In vitro killing activities of antibiotics at clinically achievable concentrations in cerebrospinal fluid against penicillin-resistant Streptococcus pneumoniae isolated from children with meningitis

Abstract

We evaluated the in vitro killing activities of ceftriaxone, imipenem, vancomycin, gentamicin, fosfomycin, and rifampin, alone and in combination, against 26 Streptococcus pneumoniae strains (penicillin G MICs, >0.125 to 2 ,ug/ml) isolated from the cerebrospinal fluid of children with meningitis. The antibiotics were tested at clinically achievable concentrations in cerebrospinal fluid. After 5 h of incubation, imipenem was the most effective drug. None of the combinations had synergistic activity. Killing by 1I-lactam antibiotics or vancomycin was enhanced by the addition of gentamicin, reduced by the addition of rifampin, and unafected by the addition of fosfomycin.Pneumococcal meningitis in children is associated with considerable morbidity and mortality. As in many other parts of the world, there has recently been an increase in the prevalence of Streptococcus pneumoniae strains with diminished susceptibility to penicillin G in France; these strains represented about 12% of all S. pneumoniae strains isolated from cerebrospinal fluid (CSF) in France in 1992 (12). Clinical failure of S. pneumoniae meningitis therapy with delayed sterilization of CSF has been reported with such strains (11, 12, 16, 33), leading to recommendations that standard P-lactam antimicrobial agents be replaced by broad-spectrum cephalosporins in this setting (16,33). However, S. pneumoniae strains resistant to broad-spectrum cephalosporins have recently been reported in the United States and Spain, together with clinical treatment failure in cases of infection caused by strains for which the ceftriaxone or cefotaxime MIC is .0.5 jxg/ml (4,5,17,29). New strategies such as the use of antimicrobial combinations are now being evaluated as first-line empiric treatment for meningitis (8,9,32).The aim of the study described here was to determine the comparative in vitro bactericidal activities of candidate antibiotics for use in childhood meningitis caused by S. pneumoniae strains with diminished susceptibilities to penicillin G. We used the time-killing curve method with clinically achievable CSF antibiotic concentrations and experimental conditions mimicking clinical conditions, such as a large inoculum (3) in the stationary growth phase (7).We studied 26 S. pneumoniae strains (serotype 23, n = 18; serotype 14, n = 3; serotype 9, n = 2; serotype 19, n = 1; serotype 6, n = 1; serotype 15, n = 1) for which penicillin G MICs were increased (MICs, >0.125 to 2 p.g/ml). These strains represented all the strains isolated from the CSF of children with meningitis and collected by the French reference laboratory between 1987 and 1992. France), ceftriaxone (Roche, Neuilly-sur-Seine, France), imipenem (Merck, Sharp and Dohme-Chibret, Paris, France), gentamicin (Schering-Plough, Levallois-Perret, France), fosfomycin (Sanofi, Gentilly, France), and rifampin (Ciba-Geigy, Rueil-Malmaison, France) were determined by the dilution method on Mueller-Hinton agar supplemented with 5% sheep blood. The replicator prong delivered approximately 104 CFU per spot on...

Emergence in Vietnam of Streptococcus pneumoniae Resistant to Multiple Antimicrobial Agents as a Result of Dissemination of the Multiresistant Spain 23F -1 Clone

“…Only one isolate, from a child admitted to hospital in 2001, was ceftriaxone resistant (MIC, 2.0 g/ml). Vancomycin, to which all the isolates were susceptible, in combination with ceftriaxone would be a suitable, albeit extremely expensive treatment option if ceftriaxone-resistant pneumococcal meningitis became common (4,14).…”

Phenotypic and Genetic Diversity of Invasive Pneumococcal Isolates Recovered from French Children

“…Penicillin MICs were determined by the dilution method on Mueller-Hinton agar supplemented with 5% sheep blood, as previously reported (6). Serotyping was performed by coagglutination with antiserum-coated latex particles.…”

Killing activity of cefpirome against penicillin-resistant Streptococcus pneumoniae isolates from patients with meningitis in a pharmacodynamic model simulating the cerebrospinal fluid concentration profile

“…Chloramphenicol has potential for use against pneumococcal meningitis, but its bactericidal activity against many penicillin-resistant strains is poor and may not be sufficient in the central nervous system to effect a cure (11). Vancomycin has also been suggested as an alternative therapy for pneumococcal meningitis, but the levels in CSF vary over a wide range and are not clearly related to the simultaneous levels in serum, suggesting variability in penetration through the blood-brain barrier (8). Thus, a search for new and more effective drugs for the treatment of such causes of meningitis is desirable.…”

“…Cases of meningitis caused by S. pneumoniae strains resistant to broad-spectrum cephalosporins have recently been reported, together with therapeutic failures and delayed sterilization of cerebrospinal fluid (CSF) when these drugs were used (5,6,13,16,22). Imipenem has an excellent in vitro activity against penicillin-resistant pneumococci, but its value in patients with meningitis is limited because of its seizure activity (8). Chloramphenicol has potential for use against pneumococcal meningitis, but its bactericidal activity against many penicillin-resistant strains is poor and may not be sufficient in the central nervous system to effect a cure (11).…”

“…These strains were isolated from the CSF of patients with meningitis and were collected by the French reference laboratory between 1987 and 1992 (8). The MICs of penicillin G (Diamant, Puteaux, France), ceftriaxone (Roche, Neuilly-sur-Seine, France), and cefpirome (Roussel UCLAF, Romainville, France) were determined by the dilution method on Mueller-Hinton agar supplemented with 5% sheep blood according to the recommendations of the National Committee for Clinical Laboratory Standards (20).…”