Experimental study of meropenem in the therapy of cephalosporin-susceptible and -resistant pneumococcal meningitis.

Meropenem is a carbapenem antibiotic that is highly active against the pathogens causing meningitis. Results with meropenem in the experimental rabbit model of penumococcal meningitis have been controversial, and the possible role of renal dehydropeptidase I in meropenem efficacy has been suggested. The aim of this study was to determine the efficacy of meropenem in two meningitis models and the possible influence of the animal model over results. Two strains of Streptococcus pneumoniae with different susceptibility to beta-lactams have been used in a guinea pig model and the classical rabbit meningitis model. Meropenem was bactericidal at 6 h in the guinea pig model against both strains with a reduction of >4 log ufc/ml. In the rabbit model it was bactericidal at 6 h against the susceptible strain, but against the resistant 3/8 therapeutical failures were recorded at 6 h, being bactericidal at 24 h. In conclusion, meropenem has shown bactericidal activity in both experimental models. This work emphasises the importance of an adequate election of the animal model for the appropriate development of studies of antimicrobial efficacy. We believe that guinea pig should be considered the best choice among laboratory animal species when assessing meropenem efficacy.

Enterobacter meningitis: organism susceptibilities, antimicrobial therapy and related outcomes.

BACKGROUND: Meningitis due to Enterobacter species is an uncommon infection in adults; however, when present, treatment is frequently complicated by resistance of many Enterobacter isolates to third-generation cephalosporins and poor central nervous system penetration of other antibiotics. The aim of this study was to retrospectively review cases of meningitis caused by Enterobacter species at our institution, to better characterize patient factors, pathogen characteristics, and treatment options for this infection. METHODS: We reviewed all cases of Enterobacter meningitis in a 12-year period at a tertiary care center. Data collected included patient demographics, antibiotic sensitivities of Enterobacter isolates, antimicrobial therapy, and patient outcomes. RESULTS: Nineteen cases were identified, primarily in patients with neurotrauma and in neurosurgical patients. Enterobacter cloacae was the most frequent Enterobacter species isolated followed by Enterobacter aerogenes and Enterobacter agglomerans (50%, 34%, and 16% of cultures, respectively). Overall, clinical cure/improvement was achieved in 47% of patients, and the mortality rate was 21%. Antibiotic treatment varied substantially and included third-generation cephalosporins, intravenous and intrathecal aminoglycosides, trimethoprim-sulfamethoxazole (TMP-SMX), piperacillin, ciprofloxacin, and other miscellaneous antibiotics. Treatment with TMP-SMX was associated with a high rate of clinical cure/improvement, whereas third-generation cephalosporins were less efficacious. CONCLUSIONS: Enterobacter meningitis is an infrequent complication of neurological insult. Treatment is often complicated by resistance of Enterobacter species to third-generation cephalosporins. Our results indicate that while third-generation cephalosporins are not the most appropriate choice of agents to treat Enterobacter meningitis, TMP-SMX may yield satisfactory results.

Pharmacodynamics of trovafloxacin in a mouse model of cephalosporin-resistant Streptococcus pneumoniae pneumonia.

Trovafloxacin is a potentially useful agent for treatment of infections caused by cephalosporin-resistant Streptococcus pneumoniae. We studied the effectiveness of trovafloxacin therapy and examined the correlation between pharmacodynamic indices in serum and lung, and bacterial killing. Immunocompetent Balb/c mice were infected by intranasal inoculation of a cephalosporin-resistant S. pneumoniae isolate (MIC of ceftriaxone and trovafloxacin 2 and 0.06 mg/L, respectively). Trovafloxacin 10-30 mg/kg/day in one or three divided doses was started 15 h after infection. Serum and lung drug concentrations were measured at multiple time points for 24 h. Serum concentrations peaked at 30-60 min and lung concentrations approximately 30 min later. The serum T1/2 was approximately 9 h and lung T1/2 varied from 5 to 9 h. Lung AUC and Cmax values were 2-3 times greater than those in serum. At the start of therapy lung bacterial concentrations were 8.4 +/- 0.3 log10 cfu/mL and 24 h later had decreased by 3.5 +/- 0.2, 4.0 +/- 0.2, 0.8 +/- 0.3 and 1.0 +/- 1.2 log10 cfu/mL with 30 mg/kg x 1, 10 mg/kg x 3, 10 mg/kg x 1 and 3.3 mg/kg x 3 regimens, respectively. Although the larger dosages were more effective (P < 0.001) the differences between divided and single dosage regimens were not significant. Trovafloxacin serum AUC/MIC ratio correlated best with bacterial killing in the lungs over 24 h. Trovafloxacin is likely to be useful in the treatment of cephalosporin-resistant S. pneumoniae pneumonia.