cefepime and Pneumonia--Pneumococcal

In a randomized, evaluator-blind, multicenter trial, we compared cefepime (2 g three times a day) with imipenem-cilastatin (500 mg four times a day) for the treatment of nosocomial pneumonia in 281 intensive care unit patients from 13 centers in six European countries. Of 209 patients eligible for per-protocol analysis of efficacy, favorable clinical responses were achieved in 76 of 108 (70%) patients treated with cefepime and 75 of 101 (74%) patients treated with imipenem-cilastatin. The 95% confidence interval (CI) for the difference between these response rates (-16 to 8%) failed to exclude the predefined lower limit for noninferiority of -15%. In addition, therapy of pneumonia caused by an organism producing an extended-spectrum beta-lactamase (ESBL) failed in 4 of 13 patients in the cefepime group but in none of 10 patients in the imipenem group. However, the clinical efficacies of both treatments appeared to be similar in a secondary intent-to-treat analysis (95% CI for difference, -9 to 14%) and a multivariate analysis (95% CI for odds ratio, 0.47 to 1.75). Furthermore, the all-cause 30-day mortality rates were 28 of 108 (26%) patients in the cefepime group and 19 of 101 (19%) patients in the imipenem group (P = 0.25). Rates of documented or presumed microbiological eradication of the causative organism were similar with cefepime (61%) and imipenem-cilastatin (54%) (95% CI, -23 to 8%). Primary or secondary resistance of Pseudomonas aeruginosa was detected in 19% of the patients treated with cefepime and 44% of the patients treated with imipenem-cilastatin (P = 0.05). Adverse events were reported in 71 of 138 (51%) and 62 of 141 (44%) patients eligible for safety analysis in the cefepime and imipenem groups, respectively (P = 0.23). Although the primary end point for this study does not exclude the possibility that cefepime was inferior to imipenem, some secondary analyses showed that the two regimens had comparable clinical and microbiological efficacies. Cefepime appeared to be less active against organisms producing an ESBL, but primary and secondary resistance to imipenem was more common for P. aeruginosa. Selection of a single agent for therapy of nosocomial pneumonia should be guided by local resistance patterns.

Topics: Adult; Aged; APACHE; Cefepime; Cephalosporins; Cilastatin; Critical Care; Cross Infection; Double-Blind Method; Drug Therapy, Combination; Endpoint Determination; Female; Humans; Imipenem; Male; Middle Aged; Pneumonia, Pneumococcal; Prospective Studies; Protease Inhibitors; Respiration, Artificial; Thienamycins

The global emergence of Streptococcus pneumoniae resistance to fluoroquinolones is alarming and has grown to be a cause for significant concern worldwide. We report the first three cases of levofloxacin resistant S. pneumoniae isolates in a tertiary medical center in Beirut, Lebanon. Judicious use of antimicrobial agents is imperative to limit the spread of such resistant strains.

Topics: Aged; Anti-Bacterial Agents; Cefepime; Ceftazidime; Cephalosporins; Clarithromycin; Drug Resistance, Multiple, Bacterial; Humans; Imipenem; Lebanon; Levofloxacin; Male; Ofloxacin; Pneumococcal Infections; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Vancomycin

S-3578 is a novel beta-lactam with enhanced activity against drug-resistant gram-positive cocci such as methicillin-resistant Staphylococcus aureus (MRSA). We used murine penicillin-resistant Streptococcus pneumoniae lung infection and neutropenic murine systemic MRSA infection models to determine the pharmacokinetic (PK)-pharmacodynamic (PD) parameter that best correlated with efficacy. Pharmacokinetic studies revealed that the maximum concentration in serum/dose values for S-3578 and cefepime in plasma in the lung infection model were 1.21 to 1.54 and 0.97 to 1.29, respectively; those for S-3578 in plasma in the systemic infection model were 0.78 to 1.02. The area under the concentration-time curve (AUC)/dose values for S-3578 and cefepime in plasma in the lung infection model were 0.98 to 1.13 and 0.77 to 1.04, respectively, and those for S-3578 in plasma in the systemic infection model were 1.03 to 1.11. The half-lives of S-3578 and cefepime in plasma in the lung infection model were 0.29 to 0.38 and 0.29 to 0.34, respectively, and those of S-3578 in plasma in the systemic infection model were 0.40 to 0.61. The time above the MIC was the PK-PD parameter that best correlated with efficacy in the murine lung infection model (R(2) = 84 and 92% for S-3578 and cefepime in plasma, respectively). There was a twofold increase in the dose of S-3578 in the systemic infection model compared to that in the pneumonia model, yet the AUCs were the same. This may be due to the different MICs for the two pathogens.

Topics: Animals; Area Under Curve; Cefepime; Cephalosporins; Colony Count, Microbial; Female; Injections, Subcutaneous; Lung; Methicillin Resistance; Mice; Mice, Inbred CBA; Mice, Inbred ICR; Microbial Sensitivity Tests; Pneumonia, Pneumococcal; Sepsis; Staphylococcal Infections; Staphylococcus aureus; Survival Analysis; Tissue Distribution