurred in 17 (81%) patients in the once-daily cefazolin and probenecid arm compared with 4 (80%) patients in the 8-hourly cefazolin arm (p value NR). Although the authors stated that there was no difference in the incidence of adverse effects between groups, 9 adverse events were reported in 21 patients receiving once-daily cefazolin with probenecid compared with one adverse event (fatigue) in 5 patients receiving the 8-hourly cefazolin dosing regimen. Adverse events in the once-daily cefazolin group included fatigue (n = 3), nausea (n = 2), headache (n = 2), sore gums (n = 1), and rash (n = 1).

Clinical Trials

A prospective, single-center study was conducted using patients presenting to the ED with either soft tissue infection or cellulitis severe enough to require intravenous antibiotics but not requiring immediate hospitalization as assessed by the ED physician.¹² Patients with an allergy to study medications or with renal impairment (not defined) were excluded. Patients were randomized to receive blinded administration of either cefazolin 2 g or ceftriaxone 2 g daily for an unspecified number of days. Each patient received probenecid 1 g with each dose of antibiotic and a prescription for a 7-day course of oral penicillin V 500 mg and cloxacillin 500 mg, both taken 4 times daily. The outcome measure was the ratio of each patient's area of cellulitis on the last visit compared with the area of affected tissue on the initial visit. Relapses were assessed by review of hospital records for the 30-day period following each patient's treatment course. The investigators assumed that all patients would seek medical care from the same center if relapse occurred.

One hundred ninety-four patients were evaluated in the final analysis. In the 96 patients receiving ceftriaxone, the mean length of treatment ± SD was 2.5 ± 1.5 days compared with 2.8 ± 1.9 days in the 98 patients receiving cefazolin. In most patients, the cause of infection was intravenous drug use (45% with ceftriaxone vs 56% with cefazolin), and the most common site of infection was the arm (48% with ceftriaxone vs 53% with cefazolin). The investigators found a similar ratio of infected area on the last ED assessment between groups (0.8 ± 0.5 with ceftriaxone vs 0.7 ± 0.4 with cefazolin; p = NS); however, considering that a ratio of 1 would be interpreted as no change in the area of cellulitis, most patients did not appear to experience much decrease in the size of their infection. The number of failures, defined as lack of resolution of the infection requiring hospital admission, change in antibiotic therapy, or relapse, was similar between groups (7 [7%] ceftriaxone vs 8 [8%] cefazolin). Adherence with oral antibiotics was assessed by verbal interview; 59 (61%) patients receiving ceftriaxone and 49 (50%) patients receiving cefazolin were nonadherent (not defined) with oral antibiotics. The only adverse effect was hives, which developed immediately in one patient upon drug administration (group unclear). The authors concluded that these results suggest that the 2 treatment regimens, in combination with oral therapy, are equally effective.¹².

A second study evaluated the equivalency of cefazolin plus probenecid versus ceftriaxone in the treatment of cellulitis.¹³ This multicenter trial included patients with moderate to severe cellulitis requiring parenteral antibiotics and hospital admission due to the severity of the cellulitis, presence of sepsis, or failure of previous oral or intravenous therapy. Patients were excluded if they had mild to moderate cellulitis deemed treatable with oral antibiotics, nosocomial cellulitis, or cellulitis associated with osteomyelitis, septic shock, or suspected bacteremia. Patients were also excluded for safety reasons (ie, allergies to β-lactam antibiotics, renal or hepatic impairment) or if they were assessed to be unsuitable for home intravenous antibiotic therapy. Patients were randomized to receive once-daily blinded treatment with probenecid 1 g followed 10–15 minutes later with cefazolin 2 g (n = 67) or placebo tablets followed by ceftriaxone 1 g (n = 67). The duration of therapy was left to the discretion of the attending physician. The primary outcome, clinical cure, was assessed at the end of therapy and one month following treatment. Microbiologic cure was also assessed.

The most common predisposing risk factors for cellulitis were tinea pedis and previous trauma, and the most frequent site of infection was the lower limbs (73% of pts.). Fifty-one percent of patients in the cefazolin–probenecid group and 54% of patients receiving ceftriaxone had received antibiotics prior to enrollment in this study. The mean ± SD number of doses of study antibiotic was similar between groups (6.97 ± 2.6 cefazolin–probenecid vs 6.12 ± 2.1 ceftriaxone).¹³.

