Meropenem Alone and in Combination with Vancomycin in Experimental Meningitis Caused by a Penicillin-Resistant Pneumococcal Strain

 In a rabbit model of meningitis caused by a pneumococcus highly resistant to penicillin (MIC, 4 μg/ml), meropenem, a broad-spectrum carbapenem, was bactericidal (–0.48±0.14 Δlog₁₀ cfu/ml·h) and slightly superior to ceftriaxone (–0.34±0.23 Δlog₁₀ cfu/ml·h) and vancomycin (–0.39±0.19 Δlog₁₀ cfu/ml·h). Although the combination of vancomycin with ceftriaxone was significantly more active than ceftriaxone alone (–0.55±0.19 Δlog₁₀ cfu/ml·h), only an insignificant gain was observed by the addition of vancomycin to meropenem (–0.55±0.28 Δlog₁₀ cfu/ml·h).     

Evaluation of meropenem alone and combined with rifampin in the guinea pig model of pneumococcal meningitis

Meropenem is a broad-spectrum carbapenem antibiotic that is highly active against the pathogens causing meningitis. The aims of this study was to determine the efficacies of meropenem alone and combined with rifampin against two Streptococcus pneumoniae strains with different susceptibility to β-lactams using the guinea pig meningitis model and compare them with the standard ceftriaxone plus vancomycin therapy. All treatments except rifampin were bactericidal from 6 h. The addition of rifampin did not improve the activity of meropenem alone. Our results provide good evidence of the efficacy of meropenem in the treatment of penicillin- and cephalosporin-susceptible and -resistant pneumococcal meningitis similar to that of ceftriaxone plus vancomycin, suggesting that meropenem might be a good option in the management of this infection.     

Experimental rabbit model of meningitis produced by Haemophilus influenzae serotype c.

The virulence of Haemophilus influenzae type c when inoculated intracisternally (i.c.) into rabbits was evaluated. Rabbits are relatively resistant to infection with H. influenzae type b, such that inocula of the order of 10(6-9) cfu are required to produce meningitis in this model. In contrast, fatal meningitis was produced in this study when 10(3) cfu of a type-c strain were injected i.c. into rabbits. Numbers of bacteria in cerebrospinal fluid (CSF) of control (untreated) animals generally increased to 10(7) cfu/ml. Increases in white blood cells, protein and lactate in the CSF were similar to those which had been observed during meningitis due to Streptococcus pneumoniae in rabbits. The infection was amenable to therapy with ampicillin 50 mg/kg given intravenously 12 h after infection. Numbers of bacteria in CSF were reduced to 2.2 x 10(3) cfu/ml (SEM 0.2 x 10(3)) at 8 h after treatment with a single dose of ampicillin. Two doses of ampicillin, given 12 and 20 h after infection, significantly increased the mean survival time. In contrast to previous experimental studies with rabbits, the penetration of ampicillin into the CSF was high--46 (SEM 10) % of the blood level. Since considerable replication of H. influenzae type c occurred within the CSF in this model, the nature of the meningeal damage produced was likely to be similar to that which takes place in man. Hence, H. influenzae type c meningitis in rabbits may provide a useful model in which therapeutic and other experimental studies of H. influenzae meningitis can be performed.     

Meropenem Prevents Levofloxacin-Induced Resistance in Penicillin-Resistant Pneumococci and Acts Synergistically with Levofloxacin in Experimental Meningitis

The aim of the present study was to investigate the potential synergy between meropenem and levofloxacin in vitro and in experimental meningitis and to determine the effect of meropenem on levofloxacin-induced resistance in vitro. Meropenem increased the efficacy of levofloxacin against the penicillin-resistant pneumococcal strain KR4 in time-killing assays in vitro and acted synergistically against a second penicillin-resistant strain WB4. In the checkerboard, only an additive effect (FIC indices: 1.0) was observed for both strains. In cycling experiments in vitro, levofloxacin alone led to a 64-fold increase in the MIC for both strains after 12 cycles. Addition of meropenem in sub-MIC concentrations (0.25×MIC) completely inhibited the selection of levofloxacin-resistant mutants in WB4 after 12 cycles. In KR4, the addition of meropenem led to just a twofold increase in the MIC for levofloxacin after 12 cycles. Mutations detected in the genes encoding for topoisomerase IV (parC) and gyrase (gyrA) confirmed the levofloxacin-induced resistance in both strains. Addition of meropenem was able to completely suppress levofloxacin-induced mutations in WB4 and led to only one mutation in parE in KR4. In experimental meningitis, meropenem, given in two doses (2×125 mg/kg), produced a good bactericidal activity (–0.45 log₁₀ cfu/ml·h) comparable to one dose (1×10 mg/kg) of levofloxacin (–0.44 log₁₀ cfu/ml·h) against the penicillin-resistant strain WB4. Meropenem combined with levofloxacin acted synergistically (–0.93 log₁₀ cfu/ml·h), sterilizing the CSF of all rabbits.     

