Medical Grand Rounds

Update in infectious disease treatment

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References

IS CEFEPIME SAFE?

Yahav D, Paul M, Fraser A, Sarid N, Leibovici L. Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis 2007; 7:338 348.

Cefepime (Maxipime) is a broad-spectrum, fourth-generation cephalosporin. It is widely used for its approved indications: pneumonia; bacteremia; urinary tract, abdominal, skin, and soft-tissue infections; and febrile neutropenia.

In 2006, Paul et al6 reviewed 33 controlled trials of empiric cefepime monotherapy for febrile neutropenia and found a higher death rate with cefepime than with other beta-lactam antibiotics. That preliminary study spawned the following more comprehensive review by the same group.

The study. Yahav et al7 performed a meta-analysis of randomized trials that compared cefepime with another beta-lactam antibiotic alone or combined with a non-beta-lactam drug given in both treatment groups. Two reviewers independently identified studies from a number of databases and extracted data.

The primary end point was the rate of death from all causes at 30 days. Secondary end points were clinical failure (defined as unresolved infection, treatment modification, or death from infection), failure to eradicate the causative pathogens, superinfection with different bacterial, fungal, or viral organisms, and adverse events.

More than 8,000 patients were involved in 57 trials: 20 trials evaluated therapy for neutropenic fever, 18 for pneumonia, 5 for urogenital infections, 2 for meningitis, and 10 for mixed infections.

Comparison drugs for febrile neutropenia were ceftazidime (Ceptaz, Fortaz, Tazicef); im-ipenem-cilastatin (Primaxin) or meropenem (Merrem); piperacillin-tazobactam (Zosyn); and ceftriaxone (Rocephin). Aminoglycosides were added to both treatment groups in six trials and vancomycin was added in one trial.

For pneumonia, comparison drugs were ceftazidime, ceftriaxone, cefotaxime (Claforan), and cefoperazone-sulbactam.

Adequate allocation concealment and allocation-sequence generation were described in 30 studies. Scores for baseline patient risk factors did not differ significantly between study populations.

Findings. The death rate from all causes was higher in patients taking cefepime than with other beta-lactam antibiotics (risk ratio [RR] 1.26, 95% confidence interval [CI] 1.08–1.49, P = .005). The rate was lower with each of the alternative antibiotics, but the difference was statistically significant only for cefepime vs piperacillin-tazobactam (RR 2.14, 95% CI 1.17–3.89, P = .05).

The rate of death from all causes was higher for cefepime in all types of infections (except urinary tract infection, in which no deaths occurred in any of the treatment arms), although the difference was statistically significant only for febrile neutropenia (RR 1.42, 95% CI 1.09–1.84, P = .009). No differences were found in secondary outcomes, either by disease or by drug used.

Comments. This meta-analysis supports previous findings that more patients die when cefepime is used. The mechanism, however, is unclear. The authors call for reconsideration of the use of cefepime for febrile neutropenia, community-acquired pneumonia, and health-care associated pneumonia. In November 2007, the US Food and Drug Administration (FDA) launched an investigation into the risk of cefepime but has not yet made recommendations. Practitioners should be aware of these data when considering antimicrobial options for treatment in these settings. Knowledge of local antimicrobial susceptibility data of key pathogens is essential in determining optimal empiric and pathogen-specific therapy.

AN ANTIBIOTIC AND A NASAL STEROID ARE INEFFECTIVE IN ACUTE SINUSITIS

Williamson IG, Rumsby K, Benge S, et al. Antibiotics and topical nasal steroid for treatment of acute maxillary sinusitis: a randomized controlled trial. JAMA 2007; 298:2487 2496.

In the United States and Europe 1% to 2% of all primary care office visits are for acute sinusitis. Studies indicate that 67% to nearly 100% of patients with symptoms of sinusitis receive an antibiotic for it, even though the evidence of efficacy is weak and guidelines do not support this practice. Cochrane reviews8,9 have suggested that topical corticosteroids, penicillin, and amoxicillin have marginal benefit in acute sinusitis, but the studies on which the analyses were based were flawed.

The Berg and Carenfelt criteria were developed to help diagnose bacterial sinusitis.10 At the time they were developed, computed tomography was not routinely done to search for sinusitis, so plain film diagnosis was compared with clinical criteria. The Berg and Carenfelt criteria include three symptoms and one sign: a history of purulent unilateral nasal discharge, unilateral facial pain, or bilateral purulent discharge and pus in the nares on inspection. The presence of two criteria has reasonable sensitivity (81%), specificity (89%), and positive predictive value (86%) for detecting acute bacterial or maxillary sinusitis in the office setting.

The study. Williamson et al11 conducted a double-blind, randomized, placebo-controlled trial of antibiotic and topical nasal steroid use in patients with suspected acute maxillary sinusitis. The trial included 240 patients who were seen in 58 family practices over 4 years in the United Kingdom and who had acute nonrecurrent sinusitis based on Berg and Carenfelt criteria. Patients were at least 16 years old; the average age was 44. Three-quarters were women. Few had fever, and 70% met only two Berg and Carenfelt criteria; the remaining 30% met three or all four criteria. Patients were excluded who had at least two sinusitis attacks per year, underlying nasal pathology, significant comorbidities, or a history of penicillin allergy, or if they had been treated with antibiotics or steroids during the past month.

Patients were randomized to receive one of four treatments:

  • Amoxicillin 500 mg three times a day for 7 days plus budesonide (Rhinocort) 200 μg in each nostril once a day for 10 days
  • Placebo amoxicillin plus real budesonide
  • Amoxicillin plus placebo budesonide
  • Placebo amoxicillin plus placebo budes-onide.

The groups were well matched. Outcomes were based on a questionnaire and a patient diary that assessed the duration and severity of 11 symptoms.

Findings. No difference was found between the treatment groups in overall outcome, in the proportion of those with symptoms at 10 days, or in daily symptom severity. The secondary analysis suggested that nasal steroids were marginally more effective in patients with less severe symptoms.

The authors concluded that neither an antibiotic nor a nasal steroid, alone or in combination, is effective for acute maxillary sinusitis in the primary care setting, and they recommended against their routine use.

Comments. This study had limitations. Some cases of viral disease may have been included: no objective reference standard (ie, computed tomography of the sinuses or sinus aspiration) was used, and although the Berg and Carenfelt criteria have been validated in secondary care settings, they have not been validated in primary care settings. In addition, fever was absent in most patients, and mild symptoms were poorly defined. Moreover, recruitment of patients was slow, raising questions of bias and generalizability. The study also did not address patients with comorbidities.

Nevertheless, the study shows that outpatients with symptoms of sinusitis without fever or significant comorbidities should not be treated with oral antibiotics or nasal steroids. Otherwise, antibiotic therapy may still be appropriate in certain patients at high risk and in those with fever.

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