At the end of intravenous therapy, 8 patients in the cefazolin–probenecid group and 10 patients receiving ceftriaxone were reported to have indeterminate clinical outcomes defined as either inappropriate enrollment in the study (n = 10), non-therapy complications (n = 3), concomitant administration of other antibiotics (n = 3), hospitalization for debridement despite improving infection (n = 1), and possible adverse reaction to therapy (n = 1). These patients were excluded from the clinical outcome analysis. Clinical cure (complete resolution of signs and symptoms enabling discontinuation of intravenous therapy or switch to oral antibiotics) was reported in 51 (86%) of the remaining 59 patients receiving cefazolin–probenecid compared with 55 (96%) of 57 patients receiving ceftriaxone (p = 0.11). Treatment failure or improvement alone was reported in 8 (14%) patients receiving cefazolin–probenecid compared with 2 (4%) patients receiving ceftriaxone (p value NR). In the patients with clinical cure at the end of intravenous therapy, 3 receiving cefazolin–probenecid were lost to follow-up at one month. Thus, 46 (96%) of 48 patients remained cured in the cefazolin–probenecid group. In patients randomized to receive ceftriaxone and achieving clinical cure at the end of intravenous therapy, 50 (91%) of 55 patients remained cured at one month (p = 0.25).¹³.

Of 20 patients receiving cefazolin–probenecid who had wound cultures performed, pathogens were isolated in 14 (70%); 2 of these patients with positive cultures were reported to have treatment failure. One patient grew methicillin-sensitive S. aureus (MSSA), cefazolin-resistant Escherichia coli, and mixed anaerobes; the other patient grew MSSA on initial culture. In 27 patients receiving ceftriaxone with initial wound cultures performed, 20 (74%) wound cultures yielded pathogens, and one of these patients was reported to have treatment failure. This patient's initial cultures grew MSSA, but the patient developed an abscess requiring surgical drainage after 2 days of therapy.¹³.

The median serum cefazolin trough concentration (n = 40) was 2.35 μg/mL (range <0.4–85.7), and the median serum peak concentration (n = 32) was 137.65 μg/mL (76.6–656.6). In patients receiving ceftriaxone, the median serum trough concentration (n = 40) was 15.45 μg/mL (0.9–38.8), and the median serum peak concentration (n = 33) was 119.8 μg/mL (45.2–166.4). The investigators noted, however, that clinical outcome did not appear to correlate with serum antibiotic concentrations.¹³.

Adverse reactions appeared to be more common in patients receiving cefazolin–probenecid than in those receiving ceftriaxone (14 [21%] vs 7 [10%] pts., respectively; p = 0.15). Nausea and vomiting occurred more frequently in patients receiving cefazolin–probenecid (n = 11) than in those receiving ceftriaxone (n = 3; p = 0.048), and one patient receiving cefazolin–probenecid required hospital admission for severe nausea, vomiting, and diarrhea. The investigators concluded that the once-daily regimen of cefazolin–probenecid is a safe, practical, and effective treatment option for home-based treatment of patients with moderate to severe cellulitis.¹³.

Discussion

Cefazolin is a cell-wall–acting agent that has a rapid bactericidal effect against S. aureus and β-hemolytic streptococci. As with other β-lactam antibiotics, cefazolin possesses time-dependent killing characteristics and has a postantibiotic effect against gram-positive organisms.^28–30 The pharmacokinetic–pharmacodynamic surrogate marker that is best correlated with antimicrobial activity of cephalosporins is the duration of time the serum concentration remain above the minimum inhibitory concentration (MIC) throughout the dosing interval.^28–30 In vitro and pharmacodynamic studies, as well as limited clinical trials, have suggested that, with cephalosporins, optimal microbiologic eradication and clinical cures can be obtained when the serum concentration of the cephalosporin exceeds the MIC of the organism for 60–70% of the dosing interval.^31–33 In fact, S. aureus is maximally killed when serum concentrations exceed the MIC for 40–50% of the dosing interval.^31–34 The cefazolin serum concentrations reported 24 hours after administration of cefazolin and probenecid in 3 studies^13,26,27 remain approximately twice the MIC of the most common pathogenic organisms in cellulitis such as S. aureus (1.0 μg/mL) and β-hemolytic streptococci (<0.2 μg/mL).³⁵ Thus, it appears that the pharmacokinetic parameters of either intravenous cefazolin 2 g daily plus oral probenecid 1 g once daily or 500 mg 4 times daily will, in theory, provide adequate serum concentrations of cefazolin to permit bactericidal activity against the most common infectious organisms found in patients with cellulitis.

