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Is once-daily cefazolin plus probenecid similar to twice-daily cefazolin in the treatment of cellulitis?

Three Part Question

In [patients with moderate to severe soft tissue infection], is [daily cefazolin plus oral probenecid] compared to [two or three times a day intravenous cefazolin alone] associated with [success in therapy] ?

Clinical Scenario

A 43 years old man presents to the emergency department with a moderate cellulitis with lymphangitis of the forearm following a trivial skin trauma in the previous days. The patient is not known for any health problem nor does he have any risk factor for CA-MRSA. You wonder if daily intravenous cefazolin following oral probenecid is as effective as two or three times a day intravenous cefazolin treatment.

Search Strategy

The search was performed on January 8th, 2013.
MEDLINE (through PubMED)
EMBASE 1966 to 01/2013
MEDLINE: skin diseases, infectious[MeSH Terms] AND probenecid[MeSH Terms] AND cefazolin[MeSH Terms]

EMBASE: \"skin infection\" and \"cefazolin\" and \"probenecid\"

Search Outcome

32 papers were screened for relevance. Of those, one was found relevant to the question.

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Patients > 18 years old referred to a hospital-in-the-home service for treatment of uncomplicated cellulitis. Exclusion criteria: pregnancy or breast-feeding, allergy to cefazolin or probenecid, ALT, AST or AP level > twice upper reference limit, CrCl < 40 ml/min, C-I to cefazolin or probenecidProspective observational cohortTime until non-progression (TTPN)TTPN was similar in each group: 2.11 (1.98-2.23) and 2.13 (1.81-2.45) for once and twice daily regimen, respectively.1) No randomization, no blinding to treatment groups 2) Two different groups compared: patients in the twice-daily regimen were older and had more comorbidities 3) No intention-to-treat analysis: Only patients completing prescribed therapy are included in the analysis 4) Mean duration of cellulitis before initiation of i.v. treatment of 3 days in once-daily treatment compared with 6 days in twice-daily treatment 5) Few follow-up data available
Length of stay (LOS)Mean LOS of 6.55 (5.96-7.15) in once-daily regimen and 7.67 (6.69-8.65) in twice-daily regimen.
Treatment failureTreatment failure in 7 patients in once-daily (3%) and 10 patients (9%).
Treatment related side-effectsTreatment side effects in 15.5% (33/213) of once-daily regimen and in 9.1% (8/88) of twice-daily regimen, including mostly nausea, drowsiness and diarrhea.


Once-daily cefazolin plus probenecid is a commonly prescribed antibiotic regimen in uncomplicated cellulitis. However, data supporting this practice is limited. Most studies have focused on pharmacokinetic evidence (2) or comparison with another broad-spectrum agent (3). Despite a lack of similar control group in the only clinical study addressing the question, this treatment appears to be safe in selected population. 2) Cox VC, Zed PJ, “Once-daily cefazolin and probenecid for skin and soft tissue infections”, Annals of Pharmacotherapy, 2004, 38(3):458-63. 3) Brown G, et al., “Ceftriaxone versus cefazolin with probenecid for severe skin and soft tissue infections”, Journal of Emergency Medicine, 1996; 14:547-51.

Clinical Bottom Line

In young (≤ 75) and healthy patients, once-daily cefazolin plus probenecid appears to be safe regarding TTPN and treatment failure in uncomplicated cellulitis, although one might expect more treatment related side-effects. However, no conclusion can be drawn about the relative efficacy compared to twice-daily regimen. Better-designed studies are needed to precisely answer this question.


  1. Garrett T, Harbort Y, Trebble M, et al. Once or twice-daily, algorithm-based intravenous cephazolin for home-based cellulitis treatment Emergency Medicine Australia 2012; 24, 383-392