Adjunctive daptomycin attenuates brain damage and hearing loss more efficiently than rifampin in infant rat pneumococcal meningitis

Exacerbation of cerebrospinal fluid (CSF) inflammation in response to bacteriolysis by beta-lactam antibiotics contributes to brain damage and neurological sequelae in bacterial meningitis. Daptomycin, a nonlytic antibiotic acting on Gram-positive bacteria, lessens inflammation and brain injury compared to ceftriaxone. With a view to a clinical application for pediatric bacterial meningitis, we investigated the effect of combining daptomycin or rifampin with ceftriaxone in an infant rat pneumococcal meningitis model. Eleven-day-old Wistar rats with pneumococcal meningitis were randomized to treatment starting at 18 h after infection with (i) ceftriaxone (100 mg/kg of body weight, subcutaneously [s.c.], twice a day [b.i.d.]), (ii) daptomycin (10 mg/kg, s.c., daily) followed 15 min later by ceftriaxone, or (iii) rifampin (20 mg/kg, intraperitoneally [i.p.], b.i.d.) followed 15 min later by ceftriaxone. CSF was sampled at 6 and 22 h after the initiation of therapy and was assessed for concentrations of defined chemokines and cytokines. Brain damage was quantified by histomorphometry at 40 h after infection and hearing loss was assessed at 3 weeks after infection. Daptomycin plus ceftriaxone versus ceftriaxone significantly (P < 0.04) lowered CSF concentrations of monocyte chemoattractant protein 1 (MCP-1), MIP-1α, and interleukin 6 (IL-6) at 6 h and MIP-1α, IL-6, and IL-10 at 22 h after initiation of therapy, led to significantly (P < 0.01) less apoptosis, and significantly (P < 0.01) improved hearing capacity. While rifampin plus ceftriaxone versus ceftriaxone also led to lower CSF inflammation (P < 0.02 for IL-6 at 6 h), it had no significant effect on apoptosis and hearing capacity. Adjuvant daptomycin could therefore offer added benefits for the treatment of pediatric pneumococcal meningitis.     

Daptomycin is highly efficacious against penicillin-resistant and penicillin- and quinolone-resistant pneumococci in experimental meningitis

The penetration of daptomycin, a new lipopeptide antibiotic, into inflamed meninges ranged between 4.37 and 7.53% (mean, 5.97%). Daptomycin was very efficacious in the treatment of experimental pneumococcal meningitis, producing a decrease of -1.20 +/- 0.32 Deltalog(10) CFU/ml. h in the bacterial titer of Streptococcus pneumoniae against a penicillin-resistant strain and of -0.97 +/- 0.32 Deltalog(10) CFU/ml. h against a penicillin- and quinolone-resistant strain found in cerebrospinal fluid (CSF). For both strains, daptomycin was significantly superior to the standard regimen of a combination of ceftriaxone with vancomycin, sterilizing 9 of 10 CSF samples after 4 h. In vitro, daptomycin produced highly bactericidal activity in concentrations above the MIC.     

Attenuation of Cerebrospinal Fluid Inflammation by the Nonbacteriolytic Antibiotic Daptomycin versus That by Ceftriaxone in Experimental Pneumococcal Meningitis