The available clinical evidence suggests that treatment of SSTI in the ED with cefazolin 2 g plus probenecid 1 g may result in clinical cure rates of approximately 85%; however, the limitations of these trials must be discussed.^12,13 Several methodologic flaws in the study design by Brown et al.¹² may confound interpretation of the results. Although those authors stated that probenecid does not alter the pharmacokinetics of ceftriaxone, another study comparing the pharmacokinetic parameters of intravenous ceftriaxone 1 g with those of ceftriaxone plus oral probenecid 1 g given 2 hours and 1 hour before ceftriaxone administration, followed by oral probenecid 500 mg every 6 hours continued for 48 hours, showed different results.³⁶ The addition of probenecid to ceftriaxone significantly decreased the mean ± SD total AUC of ceftriaxone (from 1024 ± 349 to 767 ± 164 μg•h/mL; p < 0.01), increased the total clearance of the drug (from 0.244 ± 0.074 to 0.312 ± 0.085 mL/min/kg; p < 0.01), and shortened the elimination half-life (from 8.1 ± 2.1 to 6.5 ± 1.4 h; p < 0.01). Although the probenecid doses in this study were much higher than used by Brown et al.,¹² pharmacokinetic alterations do appear to occur with the concomitant administration of ceftriaxone and probenecid. It is unclear whether these changes, although statistically significant, would result in clinically important alterations in the pharmacokinetics of ceftriaxone. Moreover, since the trough concentrations of ceftriaxone reported by Brown et al. are above the MIC₉₀ for both S. aureus (4.0 μ g/mL) and β-hemolytic streptococci (<0.5 μg/mL), it is unlikely that clinical outcomes were affected by the addition of probenecid.^35,37 Administration of blinded oral placebo in conjunction with ceftriaxone would have been preferable to probenecid administration, thereby duplicating the clinical practice of administering ceftriaxone monotherapy and eliminating any possible influence of probenecid on ceftriaxone pharmacokinetics.

Another confounding influence in study design was the administration of oral antibiotics with antimicrobial activity against common pathogens in SSTI concurrently with intravenous therapy. Adherent patients may have achieved clinical cure due to the oral antibiotic therapy. Although adherence was assessed through verbal interview and appeared to be equal between groups, perhaps a more objective assessment of adherence could be made through analysis of prescription fill records to ensure that the drug was dispensed as ordered, followed by tablet count. The short duration of intravenous therapy also makes it difficult to ascertain whether both treatments are equivalent in achieving clinical cure. Given that patients received approximately 2.5 days of intravenous therapy and experienced a mean decrease of 20–30% in the area of cellulitis, it seems the duration of treatment was likely not sufficient to exclude a difference between treatment regimens. Rather than using the ratio of affected area of cellulitis as the primary outcome, it would be more useful to assess clinical cure rates. It appears that most patients did not achieve clinical cure since the ratio of infection did not appear to be much less than 1; however, clinical cure was assumed since the patients did not return to the same center for follow-up. In an unreliable and transient population such as intravenous drug users, this assumption may not be valid; failure to return for follow-up should not be interpreted as treatment success.¹².

The clinical trial by Grayson et al.¹³ had less confounding factors. Although most patients received a 7- to 10-day course of oral antibiotics (cephalexin or clindamycin) following intravenous therapy, it appears that subjects did not take oral antibiotics with intravenous treatment; however, this was not confirmed in the text. Placebo tablets rather than probenecid were used in conjunction with ceftriaxone therapy. The administration of a lower dose of ceftriaxone (ie, 1 g rather than 2 g) may have minimized apparent differences between treatments in this equivalency trial. Although the authors reported a power analysis to determine equivalency of the dosing regimens, the number of patients required to achieve that power was not stated, and it is uncertain whether the ability to determine equivalency was attained.

