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Study 1 Citation: Grayson ML,
McDonald M, Gibson K, Athan E, Munckhof WJ, Paull P, Chambers F. Med J Aust 2002 May 6;176(9):440-5Infectious Diseases Department, Austin & Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia. Lindsay. Grayson@armc.org.au |
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Abstract:
This study compared the use of an IV antibiotic plus oral probenecid with a different IV antibiotic plus oral placebo. Once-daily cefazolin (2g IV) plus probenecid (1g by mouth) was trialed against once-daily ceftriaxone (1g IV) and oral placebo in a randomized, double-blind trial utilizing home-based therapy. 116 adult moderate-to-severe cellulitis patients were assessed for clinical cure at end of treatment, and at one-month follow-up. The number of treatment doses was similar in both arms of the study, as was the rates of adverse reactions.
The authors concluded from their results that once-daily cafazolin-probenecid was a cheap, practical and effective treatment option for the type of patients admitted into this study, and that it is cost-effective as well by avoiding the use of more expensive third-generation cephalosporins in most patients.
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|
cefazolin-probenecid |
|
ceftriaxone-placebo |
|
# of patients |
59 |
|
57 |
|
achieved clinical cure |
86% |
|
96% |
|
retained cure at |
96% |
|
91% |
|
1-month follow-up |
|
|
|
|
# of treatment doses (mean) |
6.97 +/- 2.6 |
|
6.12 +/- 2.1 |
|
trough concentrations |
2.35 microgram/mL |
|
15.45 microgram/mL |
Table 1
placebo, trough, first generation antibiotic, third generation antibiotic, clinical cure, cellulitis
Discussion:
Cellulitis is most often caused by bacterial and fungal infections 1. In patients seen with normal immune systems, the most common organisms responsible are group A streptococci and Staphylococcus aureus. In patients seen that have compromised immune systems, the most common organism responsible are gram-negative rods or fungi (although the authors note that fungal cellulites is rare). For immunocompromised patients that come in contact with fresh water, the causative organism may be Aeromanas hydophila (a gram-negative rod). The same patients could have a type of cellulites caused by pneumococcus, which is most commonly linked to sepsis and tissue necrosis.
Patients considered for the study were declined entry for the following reasons:
1. they could be treated with oral antibiotics and had mild-to-moderate cellulitis
2. their cellulites was obtained through nosocomial origins
3. their cellulitis was associated with either septic shock, osteomyelitis or bacteremia.
It is worth noting some of the mechanics of this study. Namely that it was a randomized, prospective trial. Participants were assessed at the end of therapy and at a 1-month follow-up visit. Clinical end-point definitions for the assessment for both groups were as follows. For the end-of-therapy assessment, "cure" was defined as complete resolution of signs and symptoms of soft-tissue infection that was sufficient enough to result in either discontinuation of all antibiotic therapy or a switch to the use of oral agents. For the 1-month follow-up assessment, "cure" was defined as clinical cure with no recurrence of cellulitis at the same site within 1 month of completion of treatment. For the end-of-therapy assessment, "improvement-only" was defined as alleviation but incomplete resolution of >2 presenting signs and symptoms, such that improvement in the patient's condition was insufficient to allow for a switch to the use of oral agents after up to 14 days of administration of intravenous therapy; patients who were initially classified as having improvement only were considered to have had treatment failure in all statistical analyses. So from this standpoint this was a very fair study.
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Study Group Breakdown Cefazolin-probenecid Ceftriaxone-placebo # of patients 50 (76%) 46 (64%) Site of cellulitis
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Table 2
Results:
It is well accepted that individuals with complicated cellulitis, those patients with an underlying illness, or with signs of systemic toxicity require intravenous antibiotics[1]. However, recommended methods of antibiotic therapy vary between physician, institution and specialty. Past practice included treatment with penicillin and/or an antistaphylococcal penicillin (e.g. flucloxacillin or dicloxacillin). More recently, regimes with once-daily dosing schedules such as ceftriaxone have been used for home-based, intravenously administered therapy, to avoid the need for admission to the hospital and to minimize the number of nursing visits needed [2-3]. However, these third generation antibiotics may be more than required and therefore the first generation antibiotics may be more effective for the first line therapy[4].
| Clinical Outcome Cefazolin-probenecid Ceftriaxone-placebo At end-of-therapy cases assessed
59
57 At 1-month follow-up visit cases assessed
48
55 |
Table 3
Summary of Study 1
| The authors of this study compared a once-daily
regimen of cefazolin plus PO probenecid to a once-daily regimen of
ceftriazone plus a PO placebo. Cefazolin (Ancef, Kefzol, Zolicef) is a first-generation semi-synthetic cephalosporin. Ceftriaxone (Rocephin) is a third-generation cephalosporin. The true nature of this study was two-fold. That of comparing first generation antibiotics to third, and of looking at the effectiveness of home-based antibiotic treatment therapy. The authors found that in certain instances, first generation antibiotics were sufficient, and even preferable, to third generation antibiotics. The authors stressed that third generation antibiotics may be more than are required for some infections. The authors concluded that careful consideration should be used when making this choice and that in some cases first generation antibiotics may be a better choice. They also found that home-based antibiotic treatment regimens worked very well, with the emphasis in this study being on IV administration routes in the home, resolving patient compliance and dosing concerns. Financial considerations were also addressed by the authors, although, it is felt, more emphasis should have been placed on this aspect and, indeed, this is lacking in most clinical analyses. The cefazolin-probenecid regimen reflects a substantially lower purchase price than does the ceftriaxone-placebo regimen ($5.70 vs. $9.70 per 1g). There were some possible limitations with this study as noted by the authors. First, there is a question as to the inclusion criteria and how patients were classified with moderate-to-severe cellulitis. The study's inclusion criteria was typical pf that routinely used to select patients for homecare, and so patients likely to need surgical intervention were excluded from participating. Second, differences in treatment efficacy of <15% may not have been detected in the study, note the authors, because of the small size of the study population. Nevertheless, similarities in the study outcomes were small enough to indicate that differences were likely to be very small. |
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References:
1. Swartz MN. Cellulitis and subcutaneous tissue infections. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000: 1037-1057.
2. Tice AD. Once-daily ceftriaxone outpatient therapy in adults with infections. Chemotherapy 1991;37(Suppl13):7-10.
3. Grayson ML, McDonald M, Gibson K, Athan E, Munckhof WJ, Paull P, Chambers F. 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. Med J Aust 2002 May 6;176(9):440-5
4. World Health Organization. Global strategy for containment of antimicrobial resistance. September 2001. Available at http://www.who.int/emc/amr.html.