Antibiotic-induced bacteriolysis exacerbates inflammation and brain damage in bacterial meningitis. Here the quality and temporal kinetics of cerebrospinal fluid (CSF) inflammation were assessed in an infant rat pneumococcal meningitis model for the nonbacteriolytic antibiotic daptomycin versus ceftriaxone. Daptomycin led to lower CSF concentrations of interleukin 1β (IL-1β), IL-10, IL-18, monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1 alpha (MIP-1α) (P < 0.05). In experimental pneumococcal meningitis, daptomycin treatment resulted in more rapid bacterial killing, lower CSF inflammation, and less brain damage than ceftriaxone treatment.Up to half of the survivors of pneumococcal meningitis are left with neurological sequelae, the rate of which remained unchanged over the last few decades despite continuous improvements in therapy (16). In patients and in corresponding experimental models, brain injury caused by bacterial meningitis has been shown to prominently affect three brain structures, the cortex, the hippocampus, and the inner ear (2, 6). The different forms of tissue damage represent the morphological correlate of the functional deficits observed in survivors, including cerebral palsy, deficits in learning and memory, and hearing loss (9, 12).Inflammation has been shown to play a key role in the pathophysiology leading to the development of brain damage consecutive to bacterial meningitis (11). Anti-inflammatory corticosteroids have been used as adjunctive therapy for bacterial meningitis, but conclusive evidence for a beneficial effect on brain damage, specifically in pediatric pneumococcal meningitis, is lacking (20). Prevention of the inflammatory reaction leads to less brain damage in experimental bacterial meningitis (14). Avoidance of the release of proinflammatory bacterial components upon use of nonbacteriolytic antibiotics is a promising strategic alternative to the use of corticosteroids (7, 14, 17). The nonbacteriolytic lipopeptide daptomycin was at least as efficient as ceftriaxone at eliminating bacteria from the cerebrospinal fluid (CSF) in experimental pneumococcal meningitis. Furthermore, daptomycin significantly lowered the CSF concentration of matrix-metalloproteinase 9 (MMP-9), an enzyme critically involved in the pathophysiology of brain damage, and in consequence caused less brain damage than ceftriaxone (7). Here we extended these observations by investigating the quality and temporal kinetics of CSF inflammation in infant rats with pneumococcal meningitis after treatment with daptomycin versus that with ceftriaxone.All animal studies were approved by the Animal Care and Experimentation Committee of the Canton of Bern, Switzerland, and followed the Swiss national guidelines for performance of animal experiments. Eleven-day-old Wistar rats (n = 28; Charles River, Germany) were injected intracisternally (i.c.) with 10 μl of saline containing 1.5 × 10⁴ CFU of Streptococcus pneumoniae (clinical isolate of a serotype 3 strain) as previously described (7, 10). Eighteen hours later, animals were randomly chosen to receive daptomycin (n = 14) (50 mg/kg body weight, administered subcutaneously [s.c.]; Cubicin, kindly provided by Cubist Pharmaceuticals, Lexington, MA) or ceftriaxone (n = 14) (100 mg/kg body weight given s.c.; Rocephine; Roche Pharma, Basel, Switzerland). The dosages of daptomycin and ceftriaxone used in this study are equal to those used in previously published work (7). Available data on pharmacokinetics/pharmacodynamics (PK/PD) of daptomycin in the CSF during experimental pneumococcal meningitis are derived from the rabbit model (3). For daptomycin, a comparable dosage in adult rats (40 mg/kg, s.c.) resulted in a maximum concentration of drug (C_max) and an area under the concentration-time curve from 0 to 24 h (AUC_0-24) in serum comparable to what is seen in humans with a 6- to 8-mg/kg dose given intravenously (i.v.) (15). More recently, a similar C_max was also obtained in adult mice after a dosage of 25 mg/kg given i.p. (13). Based on a comparable body weight of infant rats and adult mice of approximately 25 to 30 g, a 50-mg/kg dosage, adjusted for an increased metabolism in younger animals, is expected to lead to comparable serum levels of daptomycin. CSF samples were obtained by puncture of the cisterna at defined time points after infection, i.e., 18, 20, and 24 h (n = 7 for each treatment group) and 40 h (n = 7 for daptomycin and n = 8 for ceftriaxone) after infection. A control experiment with untreated animals was not performed, because excessive mortality is observed at these time points without antibiotic treatment. Bacterial killing was significantly more rapid by therapy with daptomycin than by that with ceftriaxone 2 h after the initiation of therapy. Four hours of daptomycin therapy decreased CSF bacterial titers below the detection limit (<10³ CFU/ml), leading to a more rapid sterilization of the CSF (see Fig. ​Fig.2A2A).Open in a separate windowFIG. 2.