Activities of Ertapenem, a New Long-Acting Carbapenem, against Penicillin-Sensitive or -Resistant Pneumococci in Experimental Meningitis

Abstract

The penetration of ertapenem, a new carbapenem with a long half-life, reached 7.1 and 2.4% into inflamed and noninflamed meninges, respectively. Ertapenem had excellent antibacterial activity in the treatment of experimental meningitis due to penicillin-sensitive and -resistant pneumococci, leading to a decrease of 0.69 ؎ 0.17 and 0.59 ؎ 0.22 log 10 CFU/ml ⅐ h, respectively, in the viable cell counts in the cerebrospinal fluid. The efficacy of ertapenem was comparable to that of standard regimens (ceftriaxone monotherapy against the penicillin-sensitive strain and ceftriaxone combined with vancomycin against the penicillin-resistant strain). In vitro, ertapenem in concentrations above the MIC was highly bactericidal against both strains. Even against a penicillin-and quinolone-resistant mutant, ertapenem had similar bactericidal activity in vitro.The continuous global increase and spread of resistant pneumococci has jeopardized the treatment of pneumococcal infections (3). Furthermore, additional resistance to cephalosporins has limited the therapeutic options against penicillin-resistant isolates. Nevertheless, ␤-lactam antibiotics remain the first-line drugs for pneumococcal infections, except when penetration into infected tissues is compromised, as in meningitis. Currently the standard regimen for meningitis due to penicillin-resistant strains is the combination of an extended-spectrum cephalosporin with vancomycin (3, 12).In addition, pneumococcal strains resistant to quinolones have been isolated, limiting the choice of alternative therapies (4). A regimen based on monotherapy would represent a clear advantage, especially when quinolone-resistant strains are suspected.Ertapenem is a new carbapenem with a long half-life and activity against the majority of human bacterial pathogens, including penicillin-resistant pneumococci (11,16,17). On the other hand, little is known about the penetration and kinetics of ertapenem into the cerebrospinal fluid (CSF) and its efficacy in pneumococcal meningitis. The aim of this study was to investigate the penetration of ertapenem into inflamed and noninflamed meninges and to test its bactericidal properties against a penicillin-sensitive strain and a penicillin-resistant strain in experimental pneumococcal meningitis.(This study was partially presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill., 16 to 19 December 2001.) MATERIALS AND METHODSStrains. The penicillin-resistant pneumococcal strain WB4 serotype 6 was isolated from a patient with pneumonia at the University Hospital of Bern, Bern, Switzerland. The MICs for this strain were as follows: penicillin, 4 mg/liter; ceftriaxone, 0.5 mg/liter; vancomycin, 0.12 to 0.25 mg/liter; and ertapenem 0.5 mg/liter. The penicillin-sensitive strain was kindly provided by the Institute for Infectious Diseases, University of Bern (MICs for this strain: penicillin, 0.05 mg/liter; ceftriaxone, 0.05 mg/liter; and ertapenem, 0.03 mg/liter). The penicillinand quinolone-resistant mutant was ...

Amp C β-lactamase-producing Escherichia coli in neonatal meningitis: diagnostic and therapeutic challenge

“…Carbapenems with activity against AmpC b-lactamases include imipenem, meropenem and the newer agent, ertapenem. 16 Imipenem-cilastatin is not recommended for meningitis because of AmpC-resistant E. coli in neonates E Fakioglu et al early reports of drug-associated seizures. However, meropenem offers an efficacy and safety profile similar to that of cefotaxime for bacterial meningitis in infants and children.…”

Epileptogenic Potential of Carbapenem Agents: Mechanism of Action, Seizure Rates, and Clinical Considerations

“…One investigation demonstrated equal efficacy of ertapenem with standard-of-care ceftriaxone and vancomycin for penicillin-sensitive and penicillin-resistant pneumococcal strains in a rabbit model of meningitis. 89 After administration of doses of 60 mg/kg, CSF penetration was 7.1% and 2.4% in inflamed and noninflamed meninges, respectively.…”

“…The presence of hypoalbuminemia may also be an independent risk factor for seizures associated with ertapenem compared with the other carbapenems, increasing the amount of free drug and subsequently maximum concentration and AUC. 89,115 The clinical effect of this difference on seizure propensity is unknown. This increase in free drug concentration could potentiate the movement of ertapenem across the blood-brain barrier.…”

Daptomycin Is Highly Efficacious against Penicillin-Resistant and Penicillin- and Quinolone-Resistant Pneumococci in Experimental Meningitis

“…A zero-order input (bolus injection), first-order elimination, expanded three-compartment model is used to describe the time course of serum and CSF drug concentrations. The three-compartment model consists of a central compartment (serum), which is linked to a peripheral compartment and the CSF compartment (7,20). Influx and efflux clearances in the CSF compartment are modeled as CL in ϭ CL diff , CL out ϭ CL diff ϩ CL bulk ϩ CL metab , and P csf ϭ CL in /CL out , where CL in is the total clearance from the central compartment to the CSF compartment in milliliters per minute, assumed to be equal to CL diff , the passive transcellular diffusion clearance (i.e., active influx clearance is absent).…”