Experimental study of clinafloxacin alone and in combination in the treatment of ciprofloxacin-susceptible and -resistant pneumococcal meningitis

The increasing incidence of ciprofloxacin resistance in Streptococcus pneumoniae may limit the efficacy of the new quinolones in difficult-to-treat infections such as meningitis. The aim of the present study was to determine the efficacy of clinafloxacin alone and in combination with teicoplanin and rifampin in the therapy of ciprofloxacin-susceptible and ciprofloxacin-resistant pneumococcal meningitis in rabbits. When used against a penicillin-resistant ciprofloxacin-susceptible strain (Clinafloxacin MIC 0.12 microg/ml), clinafloxacin at a dose of 20 mg/kg per day b.i.d. decreased bacterial concentration by -5.10 log cfu/ml at 24 hr. Combinations did not improve activity. The same clinafloxacin schedule against a penicillin- and ciprofloxacin-resistant strain (Clinafloxacin MIC 0.5 microg/ml) was totally ineffective. Our data suggest that a moderate decrease in quinolone susceptibility, as indicated by the detection of any degree of ciprofloxacin resistance, may render these antibiotics unsuitable for the management of pneumococcal meningitis.     

Production of the hexitol D-mannitol by Cryptococcus neoformans in vitro and in rabbits with experimental meningitis.

We studied the ability of Cryptococcus neoformans to produce the hexitol D-mannitol in vitro and in rabbits with experimental meningitis. Twelve of twelve human isolates of C. neoformans produced D-mannitol in yeast nitrogen base plus 1% glucose and released D-mannitol into the medium. In a pilot study, pooled cerebrospinal fluid (CSF) from cortisone-treated rabbits given 3 x 10(7) C. neoformans H99 intracisternally contained more D-mannitol (identified by gas chromatography and enzymatically) than CSF from normal controls or cortisone-untreated rabbits with self-limited meningitis. In a second experiment, cortisone-treated rabbits given C. neoformans intracisternally had significantly higher CSF D-mannitol concentrations than controls given cortisone alone at 4, 6, and 8 days after infection. Moreover, log10 CSF D-mannitol correlated well with log10 CSF CFU (r = 0.81) and log10 CSF cryptococcal antigen titers (r = 0.78). Lastly, the initial volume of distribution and elimination half-life of D-mannitol given intracisternally to normal rabbits suggested that D-mannitol was distributed in total CSF and was removed by CSF bulk flow. Thus, C. neoformans produces D-mannitol in vitro and in vivo, and D-mannitol is a quantitative marker for experimental cryptococcal meningitis. D-Mannitol produced by C. neoformans may also contribute to brain edema and interfere with phagocyte killing by scavenging hydroxyl radicals.     

Activity of teicoplanin and vancomycin against penicillin-resistant pneumococci

Conclusions There are few therapeutic options available for the management of penicillin- and cephalosporin-resistant pneumococcal disease. The glycopeptide agents vancomycin and teicoplanin remain universally active against pneumococci. Against systemic isolates vancomycin demonstrates reliable clinical efficacy, but its use in meningitis is hampered by unreliable CSF penetration. The drug may be used in combination with a third-generation cephalosporin for the treatment of meningitis in settings where resistant strains are common. More data are however required on the interaction of vancomycin and third-generation cephalosporins in the CSF of infected patients. The superior in vitro activity of teicoplanin over vancomycin suggests that further CSF penetration studies are required. Additional studies should also address the interaction of teicoplanin with third generation cephalosporins in vitro and perhaps its use as adjunctive combination therapy for resistant pneumococcal meningitis.     