(A) CSF bacterial titers after antibiotic therapy. Sterilization of CSF was more rapid with therapy with daptomycin (DAP) than with therapy with ceftriaxone (CRO). Six hours after therapy, CSF was sterilized with daptomycin. At 2 and 4 h after therapy, bacterial titers differed significantly (P < 0.05, Mann-Whitney) between treatment groups. (B) Brain damage in experimental pneumococcal meningitis. The extent of cortical damage is significantly reduced (P = 0.02 Mann-Whitney) by daptomycin treatment versus that with ceftriaxone treatment. (C) Histopathology (overview). Cortical injury assessed by Nissl staining is characterized by wedge-shaped areas of decreased neuronal density (arrowheads), suggestive of ischemic necrosis (cresyl violet; original magnification, ×5; scale bar = 1 mm). (D) Histopathology. Focus of cortical neuronal loss (left side; arrowheads) containing neurons with morphological features of necrosis, including pyknotic nuclei, cell swelling, and fading of cytoarchitecture, is sharply demarcated from preserved brain tissue (right side; original magnification, ×200; scale bar, 50 μm; cresyl violet).The CSF concentrations of defined inflammatory mediators (interleukin 1β [IL-1β], IL-2, IL-6, IL-10, IL-18, tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], granulocyte-macrophage colony-stimulating factor [GM-CSF], chemokine [C-X-C motif] ligand 1 [CXCL1], macrophage inflammatory protein 1 alpha [MIP-1α], and monocyte chemoattractant protein 1 [MCP-1]) were assessed, using a microsphere-based multiplex assay (Lincoplex; Millipore Corporation) as described previously (5). The addition of 1, 10, or 100 μg/ml of daptomycin or ceftriaxone to a mixture of cyto- and chemokines at known concentrations had no effect on the performance and the results of immunoassay (data not shown). Statistically significant (P < 0.05) differences in the profiles of IL-1β, IL-10, IL-18, MCP-1, and MIP-1α protein expression were found between the two therapeutic modalities, as determined by two-way analysis of variance ANOVA (Fig. ​(Fig.1).1). Ceftriaxone led to a marked increase in the CSF concentration of the above-detailed cyto- and chemokines at 2 to 6 h after the initiation of therapy, while the reaction to daptomycin treatment was limited to a moderate increase in IL-18 only (Fig. ​(Fig.1).1). It has been shown that daptomycin does not exhibit an immunomodulatory effect in an experimental endotoxin model of human whole blood (19). It is therefore unlikely that the lower CSF levels of cyto- and chemokines with treatment with daptomycin is due to an anti-inflammatory activity of daptomycin by itself.Open in a separate windowFIG. 1.Profile of cyto-/chemokine concentration in the CSF for treatment with daptomycin versus that with ceftriaxone at different time points (2, 6, and 40 h) after initiation of therapy. The concentrations of IL-1β, IL-10, IL-18, MCP-1, and MIP-1α were significantly (P < 0.05, two-way ANOVA) lower in daptomycin-treated animals.For histopathological examination of brain damage, animals were sacrificed at 40 h after infection. Twelve coronal brain sections per animal were evaluated for neuronal injury of the cortex (Fig. 2C and D) and hippocampus, as described previously (5). The area of cortical necrosis was expressed as the percentage of the total area of cortex in each section, and the mean value per animal was calculated. Treatment with daptomycin versus that with ceftriaxone significantly reduced the occurrence (1/14 versus 6/14; P < 0.08, Fischer''s exact test) and severity of cortical damage (0.13% ± 0.5% versus 4.7% ± 8.8% of total cortical volume; n = 14 for each group; P = 0.03, Mann Whitney) (Fig. ​(Fig.2B).2B). Apoptosis in the dentate gyrus was not significantly different between the two treatment groups (data not shown).Daptomycin disrupts membrane functions of Gram-positive bacteria. It has also recently been shown to bind to YycG, interfering with the function of this key sensor kinase, leading to cell death without lysis (1). Accordingly, the release of [³H]choline from the cell wall of labeled bacteria was diminished in daptomycin-treated rabbits in comparison to results with ceftriaxone during experimental pneumococcal meningitis (18). In the present experimental model, treatment with daptomycin compared to that with ceftriaxone led to a more rapid decrease in CSF bacterial titers and a reduction in the occurrence of cortical neuronal injury (7). A decrease in the inflammatory reaction, as suggested by a significant difference in metalloprotease-9 activity 22 h after treatment, was proposed as a factor contributing to the improved outcome with daptomycin (7). In the present study, we extended these observations by focusing on the quality and temporal kinetics of the inflammatory reaction over 22 h after antibiotic therapy, a critical time with respect to the pathophysiological mechanisms leading to neuronal injury. From the 11 cyto- and chemokines measured, significantly lower concentrations of IL-1β, IL-10, IL-18, MCP-1, and MIP-1α were documented in the CSF of daptomycin-treated animals than in that of ceftriaxone-treated animals. Although not significant, CSF levels of IL-6, CXCL1, and TNF-α were also lower in daptomycin-treated animals.In a murine model, it has recently been shown that daptomycin and vancomycin, in combination with dexamethasone, were similarly active for the treatment of pneumococcal meningitis (13). The effect of dexamethasone was shown to only marginally affect the antibactericidal activity of daptomycin alone or in combination with ceftriaxone, although the penetration of daptomycin in the inflamed meninges was reduced (4).Successful treatment of a patient with methicillin-resistant Staphylococcus aureus with daptomycin has recently been reported (8). But because the activity of daptomycin is limited against Gram-positive bacteria, clinical use as an empirical therapy of bacterial meningitis would require combination with a broad-spectrum antibiotic. Sequential therapy with a nonlytic antibiotic, i.e., rifampin with ceftriaxone, has been recently demonstrated to cause less brain injury (17). Important in the context of a prospective clinical application is the recent finding that the combination of daptomycin with ceftriaxone was shown to be more active than vancomycin plus ceftriaxone in experimental rabbit meningitis (4). The present evidence supports further investigations of the use of daptomycin in combination therapy for bacterial meningitis and how it influences the inflammatory reaction and the development of neurological damage.     