An abstract reported similar cure rates in patients receiving cefazolin 2 g daily in addition to probenecid 1 g daily for treatment of SSTI in the ED.²¹ The majority (88%) of 346 patients in a one-year period receiving this combination for a mean ± SD treatment duration of 3.5 ± 1.9 days achieved treatment success, defined as discharge from the outpatient program on either no therapy or oral antibiotics alone following improvement or resolution of the infection. These clinical cure rates, along with those found by Grayson et al.,¹³ compare favorably with historical controls in which cefazolin monotherapy, administered 0.5–1.0 g intravenously every 8 hours, demonstrated clinical cure rates ranging from 77% to 100%.^{5,6,8–11,14} The addition of probenecid does appear to increase the risk of adverse gastrointestinal effects. The only trial reporting adverse effects found a 21% incidence of any adverse effects in patients receiving cefazolin and probenecid compared with 10% of patients receiving ceftriaxone alone; 11 (16%) versus 3 (4.4%), respectively, involved the gastrointestinal tract.¹³.

Summary

Pharmacokinetic data suggest that intravenous cefazolin 2 g once daily, in addition to oral probenecid 1 g once daily or 500 mg 4 times daily, may provide sufficient cefazolin serum concentrations to enable microbial killing of the most common pathogens in SSTI. The available clinical information suggests that this regimen is effective for treatment of SSTI in the ED. Whether this regimen is equivalent to that using ceftriaxone 1–2 g daily has not been proven by current investigations; however, as demonstrated in one trial,¹³ clinical cure rates appear to be similar to historical regimens of cefazolin 0.5–1.0 g every 8 hours.^{5,6,8–11,14} Cefazolin–probenecid combinations have the advantage of providing narrow-spectrum antimicrobial coverage, theoretically limiting the development of antimicrobial resistance. This once-daily combination is convenient and inexpensive to administer as outpatient antimicrobial therapy for empiric treatment of SSTI; however, it may cause more adverse effects than cefazolin alone. Further studies need to be designed with the statistical power to determine equivalency to traditional regimens so that cefazolin and probenecid may be confidently prescribed for the treatment of SSTI in the ED.

References

1. Hook

Hooton

Horton

Coyle

Ramsey

Turck

Microbiologic evaluation of cutaneous cellulitis in adults. Arch Intern Med 1986;146:295–7.

2. Goldgeier

MH.

The microbial evaluation of acute cellulitis. Cutis 1983;31:649–56.

3. Sachs

MK.

The optimum use of needle aspiration in the bacteriologic diagnosis of cellulitis in adults. Arch Intern Med 1990;150:1907–12.

4. Ginsberg

MB.

Cellulitis: analysis of 101 cases and review of the literature. South Med J 1981;74:530–3.

5. Bradsher

Snow

RM.

Ceftriaxone treatment of skin and soft tissue infections in a once daily regimen. Am J Med 1984;77:63–7.

6. Gordin

Wofsy

Mills

Once-daily ceftriaxone for skin and soft tissue infections. Antimicrob Agents Chemother 1985;27:648–9.

7. Scully

Neu

HC.

Pharmacokinetics of ceftriaxone after intravenous infusion and intramuscular injection. Am J Med 1984;77:112–7.

8. Goldstein

Topiel

Ehrlich

Simon

A comparative study of ceftriaxone vs cefazolin in the treatment of cellulitis. Curr Ther Res 1984;36:653–7.

9. Slutkin

Marzouk

Dall

Mills

Comparision of cefonicid and cefazolin for treatment of soft tissue infections. Rev Infect Dis 1984;6(suppl 4):S853–6.

10.

10. Parish

Witkowski

JA.

Ceforanide compared with cefazolin in skin and soft tissue infections. Cutis 1984;33:313–9.

11.

11. Chirurgi

Edelstein

Oster

Karp

Cassano

Aiken

Randomized comparison trial of teicoplanin IV, teicoplanin IM and cefazolin for skin and soft tissue infections caused by gram-positive bacteria. South Med J 1994;87:875–80.

12.

12. Brown

Chamberlain

Goulding

Clarke

Ceftriaxone versus cefazolin with probenecid for severe skin and soft tissue infections. J Emerg Med 1996;14:547–51.

13.

13. Grayson

McDonald

Gibson

Athan

Munckhof

Paull

Once-daily intravenous cefazolin plus oral probenecid is equivalent to once-daily intravenous ceftriaxone plus oral placebo for the treatment of moderate-to-severe cellulitis in adults. Clin Infect Dis 2002;34:1440–8.