The antimicrobial susceptibility in adult invasive pneumococcal disease in the era of pneumococcus vaccination: A hospital-based observational study in Taiwan

BackgroundA regional antibiotic susceptibility data of common pathogens is crucial to first-line physician for clinical judgment and appropriate selection of antimicrobial agents. The aim of this study is to update the epidemiology data of drug resistance of pneumococcus causing invasive pneumococcal disease (IPD) in adults.MethodsFrom the logbooks of microbiology laboratories, we retrospectively retrieved Streptococcus pneumoniae isolates, collected from normally sterile sites in adult patients in three hospitals in Taiwan from July 2011 to June 2015. Antibiotic resistance and serotypes of the isolates and clinical manifestations were further analyzed.ResultsA total of 150 non-duplicated isolates were collected. According to CLSI meningitis breakpoint, the proportion of ceftriaxone non-susceptible pneumococcus (CNSP) showed an increasing trend from 4.5% in 2011 to > 40% in 2013–2015 (p = 0.007). Serotypes 19A and 23F were significantly associated with CNSP. Imipenem and meropenem had a relative low susceptible rate of 36.7% and 50.7%, respectively. Serotypes 6A, 14, 19A and 19F were significantly associated with the non-susceptibility to these carbepanems.ConclusionThe increase in the prevalence of CNSP using meningitis breakpoint was observed. For treating pneumococcal meningitis, empirical monotherapy with ceftriaxone might not be adequate. Imipenem and meropenem might not be a good choice for empirical treatment of adult IPDs. Antibiotic resistance of pneumococcus to ceftriaxone, cefepime, imipenem and meropenem were associated with 13-velent pneumococcal conjugate vaccine serotypes.     

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.     

Evaluation of a PCR-immunoassay technique for detection of Neisseria meningitidis in cerebrospinal fluid and peripheral blood

A multiplex PCR-immunoassay for the rapid diagnosis of bacterial meningitis from cerebrospinal fluid (CSF) or peripheral blood was compared with conventional microbiological techniques used in the routine diagnostic laboratory. The multiplex PCR was designed to detect simultaneously a universal conserved sequence coding for bacterial 16S rRNA and the Neisseria meningitidis porA gene. The PCR-immunoassay had a detection limit of (3-5) x 10(2) cfu/ml (equivalent to 1-3 cfu/PCR) with spiked CSF or blood samples, compared with (3-5) x 10(3) cfu/ml for PCR followed by conventional agarose gel electrophoresis for detection of PCR products. Of 294 CSF samples from patients suspected on clinical grounds of suffering from meningitis, the PCR-immunoassay detected bacterial DNA in 29 CSF samples, 15 of which were also positive for N. meningitidis DNA. The 29 positive CSF samples comprised 25 samples that were also reported positive and four that were reported negative by conventional methodology; the latter four were all positive for N. meningitidis by the PCR-immunoassay. Of 173 peripheral blood samples examined, the PCR-immunoassay detected bacterial DNA in 18 samples, 14 of which were also positive for N. meningitidis DNA. In comparison, only 10 samples were reported positive for N. meningitidis by conventional methodology. All negative PCR-immunoassay results correlated with those obtained by conventional methodology for both CSF and blood samples. The sensitivity and speed of the PCR-immunoassay system indicated that it could be used as a routine diagnostic test for meningococcal meningitis, enabling a diagnosis to be made within 4 h of receipt of the specimen.     

Usefulness of betalactam therapy for community-acquired pneumonia in the era of drug-resistant Streptococcus pneumoniae: a randomized study of amoxicillin-clavulanate and ceftriaxone

Empirical antibiotic therapy of community-acquired pneumonia (CAP) has been complicated by the worldwide emergence of penicillin resistance among Streptococcus pneumoniae. The impact of this resistance on the outcome of patients hospitalized for CAP, empirically treated with betalactams, has not been evaluated in a randomized study. We conducted a prospective, randomized trial to assess the efficacy of amoxicillin-clavulanate (2 g/200 mg/8 hr) and ceftriaxone (1 g/24 hr) in a cohort of patients hospitalized for moderate-to-severe CAP. Three-hundred seventy-eight patients were randomized to receive amoxicillin-clavulanate (184 patients) or ceftriaxone (194 patients). Efficacy was assessed on Day 2, after completion of therapy and at long term follow-up. There were no significant differences in outcomes between treatment groups, both in intention-to-treat and per-protocol analysis. Overall mortality was 10.3% for amoxicillin-clavulanate and 8.8% for ceftriaxone (NS). There were 116 evaluable patients with proven pneumococcal pneumonia. Rates of high-level penicillin resistance (MIC of penicillin > or = 2 microg/mL) were similar in the two groups (8.2 and 10.2%). Clinical efficacy at the end of therapy was 90.6% for amoxicillin-clavulanate and 88.9% for ceftriaxone (95% C.I. of the difference: -9.3 to +12.7%). No differences in outcomes were attributable to differences in penicillin susceptibility of pneumococcal strains. Sequential i.v./oral amoxicillin-clavulanate and parenteral ceftriaxone were equally safe and effective for the empirical treatment of acute bacterial pneumonia, including penicillin and cephalosporin-resistant pneumococcal pneumonia. The use of appropriate betalactams in patients with penumococcal pneumonia and in the overall CAP population, is reliable at the current level of resistance.     