Reduced release of pneumolysin by Streptococcus pneumoniae in vitro and in vivo after treatment with nonbacteriolytic antibiotics in comparison to ceftriaxone

Pneumolysin, a virulence factor of Streptococcus pneumoniae with cytotoxic and proinflammatory activities, occurs at concentrations from 0.85 to 180 ng/ml in cerebrospinal fluid (CSF) of meningitis patients. In pneumococcal cultures and in a rabbit meningitis model, the concentrations of pneumolysin in supernatant and CSF were lower after addition of nonbacteriolytic bactericidal antibiotics (rifampin and clindamycin) than after incubation with ceftriaxone.     

Daptomycin produces an enhanced bactericidal activity compared to ceftriaxone, measured by [3H]choline release in the cerebrospinal fluid, in experimental meningitis due to a penicillin-resistant pneumococcal strain without lysing its cell wall

Daptomycin monotherapy was superior to ceftriaxone monotherapy and was highly efficacious in experimental pneumococcal meningitis, sterilizing the cerebrospinal fluid (CSF) of three of three rabbits after 4 to 6 h. With daptomycin therapy only a negligible release of [(3)H]choline as marker of cell wall lysis was detectable in the CSF, peaking around 250 cpm/min after 4 h, compared to a peak of around 2,400 cpm/min after 4 to 6 h for the ceftriaxone-treated rabbits.     

Effect of dexamethasone on therapy of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

Treatment of pneumococcal meningitis has become problematic because of the emergence of penicillin- and cephalosporin-resistant strains and because of the concern that dexamethasone therapy might reduce penetration of antibiotics into the cerebrospinal fluid (CSF). We addressed these issues with our rabbit meningitis model by studying two pneumococcal isolates that were resistant to penicillin and ceftriaxone and susceptible to vancomycin and rifampin. Ceftriaxone, vancomycin, and rifampin were given alone or in combination, with or without coadministration of dexamethasone. Treatment was started 12 to 14 h after intracisternal inoculation of approximately 10(4) CFU of one of the organisms. Rifampin concentrations in serum and CSF were similar, regardless of whether dexamethasone was given, whereas those of ceftriaxone were somewhat lower at each time point in animals given dexamethasone. The penetration of vancomycin into CSF was consistently and substantially reduced with dexamethasone treatment, which resulted in a delay in CSF sterilization not observed in non-dexamethasone-treated animals. When rifampin was used with ceftriaxone for treatment of meningitis caused by the more resistant strain, bacteriologic cure occurred promptly, with or without dexamethasone therapy. In areas with high rates of occurrence of resistant pneumococcal strains, we believe initial empiric therapy of bacterial meningitis should include two antibiotics: ceftriaxone and either rifampin or vancomycin. When dexamethasone is used, the combination of ceftriaxone and rifampin is preferred for therapy.     

Pharmacodynamics and bactericidal activity of ceftriaxone therapy in experimental cephalosporin-resistant pneumococcal meningitis.

Adequate concentrations of beta-lactam antibiotics in cerebrospinal fluid (CSF) are difficult to achieve for meningitis caused by drug-resistant Streptococcus pneumoniae. Ceftriaxone in dosages of 150 or 400 mg/kg of body weight per day, given in one or two doses, was used for the treatment of experimental highly cephalosporin-resistant (MIC and MBC, 4 microg/ml) pneumococcal meningitis. The bacterial killing rate (delta log10 CFU per milliliter per hour) and pharmacokinetic indices, including percentage of time the antibiotic concentration exceeded the MBC during a 24-h period (T>MBC), CSF peak concentration above the MBC, and area under the concentration-time curve from 0 to 24 h above MBC, were measured and correlated. By multiple stepwise regression, only T>MBC independently predicted the bacterial killing rate. There was a direct linear correlation between T>MBC in CSF and the bacterial killing rate during the first 24 h of therapy (r = 0.87; P = 0.004). Sterilization of CSF was achieved only when the T>MBC was 95 to 100%. In the first 24 h, the 200-mg/kg/12-h regimen, compared with the 400-mg/kg/24-h regimen, was associated with a greater T>MBC (87% +/- 10% versus 60% +/- 22%; P = 0.03) and greater bacterial killing rate (0.2 +/- 0.04 versus 0.13 +/- 0.07; P = 0.003), confirming that ceftriaxone exhibits time-dependent bactericidal activity. After 24 h, the T>MBC and the CSF sterilization rates were similar whether ceftriaxone was given once or twice daily.     

