Experimental study of the efficacy of vancomycin, rifampicin and dexamethasone in the therapy of pneumococcal meningitis

Using a rabbit model of meningitis, we sought to determine the efficacy of LY333328, a semisynthetic glycopeptide, in the treatment of cephalosporin-resistant pneumococcal meningitis. LY333328 was administered at a dose of 10 mg/kg of body weight/day, alone and in combination with ceftriaxone at 100 mg/kg/day with or without dexamethasone at 0.25 mg/kg/day. The therapeutic groups were treated with LY333328 with or without dexamethasone and LY333328-ceftriaxone with or without dexamethasone. Rabbits were inoculated with a cephalosporin-resistant pneumococcal strain (ceftriaxone MIC, 2 g/ml; penicillin MIC, 4 g/ml; LY333328 MIC, 0.008 g/ml) and were treated over a 26-h period beginning 18 h after inoculation. The bacterial counts in cerebrospinal fluid (CSF), the white blood cell count, the lactic acid concentration, the CSF LY333328 concentration, and bactericidal and bacteriostatic activities were determined at different time points. In vitro, LY333328 was highly bactericidal and its use in combination with ceftriaxone at one-half the MIC was synergistic. In the rabbit model, LY333328 alone was an excellent treatment for cephalosporin-resistant pneumococcal meningitis, with a rapid decrease in colony counts and no therapeutic failures. The use of LY333328 in combination with ceftriaxone improved the activity of LY333328, but no synergistic effect was observed. The combination of LY333328 with dexamethasone was also rapidly bactericidal, but two therapeutic failures were observed. The combination of LY333328 with ceftriaxone and dexamethasone was effective, without therapeutic failures.The treatment of cephalosporin-resistant pneumococcal meningitis is a challenging issue. High doses of cefotaxime have been successfully used to treat infections caused by organisms with intermediate resistance to expanded-spectrum cephalosporins, but sporadic failures have also occurred (3,6,24). Experience with the treatment of adult patients with systemic vancomycin alone is very limited, and therapeutic failures have been reported (23), especially when vancomycin is used in combination with dexamethasone. Some experimental studies have suggested that vancomycin plus ceftriaxone would be synergistic against pneumococci (11), and most experts recommend use of this combination for the empirical therapy of pneumococcal meningitis (12, 16).LY333328 is a semisynthetic glycopeptide antibiotic derived from LY264826, which is active in vitro against gram-positive pathogens including methicillin-and amynoglycoside-resistant Staphylococcus aureus; coagulase-negative staphylococci; enterococci, including some enterococci resistant to vancomycin; and susceptible and penicillin-and cephalosporin-resistant Streptococcus pneumoniae (2,10,13,20,22). LY333328 has been demonstrated to have efficacy in animal models of S. pneumoniae septicemia, vancomycin-resistant enterococcal endocarditis, S. aureus endocarditis, S. aureus catheter-related infections, S. aureus soft tissue infections, and S. aureus foreign body-related skin infections (1, 17). A...

Section: Discussionsupporting

confidence: 48%

Experimental Study of LY333328 (Oritavancin), Alone and in Combination, in Therapy of Cephalosporin-Resistant Pneumococcal Meningitis

Cabellos¹,

Fernández²,

Maiques³

et al. 2003

“…The use of rifampin (RIF) combined with either ␤-lactams or vancomycin is recommended for the treatment of meningitis caused by multiresistant pneumococcal isolates (5,26,33). The rates of RIF resistance among pneumococci are low and range from 0.1% in the United States (12) to 0.4% in Spain (23) and to 1.4% in Italy (25).…”

mentioning

confidence: 99%

New Mutations and Horizontal Transfer of rpoB among Rifampin-Resistant Streptococcus pneumoniae from Four Spanish Hospitals