Elevated body temperature restricts growth of Haemophilus influenzae type b during experimental meningitis.

Elevation of the environmental temperature appeared to counteract the temperature-depressing effects of urethane anesthetic and allowed rabbits intracisternally infected with Haemophilus influenzae type b to mimic the development of a fever following infection. Elevated core body temperature (greater than 39 degrees C) was associated with an inhibition of the growth of H. influenzae in cerebrospinal fluid (CSF) during the first 12 h postinfection, whereas bacterial growth was essentially unrestricted in rabbits with reduced (approximately 37 degrees C) body temperature. Bacterial densities 24 h postinfection were different, hyperthermic animals having log 6.0 +/- 0.4 CFU/ml of CSF and hypothermic rabbits having log 8.2 +/- 0.8 CFU/ml of CSF (P less than 0.05, Wilcoxon rank sum test). However, the growth of this bacterium in vitro, in either pooled rabbit CSF or brain heart infusion broth, was not inhibited at 39 degrees C. These results suggest that elevated body temperature associated with the development of fever during meningitis may be associated with restriction of the growth of H. influenzae in vivo but that this effect is apparently not due to an innate inability of the bacterium to grow at elevated temperatures.     

Effects of dexamethasone on aquaporin-4 expression in brain tissue of rat with bacterial meningitis

Aquaporin-4 (AQP4) is the most popular water channel protein expressed in brain tissue and plays a very important role in regulating the water balance in and outside of brain parenchyma. To investigate the expression of aquaporin-4 in the rat brain tissue after dexamethasone therapy of meningitis induced by Streptococcus pneumonia, total 40 of 3-week old Sprague-Dawley rats were divided into infection group (n=30) and normal control group (n=10). The meningitis groups were infected with 1×10⁷ cfu/ml of Streptococcus pneumoniae and then randomized into no treatment (untreated group, n=10), treatment with ceftriaxone (CTRX group, n=10) and treatment with dexamethasone combined ceftriaxone (CTRX + DEXA group, n=10). The normal control group was established by using saline. The rats were euthanized when they reached terminal illness or five days after infection, followed by detection of AQP4 through using immunohistochemistry and Western blot methods. Data has showed that expression of AQP4 in model group remained higher than the control and treatment group (P<0.05). AQP4 expression in CTRX + DEXA group was lower than that in CTRX group (P<0.05). There was no statistical difference between CTRX + DEXA group and the control group (P>0.05). These data suggested that Dexamethasone could down-regulate the expression of AQP4 in the brain tissue of rats with meningitis and provides evidence for the mechanism of protective effect of Dexamethasone on central neurosystem.     

Nationwide surveillance of antimicrobial resistance in invasive isolates of Streptococcus pneumoniae in Taiwan from 2017 to 2019

Background/purposeStreptococcus pneumoniae causes pneumonia and other invasive diseases, and is a leading cause of mortality in the elderly population. The present study aimed to provide current antimicrobial resistance and epidemiological profiles of S. pneumoniae infections in Taiwan.MethodsA total of 252 nonduplicate S. pneumoniae isolates were collected from patients admitted to 16 hospitals in Taiwan between January 2017 and December 2019, and were analyzed. The minimum inhibitory concentration of antibiotics was determined using the Vitek 2 automated system for antimicrobial susceptibility testing. Furthermore, epidemiological profiles of S. pneumoniae infections were analyzed.ResultsAmong the strains analyzed, 88% were recognized as invasive pneumococcal strains. According to the Clinical and Laboratory Standards Institute criteria for non-meningitis, the prevalence of penicillin-non-susceptible S. pneumoniae demonstrated a declining trend from 43.6% in 2017 to 17.2% in 2019. However, the rate of penicillin-non-susceptible S. pneumoniae was 85.7% based on the criteria for meningitis. Furthermore, the prevalence of ceftriaxone-non-susceptible S. pneumoniae was 62.7% based on the criteria for meningitis. Isolates demonstrated higher susceptibility toward doripenem and ertapenem than toward meropenem and imipenem. An increased rate of non-susceptibility toward levofloxacin was observed in southern Taiwan (15.1%) and elderly patients (≥65 years; 11.4%). Most isolates were susceptible to vancomycin and linezolid.ConclusionEmpirical treatment with ceftriaxone monotherapy for pneumococcal meningitis should be carefully monitored owing to its high non-susceptibility rate. The susceptibility rates of most isolates to penicillin (used for treating non-meningitis pneumococcal diseases), carbapenems (ertapenem and doripenem), respiratory quinolones (moxifloxacin and levofloxacin), vancomycin, and linezolid suggested the potential of these antibiotics in treating pneumococcal diseases in Taiwan.     