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

The object of the study was to assess the efficacy of rifampicin and the combination of rifampicin plus vancomycin in a rabbit model of experimental penicillin-resistant pneumococcal meningitis. We also studied the effect of concomitant dexamethasone on the CSF antibiotic levels and inflammatory parameters. The rabbit model of pneumococcal meningitis was used. Groups of eight rabbits were inoculated with 106 cfu/mL of a cephalosporin-resistant pneumococcal strain (MIC of cefotaxime/ceftriaxone 2 mg/L). Eighteen hours later they were treated with rifampicin 15 mg/kg/day, vancomycin 30 mg/kg/day or both plus minus dexamethasone (0.25 mg/kg/day) for 48 h. Serial CSF samples were withdrawn to carry out bacterial counts, antibiotic concentration and inflammatory parameters. Rifampicin and vancomycin promoted a reduction of >3 log cfu/mL at 6 and 24 h, and cfu were below the level of detection at 48 h. Combination therapy with vancomycin plus rifampicin was not synergic but it had similar efficacy to either antibiotic alone and it was able to reduce bacterial concentration below the level of detection at 48 h. Concomitant use of dexamethasone decreased vancomycin levels when it was used alone (P< 0.05), but not when it was used in combination with rifampicin. Rifampicin alone at 15 mg/kg/day produced a rapid bactericidal effect in this model of penicillin-resistant pneumococcal meningitis. The combination of vancomycin and rifampicin, although not synergic, proved to be equally effective. Using this combination in the clinical setting may allow rifampicin administration without emergence of resistance, and possibly concomitant dexamethasone administration without significant interference with CSF vancomycin levels.     

Evaluation of antimicrobial regimens for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

The most appropriate therapy for meningitis caused by Streptococcus pneumoniae strains resistant to the extended-spectrum cephalosporins is unknown. We evaluated ceftriaxone, vancomycin, and rifampin alone and in different combinations and meropenem, cefpirome, and clinafloxacin alone in the rabbit meningitis model. Meningitis was induced in rabbits by intracisternal inoculation of one of two pneumococcal strains isolated from infants with meningitis (ceftriaxone MICs, 4 and 1 microgram/ml, respectively). Two doses, 5 h apart, of each antibiotic were given intravenously (except that ceftriaxone was given as one dose). Cerebrospinal fluid bacterial concentrations were measured at 0, 5, 10, and 24 h after therapy was started. Clinafloxacin was the most active single agent against both strains. Against the more resistant strain, ceftriaxone or meropenem alone was ineffective. The combination of vancomycin and ceftriaxone was synergistic, suggesting that this combination might be effective for initial empiric therapy of pneumococcal meningitis until results of susceptibility studies are available.     

Evaluation of ceftriaxone, vancomycin and rifampicin alone and combined in an experimental model of meningitis caused by highly cephalosporin-resistant Streptococcus pneumoniae ATCC 51916

OBJECTIVES: The aim of the study was to assess the in vitro and in vivo efficacy of ceftriaxone, vancomycin and rifampicin alone and combined against Streptococcus pneumoniae ATCC 51916 (MIC of ceftriaxone: 32 mg/L). METHODS: In vitro killing curves were performed with clinically achievable CSF antibiotic concentrations. In the rabbit model of pneumococcal meningitis, we studied the efficacy of and effects on inflammation of treatment with ceftriaxone 100 mg/kg/day, vancomycin 30 mg/kg/day and rifampicin 15 mg/kg/day, alone and combined, over a 26 h period. RESULTS: Time-kill curves showed that vancomycin was bactericidal, and ceftriaxone and rifampicin produced a bacteriostatic effect. An additive effect was observed when combinations of ceftriaxone plus vancomycin were studied at subinhibitory concentrations. Emergence of resistance to rifampicin was detected both when rifampicin was studied alone and when combined with ceftriaxone or vancomycin. In the rabbit meningitis model, ceftriaxone was bacteriostatic, whereas rifampicin and vancomycin were bactericidal at 24 h. Although not synergistic, the combinations of ceftriaxone plus vancomycin or rifampicin, and vancomycin plus rifampicin, improved the efficacy of any antibiotic tested alone--all combinations were bactericidal from 6 h--and significantly decreased inflammatory parameters in CSF compared with control and ceftriaxone groups. CONCLUSION: Ceftriaxone plus vancomycin, and vancomycin plus rifampicin appeared to be effective in the therapy of experimental pneumococcal meningitis caused by highly cephalosporin-resistant strains such as ATCC 51916. Our results provide an experimental basis for using these combinations as empirical therapy for pneumococcal meningitis, regardless of the degree of cephalosporin resistance of the causative strain.     