14.

14. Stevens

DL.

Teicoplanin for skin and soft tissue infections: an open study and randomized, comparative trial versus cefazolin. J Infect Chemother 1999;5:40–5.

15.

15. Dong

Kelly

Oland

Holroyd

Rowe

BH.

ED management of cellulitis: a review of five urban centers. Am J Emerg Med 2001;19:535–40.

16.

16. Cephalosporins. In: McEvoy

, ed. American Society of Health-System Pharmacists drug information. 45th ed. Bethesda, MD: American Society of Health-System Pharmacists American Hospital Formulary Service, 2003:125–223.

17.

17. Uricosuric agents. In: McEvoy

, ed. American Society of Health-System Pharmacists drug information. 45th ed. Bethesda, MD: American Society of Health-System Pharmacists American Hospital Formulary Service, 2003:2557–62.

18.

18. Cunningham

Israili

Dayton

PG.

Clinical pharmacokinetics of probenecid. Clin Pharmacokinet 1981;6:135–51.

19.

19. Tjandramaga

Cucinell

Israili

Perel

Dayton

Observations on the disposition of probenecid in patients receiving allopurinol. Pharmacology 1972;8:259–72.

20.

20. Brown

GR.

Cephalosporin-probenecid drug interactions. Clin Pharmacokinet 1993;24:289–300.

21.

21. Zed

Harder

Harrison

Purssell

RA.

Efficacy of once daily cefazolin/probenecid for the outpatient management of skin and soft tissue infections (abstract). Can J Emerg Med 2001;3:139–40.

22.

22. Kirby

WMM

Regamey

Pharmacokinetics of cefazolin compared with four other cephalosporins. J Infect Dis 1973;128(suppl):S341–5.

23.

23. Karney

Turck

Holmes

KK.

Cefazolin in the treatment of gonorrhea. J Infect Dis 1973;128(suppl):S399–403.

24.

24. Duncan

WC.

Treatment of gonorrhea with cefazolin plus probenecid. J Infect Dis 1974;130:398–401.

25.

25. Rein

Westervelt

Sande

MA.

Pharmacodynamics of cefazolin in the presence of normal and impaired renal function. Antimicrob Agents Chemother 1973;4:366–71.

26.

26. Brown

Zemcov

SJV

Clarke

AM.

Effect of probenecid on cefazolin serum concentrations. J Antimicrob Chemother 1993;31:1009–11.

27.

27. Spina

Dillon

Jr. Effect of chronic probenecid therapy on cefazolin serum concentrations. Ann Pharmacother 2003;37:621–4. DOI 10.1345/aph.1C347.

28.

28. Burgess

DS.

Pharmacodynamic principles of antimicrobial therapy in the prevention of resistance. Chest 1999;115(3 suppl):19S–23S.

29.

29. Gunderson

Ross

Ibrahim

Rotschafer

JC.

What do we really know about antibiotic pharmacodynamics?

Pharmacotherapy 2001;21 (11 pt 2):302S–18S.

30.

30. Rodvold

KA.

Pharmacodynamics of antiinfective therapy: taking what we know to the patient's bedside. Pharmacotherapy 2001;21(11 pt 2):319S–30S.

31.

31. Craig

WA.

Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Mcrobiol Infect Dis 1995;22:89–96.

32.

32. Craig

WA.

Antimicrobial resistance issues of the future. Diagn Mcrobiol Infect Dis 1996;25:213–7.

33.

33. Craig

Andes

Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J 1996;15:255–9.

34.

34. Andes

Craig

WA.

Pharmacokinetics and pharmacodynamics of outpatient intravenous antimicrobial therapy. Infect Dis Clin North Am 1998;12:849–60.

35.

35. Karchmer

AW.

Cephalosporins. In: Mandell

Bennett

Dolin

, eds. Principles and practice of infectious diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:274–91.

36.

36. Stoeckel

Trueb

Dubach

McNamara

PJ.

Effect of probenecid on the elimination and protein binding of ceftriaxone. Eur J Clin Pharmacol 1988;34:151–6.

37.

37. Performance standards for antimicrobial susceptibility testing; twelfth informational supplement. NCCLS document M100-S12. Wayne, PA: National Committee for Clinical Laboratory Standards, 2002.