Combined treatment with ceftriaxone and linezolid of pneumococcal meningitis: a case series including penicillin-resistant strains

This study evaluated the role of linezolid in the treatment of patients suffering from pneumococcal meningitis. Treatment included ceftriaxone (4000 mg every 24 h), linezolid (600 mg every 12 h) and dexamethasone (8 mg every 6 h). Linezolid was withdrawn if a penicillin-susceptible isolate of Streptococcus pneumoniae was identified. Of 16 patients studied, seven were infected with penicillin-non-susceptible isolates of S. pneumoniae, two died, and three reported sequelae. No toxicity was reported. It was concluded that linezolid can be used for the treatment of pneumococcal meningitis, as an alternative to vancomycin or rifampicin, in regimens including a third-generation cephalosporin.     

Fatal Citrobacter farmeri Meningitis in a Patient with Nasopharyngeal Cancer

We describe the case of an adult male with nasopharyngeal carcinoma who had meningitis caused by Citrobacter farmeri. The isolate was confirmed as C. farmeri by two commercial identification systems and 16S rRNA gene analysis. The patient developed multiorgan failure and died despite antibiotic treatment with in vitro active agents (ceftriaxone and meropenem).     

Levels of serum immunoglobulin G, CSF IgG and IgG index in acute bacterial meningitis.

This study characterised the levels of serum immunoglobulin G (IgG), cerebrospinal fluid IgG (CSF IgG) and IgG index as an aid to the diagnosis and prognosis of acute bacterial meningitis (ABM). A total of 28 patients with proven ABM at admission (age range: one month to 10 years; 17 males, 11 females) (group A) and 17 age- and sex-matched control children (group B) were studied. Levels were also compared between patients with neurological morbidity (n = 4; group C) and without neurological morbidity (n = 24; group D) who were subsets of group A. In addition, patients were divided randomly into two groups based on the treatment received (i.e. ceftriaxone together with dexamethasone [n = 11; group A1] and ceftriaxone only [n = 9; group A2] to assess the effect of dexamethasone. The results (mean +/- SEM) demonstrated intrathecal synthesis of IgG in ABM (group A vs group B: CSF IgG (mg/L): 92.64 +/- 23.54 vs 2.12 +/- 1.08, P < 0.002; IgG index: 0.959 +/- 0.481 vs 0.029 +/- 0.006, P < 0.001) which showed good diagnostic significance. In the patients with permanent neurological morbidity (group C) vs healthy survivors (group D), the CSF IgG and IgG index showed good prognostic significance (group C vs group D: CSF IgG (mg/L): 10.75 +/- 9.75 vs 106.24 +/- 29.37, P < 0.01; IgG index: 0.046 +/- 0.039 vs 1.132 +/- 0.568, P < 0.05). Dexamethasone lowered CSF-IgG and IgG-index levels, but the effect was not statistically significant (group A1 vs group A2: P > 0.1).     

S100B in the cerebrospinal fluid—A marker for glial damage in the rabbit model of pneumococcal meningitis

The rabbit model provides an important experimental setting for the evaluation of antibiotic agents against pneumococcal meningitis. One of the primary targets of this model is the study of neuronal and glial cell damage in bacterial meningitis. The aim of this investigation was to evaluate whether a significant increase of S100B in the cerebrospinal fluid (CSF) as an indicator of white matter damage could be observed in this meningitis model. Seven rabbits were infected intracisternally with S. pneumoniae, and CSF S100B concentrations were examined serially before infection, at 12 h, 14 h, 17 h, 20 h, and at 24 h after infection. The course of CSF S100B increase and its relation to other parameters of brain tissue destruction and CSF inflammation were measured. Axonal damage was visualized by amyloid precursor protein (APP) immunostaining and demyelination by Luxol Fast Blue/Periodic Acid Schiff (LFB-PAS) stain. In each animal, we observed a distinct rise in S100B concentration in the CSF due to pneumococcal meningitis. We conclude that the CSF concentration of the glial S100B protein can be used as an additional parameter for future interventional studies focusing on glial cell damage in the rabbit model of bacterial meningitis.     