Experimental study of teicoplanin, alone and in combination, in the therapy of cephalosporin-resistant pneumococcal meningitis

OBJECTIVES: The aim of the study was to determine the efficacy of teicoplanin, alone and in combination with ceftriaxone, in a rabbit model of cephalosporin-resistant pneumococcal meningitis, and to assess the effect of concomitant therapy with dexamethasone. METHODS: In vitro killing curves of teicoplanin, with and without ceftriaxone, were performed. Groups of eight animals per treatment were inoculated with a cephalosporin-resistant pneumococcal strain (penicillin MIC, 4 mg/L; ceftriaxone MIC, 2 mg/L; teicoplanin MIC, 0.03 mg/L) and treated over a 26 h period. Teicoplanin was administered at a dose of 15 mg/kg, alone and in combination with ceftriaxone at 100 mg/kg with or without dexamethasone at 0.25 mg/kg. CSF samples were collected at different time-points, and bacterial titres, white blood cell counts, lactate and protein concentrations and bacteriostatic/bactericidal titres were determined. Blood and CSF teicoplanin pharmacokinetic and pharmacodynamic parameters were determined. RESULTS: Teicoplanin alone promoted a decrease in bacterial counts at 6 h of -2.66 log cfu/mL and was bactericidal at 24 h, without therapeutic failures. Similar good results were obtained when dexamethasone was used simultaneously, in spite of the penetration of teicoplanin into the CSF being significantly reduced, from 2.31% to 0.71%. Teicoplanin and ceftriaxone combinations were synergic in vitro, but not in the meningitis model. CONCLUSIONS: Teicoplanin alone was very effective in this model of cephalosporin-resistant pneumococcal meningitis. The use of concomitant dexamethasone resulted in lower CSF teicoplanin levels, but not in therapeutic failures. The combination of teicoplanin plus ceftriaxone and dexamethasone might be a good alternative for the empirical therapy of pneumococcal meningitis. Additional data should confirm our experiments, in advance of clinical trials to assess efficacy in humans.     

Activity of LY333328 in Experimental Meningitis Caused by a Streptococcus pneumoniae Strain Susceptible to Penicillin

In a rabbit model of Streptococcus pneumoniae meningitis single doses of 10 and 2.5 mg of the glycopeptide LY333328 per kg of body weight reduced bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as ceftriaxone at 10 mg/kg/h (changes in log CFU, -0.29 +/- 0.21 and -0.26 +/- 0.22 versus -0.34 +/- 0.15/ml/h). A dose of 1 mg/kg was bacteriostatic (change in log CFU, 0.01 +/- 0.11/ml/h). In two animals receiving LY333328 at a dose of 40 mg/kg the bacterial titers were reduced by 0.54 and 0.51 log CFU/ml/h. The penetration of CSF by LY333328 was 1 to 5%. The concentrations of lipoteichoic and teichoic acids in CSF and neuronal damage were similar in ceftriaxone- and LY333328-treated animals.     

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

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.     

Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone.

Acute bacterial meningitis may be associated with increased intracranial pressure, neurological sequelae such as communicating hydrocephalus, and a slow response to antibiotic therapy. Alterations in cerebrospinal hydrodynamics are at least partially responsible for these complications. Constant, low-flow short-duration manometric infusion studies through a hollow-bore pressure monitoring device in direct continuity with the supracortical subarachnoid space were performed in rabbits with experimental meningitis. Maximal resistance to cerebrospinal fluid (CSF) outflow from the subarachnoid to vascular space was markedly increaed in acute pneumococcal meningitis when compared to control, uninfected animals (6.77 +/- 3.52 vs. 0.26 +/- 0.04 mm Hg/microliter per min, P less than 0.001). Similar elevations (8.93 +/- 4.15 mm Hg/microliter per min were found in experimental Escherichia coli meningitis. Despite eradication of viable bacteria from the CSF by penicillin therapy during the acute stage of pneumococcal meningitis, resistance remained elevated (6.07 +/- 4.68 mm Hg/microliter per min) and had not returned to normal up to 15 d later. Administration of methylprednisolone during the early stages of acute pneumococcal meningitis reduced mean peak outflow resistance towards control values (0.59 mm Hg/microliter per min) and no "rebound" effect was apparent 24 h later. These hydrodynamic alterations in experimental meningitis prevent normal CSF absorption and decrease the ability of the bran to compensate for changes in intracranial volume and pressure.     