Ferrándiz

Ardanuy

Liñares

et al. 2005

A total of 103 (0.7%) of 14,236 Streptococcus pneumoniae isolates collected in four Spanish hospitals from 1989 to 2003 were resistant to rifampin (MICs, 4 to 512 g/ml). Only sixty-one (59.2%) of these isolates were available for molecular characterization. Resistance was mostly related to human immunodeficiency virus (HIV) infection in adult patients and to conjunctivitis in children. Thirty-six different pulsed-field gel electrophoresis patterns were identified among resistant isolates, five of which were related to international clones (Spain 23F -1, Spain 6B -2, Spain 9V -3, Spain 14 -5, and clone C of serotype 19F), and accounted for 49.2% of resistant isolates. Single sense mutations at cluster N or I of the rpoB gene were found in 39 isolates, while double mutations, either at cluster I, at clusters I and II, or at clusters N and III, were found in 14 isolates. The involvement of the mutations in rifampin resistance was confirmed by genetic transformation. Single mutations at clusters N and I conferred MICs of 2 g/ml and 4 to 32 g/ml, respectively. Eight isolates showed high degrees of nucleotide sequence variations (2.3 to 10.8%) in rpoB, suggesting a recombinational origin for these isolates, for which viridans group streptococci are their potential gene donors. Although the majority of rifampin-resistant isolates were isolated from individual patients without temporal or geographical relationships, the clonal dissemination of rifampin-resistant isolates was observed among 12 HIV-infected patients in the two hospitals with higher rates of resistance.

“…CSF (0.2 ml) was sampled at 0, 1, 2, 4, 6, and 8 h after initiation of the antibiotic treatment. Dexamethasone (1 mg/kg) was administered 15 min before antibiotics were injected (10). Untreated controls received saline solution.…”

Section: Methodsmentioning

confidence: 99%

“…4). One conceivable explanation might be the reduced penetration of vancomycin into the CSF due to the addition of dexamethasone (10).…”

Section: Vol 53 2009 Daptomycin Plus Ceftriaxone In Treatment Of Mementioning

confidence: 99%

See 1 more Smart Citation

Combination of Daptomycin plus Ceftriaxone Is More Active than Vancomycin plus Ceftriaxone in Experimental Meningitis after Addition of Dexamethasone

Egermann

Stanga

Ramin

et al. 2009

We examined the cerebrospinal fluid penetration of daptomycin after the addition of dexamethasone and its bactericidal efficacy with and without ceftriaxone in an experimental rabbit model of pneumococcal meningitis. The combination of daptomycin with ceftriaxone was the most efficacious regimen for pneumococcal meningitis. The previous addition of dexamethasone affected the antibacterial activity of daptomycin only marginally, either as monotherapy or combined with ceftriaxone, although the penetration of daptomycin into inflamed meninges was significantly reduced from 6 to 2%. Daptomycin with ceftriaxone might be a potential candidate for the empirical therapy of bacterial meningitis, although the activity of this regimen against Listeria monocytogenes remains to be demonstrated.The worldwide continuous spread of penicillin-resistant pneumococci represents one of the major challenges for clinicians and infectiologists. The epidemiological situation in Europe varies considerably with a global tendency of increasing penicillin resistance rates from 6% in 1997 to 22% in 1999 (8). In the United States and Canada, the combined rate of penicillin intermediate plus resistant strains varied between 24% and 67% as reported in the multinational SENTRY antimicrobial resistance surveillance program (5). Based on a recent study, the rates of highly resistant strains were 14.7%, 12.7%, and 15.9% for Europe, Latin America, and North America, respectively (9). In adults, pneumococci are the most frequent pathogens causing meningitis (1, 11). In meningitis due to highly resistant strains, high-dose vancomycin has been recommended, either alone or in combination with third-generation cephalosporins (1,14). In adults, the addition of steroids, now established as standard adjunctive therapy, reduces the penetration of vancomycin into the cerebrospinal fluid (CSF) by 29% (10, 12).We have previously shown that daptomycin, a cyclic lipopeptide, was very efficacious in experimental pneumococcal meningitis due to a penicillin-resistant strain and managed to sterilize the CSF samples of all rabbits at the end of the experimental period. Little is known about the effect of dexamethasone, as standard adjunctive treatment in bacterial meningitis, on the meningeal penetration and efficacy of daptomycin. The aim of this study was first to test the effect of dexamethasone on the penetration of daptomycin into inflamed meninges and second to compare the activity of the different regimens after the addition of dexamethasone in pneumococcal meningitis due to a penicillin-resistant strain. The comparator regimen was ceftriaxone combined with vancomycin, which is the standard empirical regimen. MATERIALS AND METHODSPneumococcal strain. The pneumococcal strain Streptococcus pneumoniae WB4 was isolated from a patient at the Inselspital in Bern, Switzerland, and has been routinely used in this experimental model. The MICs for this strain were as follows: 4 mg/liter for penicillin, 0.5 mg/liter for ceftriaxone, 0.12 to 0.25 mg/liter for vancomycin, a...