Using machine learning to optimize antibiotic combinations: dosing strategies for meropenem and polymyxin B against carbapenem-resistant Acinetobacter baumannii

ObjectivesIncreased rates of carbapenem-resistant strains of Acinetobacter baumannii have forced clinicians to rely upon last-line agents, such as the polymyxins, or empirical, unoptimized combination therapy. Therefore, the objectives of this study were: (a) to evaluate the in vitro pharmacodynamics of meropenem and polymyxin B (PMB) combinations against A. baumannii; (b) to utilize a mechanism-based mathematical model to quantify bacterial killing; and (c) to develop a genetic algorithm (GA) to define optimal dosing strategies for meropenem and PMB.MethodsA. baumannii (N16870; MIC_meropenem = 16 mg/L, MIC_PMB = 0.5 mg/L) was studied in the hollow-fibre infection model (initial inoculum 10⁸ cfu/mL) over 14 days against meropenem and PMB combinations. A mechanism-based model of the data and population pharmacokinetics of each drug were used to develop a GA to define the optimal regimen parameters.ResultsMonotherapies resulted in regrowth to ~10¹⁰ cfu/mL by 24 h, while combination regimens employing high-intensity PMB exposure achieved complete bacterial eradication (0 cfu/mL) by 336 h. The mechanism-based model demonstrated an SC₅₀ (PMB concentration for 50% of maximum synergy on meropenem killing) of 0.0927 mg/L for PMB-susceptible subpopulations versus 3.40 mg/L for PMB-resistant subpopulations. The GA had a preference for meropenem regimens that improved the %T > MIC via longer infusion times and shorter dosing intervals. The GA predicted that treating 90% of simulated subjects harbouring a 10⁸ cfu/mL starting inoculum to a point of 10⁰ cfu/mL would require a regimen of meropenem 19.6 g/day 2 h prolonged infusion (2 hPI) q5h + PMB 5.17 mg/kg/day 2 hPI q6h (where the 0 h meropenem and PMB doses should be ‘loaded’ with 80.5% and 42.2% of the daily dose, respectively).ConclusionThis study provides a methodology leveraging in vitro experimental data, a mathematical pharmacodynamic model, and population pharmacokinetics provide a possible avenue to optimize treatment regimens beyond the use of the ‘traditional’ indices of antibiotic action.     

A comparison of ceftriaxone and cefuroxime for the treatment of bacterial meningitis in children

To compare ceftriaxone with cefuroxime for the treatment of meningitis, we conducted a study in which 106 children with acute bacterial meningitis were randomly assigned to receive either ceftriaxone (100 mg per kilogram of body weight per day, administered intravenously once daily; n = 53) or cefuroxime (240 mg per kilogram per day, administered intravenously in four equal doses; n = 53). The mean age of the children was 3 years (range, 42 days to 16 years), and the characteristics of the two treatment groups were comparable at admission. Excluded from the study were eight other children who died within 48 hours of admission. After 18 to 36 hours of therapy, cultures of cerebrospinal fluid remained positive for 1 of the 52 children (2 percent) receiving ceftriaxone for whom cultures were available and 6 of 52 (12 percent) receiving cefuroxime (P = 0.11). In both groups the mean duration of antibiotic therapy was 10 days. The clinical responses to therapy were similar in the two treatment groups, and all 106 children were cured. Reversible biliary pseudolithiasis was detected by serial abdominal ultrasonography only in the children treated with ceftriaxone (16 of 35 vs. 0 of 35; P less than 0.001). The treatment of three children was switched from ceftriaxone to alternative antibiotics because these children had upper abdominal pain. Other side effects were infrequent in both groups. At follow-up examination two months later, moderate-to-profound hearing loss was present in two children (4 percent) treated with ceftriaxone and in nine (17 percent) treated with cefuroxime (P = 0.05); other neurologic abnormalities were similar in the two treatment groups. We conclude that ceftriaxone is superior to cefuroxime for the treatment of acute bacterial meningitis in children and that the benefits of milder hearing impairment and more rapid sterilization of the cerebrospinal fluid with ceftriaxone outweigh the problem of reversible biliary pseudolithiasis with this drug.