Evaluation of Moxifloxacin, a New 8-Methoxyquinolone, for Treatment of Meningitis Caused by a PenicillinResistant Pneumococcus in Rabbits

Moxifloxacin is a new 8-methoxyquinolone with high activity against gram-positive bacteria, including penicillin-resistant pneumococci. In an experimental meningitis model, we studied the pharmacokinetics of moxifloxacin in infected and uninfected rabbits and evaluated the antibiotic efficacies of moxifloxacin, ceftriaxone, and vancomycin against a penicillin-resistant Streptococcus pneumoniae strain (penicillin, ceftriaxone, vancomycin, and moxifloxacin MICs were 1, 0.5, 0.5, and 0.125 μg/ml, respectively). Moxifloxacin entered cerebrospinal fluid (CSF) readily, with peak values within 15 to 30 min after bolus intravenous infusion and with a mean percent penetration into normal and purulent CSF of approximately 50 and 80%, respectively. The bactericidal effect of moxifloxacin was concentration dependent, and regrowth was seen only when the concentration of moxifloxacin in CSF was below the minimal bactericidal concentration. All antibiotic-treated groups (moxifloxacin given in two doses of 40 mg/kg of body weight, moxifloxacin in two 20-mg/kg doses, ceftriaxone in one 125-mg/kg dose, and vancomycin in two 20-mg/kg doses) had significantly higher reductions in CSF bacterial concentration than the untreated group (P < 0.05). Moxifloxacin was as effective as vancomycin and ceftriaxone in reducing bacterial counts at all time points tested (3, 5, 10, and 24 h). Moreover, moxifloxacin given in two 40-mg/kg doses resulted in a significantly higher reduction in CSF bacterial concentration (in log₁₀ CFU per milliliter) than vancomycin within 3 h after the start of antibiotic treatment (3.49 [2.94 to 4.78] versus 2.50 [0.30 to 3.05]; P < 0.05). These results indicate that moxifloxacin could be useful in the treatment of meningitis, including penicillin-resistant pneumococcal meningitis.     

Quinolone antibiotics in therapy of experimental pneumococcal meningitis in rabbits.

Using a rabbit model of pneumococcal meningitis, we compared the pharmacokinetics and bactericidal activities in cerebrospinal fluid (CSF) of older (ciprofloxacin, ofloxacin) and newer (levofloxacin, temafloxacin, CP-116,517, and Win 57273) quinolones with those of the beta-lactam ceftriaxone. All quinolones penetrated into the inflamed CSF better than ceftriaxone, and the speed of entry into CSF was closely related to their degrees of lipophilicity. At a dose of 10 mg/kg.h, which in the case of the quinolones already in use in clinical practice produced concentrations attainable in the sera and CSF of humans, ciprofloxacin had no antipneumococcal activity (delta log10 CFU/ml.h, +0.20 +/- 0.14). Ofloxacin (delta log10 CFU/ml.h, -0.13 +/- 0.12), temafloxacin (delta log10 CFU/ml.h, -0.19 +/- 0.18), and levofloxacin (delta log10 CFU/ml.h, -0.24 +/- 0.16) showed slow bactericidal activity (not significantly different from each other), while CP-116,517 (delta log10 CFU/ml.h, -0.59 +/- 0.21) and Win 57273 (delta log10 CFU/ml.h, -0.72 +/- 0.20) showed increased bactericidal activities in CSF that was comparable to that of ceftriaxone at 10 mg/kg.h (delta log10 CFU/ml.h, -0.80 +/- 0.17). These improved in vivo activities of the newer quinolones reflected their increased in vitro activities. All quinolones and ceftriaxone showed positive correlations between bactericidal rates in CSF and concentrations in CSF relative to their MBCs. Only when this ratio exceeded 10 did the antibiotics exhibit rapid bactericidal activities in CSF. In conclusion, in experimental pneumococcal meningitis the activities of new quinolones with improved antipneumococcal activities were comparable to that of ceftriaxone.     

Use of ampicillin-sulbactam for treatment of experimental meningitis caused by a beta-lactamase-producing strain of Escherichia coli K-1.

We evaluated the pharmacokinetics and therapeutic efficacy of ampicillin combined with sulbactam in a rabbit model of meningitis due to a beta-lactamase-producing strain of Escherichia coli K-1. Ceftriaxone was used as a comparison drug. The MIC and MBC were 32 and greater than 64 micrograms/ml (ampicillin), greater than 256 and greater than 256 micrograms/ml (sulbactam), 2.0 and 4.0 micrograms/ml (ampicillin-sulbactam [2:1 ratio, ampicillin concentration]) and 0.125 and 0.25 micrograms/ml (ceftriaxone). All antibiotics were given by intravenous bolus injection in a number of dosing regimens. Ampicillin and sulbactam achieved high concentrations in cerebrospinal fluid (CSF) with higher dose regimens, but only moderate bactericidal activity compared with that of ceftriaxone was obtained. CSF bacterial titers were reduced by 0.6 +/- 0.3 log10 CFU/ml/h with the highest ampicillin-sulbactam dose used (500 and 500 mg/kg of body weight, two doses). This was similar to the bactericidal activity achieved by low-dose ceftriaxone (10 mg/kg), while a higher ceftriaxone dose (100 mg/kg) produced a significant increase in bactericidal activity (1.1 +/- 0.4 log10 CFU/ml/h). It appears that ampicillin-sulbactam, despite favorable CSF pharmacokinetics in animals with meningitis, may be of limited value in the treatment of difficult-to-treat beta-lactamase-producing bacteria, against which the combination shows only moderate in vitro activity.     

Bactericidal activity against cephalosporin-resistant Streptococcus pneumoniae in cerebrospinal fluid of children with acute bacterial meningitis.

There are reports of failure of extended-spectrum cephalosporin treatment in pneumococcal meningitis. On the basis of in vitro and animal experimental studies, the addition of vancomycin or rifampin to an extended-spectrum cephalosporin has been recommended for empiric treatment of these patients. Cerebrospinal fluid (CSF) was taken from 31 children with bacterial meningitis randomized to receive ceftriaxone alone (n = 11), ceftriaxone plus rifampin (n = 10), or ceftriaxone plus vancomycin (n = 10). The CSF from children receiving ceftriaxone alone was unable to kill intermediately ceftriaxone-resistant or fully resistant strains when the concentration of ceftriaxone in the CSF was less than 5 micrograms/ml. At higher concentrations bactericidal activity was present. We have shown that vancomycin penetrates reliably into the CSF of children with acute meningitis, which is in contrast to previous studies with adults. The addition of vancomycin or rifampin to ceftriaxone resulted in significantly enhanced CSF bactericidal activity compared with that of ceftriaxone alone against these resistant strains. Our data suggest that the addition of rifampin or vancomycin to ceftriaxone may be useful for the treatment of cephalosporin-resistant pneumococcal meningitis.     

Blood, Brain, and Cerebrospinal Fluid Concentrations of Several Antibiotics in Rabbits with Intact and Inflamed Meninges

Because cerebrospinal fluid (CSF) antibiotic levels fail to predict either clinical success or relapse in the treatment of bacterial meningitis, we examined simultaneous antibiotic concentrations in the blood, brain, and CSF of control rabbits and of animals with experimental pneumococcal meningitis. Cefamandole pharmacokinetics were analyzed in detail and compared with those of cephalothin, ampicillin, penicillin G, and tobramycin. After 4 h of continuous intravenous infusion, cefamandole reached concentrations in both brain and CSF in excess of the minimal bactericidal concentration for the test organism and compared favorably with ampicillin and penicillin in achieving bacteriological cure. Cephalothin levels in the central nervous system remained undetectable in both control and infected animals during this time. Tobramycin concentrations were measurable in the CSF, but not in brain tissue in association with an inflammatory stimulus.     

Gemifloxacin is efficacious against penicillin-resistant and quinolone-resistant pneumococci in experimental meningitis

In experimental rabbit meningitis, gemifloxacin penetrated inflamed meninges well (22 to 33%) and produced excellent bactericidal activity (change in log(10) [Deltalog(10)] CFU/ml/h, -0.68 +/- 0.30 [mean and standard deviation]), even superior to that of the standard regimen of ceftriaxone plus vancomycin (-0.49 +/- 0.09 deltalog(10) CFU/ml/h), in the treatment of meningitis due to a penicillin-resistant pneumococcal strain (MIC, 4 mg/liter). Even against a penicillin- and quinolone-resistant strain, gemifloxacin showed good bactericidal activity (-0.48 +/- 0.16 deltalog(10) CFU/ml/h). The excellent antibacterial activity of gemifloxacin was also confirmed by time-kill assays over 8 h in vitro.