Cephalosporin-resistant Strains Research Articles

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mg/kg/day, vancomycin 30 mg/kg/day or both plus minus dexamethasone (0.25 mg/kg/day) for 48 h. Serial CSF samples were withdrawn to carry out bacterial counts, antibiotic concentration and inflammatory parameters.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.

Effect of β-lactam antibiotics on the in vitro development of resistance in Pseudomonas aeruginosa

To investigate whether stepwise selection of resistance mutations may mirror the continued bacterial exposure to antibiotics that occurs in the clinical setting. We examined the in vitro development of resistance to a number of commonly used antibiotics (cefepime, cefpirome, ceftazidime, cefotaxime, piperacillin and imipenem) in Pseudomonas aeruginosa, a significant nosocomial pathogen. Stepwise resistance was assessed by serial passage of colonies located nearest to the inhibition zone on antibiotic-containing gradient plates. The lowest frequencies of spontaneous resistance mutations were found with cefepime and imipenem; these drugs also resulted in the slowest appearance of resistance of spontaneous resistance mutations. In five wild-type P. aeruginosa strains, cefepime-selected isolates required a mean of 30 passages to reach resistance; resistance occurred more rapidly in strains selected with other cephalosporins. P. aeruginosa strains that produced beta-lactamase or non-enzymatic resistance generally developed resistance more rapidly than wild-type strains. For most strains, resistance to all antibiotics except imipenem correlated with increased levels of beta-lactamase activity. Cross-resistance of cephalosporin-selected resistant mutants to other cephalosporins was common. Cephalosporin-resistant strains retained susceptibility to imipenem and ciprofloxacin. From our in vitro study, we can conclude that the rate of development of resistance of P. aeruginosa is lower with cefepime compared with other cephalosporines.

High rates of resistance to cephalosporins among viridans-group streptococci causing bacteraemia in neutropenic cancer patients.

The prevalence of resistance to cephalosporins among viridans-group streptococci causing 88 (18%) cases among 485 bacteraemias in neutropenic cancer patients was studied. Rates of resistance to ceftriaxone, ceftazidime, cefpirome and cefepime were 22, 53, 14 and 34%, respectively. Previous administration of beta-lactam therapy was the only factor significantly associated with bacteraemia due to cephalosporin-resistant strains; only 11 (16%) of 68 patients infected with cephalosporin-susceptible bacteria had received these antibiotics compared with 10 (50%) of 20 patients infected with cephalosporin-resistant bacteria (P = 0.0052).

Acute bacterial meningitis.

In the past 10 years the epidemiology of bacterial meningitis has changed, with a decreased incidence of meningitis caused by Haemophilus influenzae and an increasing incidence of meningitis caused by penicillin- and cephalosporin-resistant strains of Streptococcus pneumoniae. Meningococcal meningitis has become an increasing threat to college students. Successful outcome from meningitis requires not only eradication of the bacterial pathogen but also management of the neurological complications of raised intracranial pressure, stroke, and seizure activity. In this article, the pathophysiology, etiology, clinical presentation, differential diagnosis, and management of acute bacterial meningitis are reviewed. The present recommendations for the use of dexamethasone in the treatment of this infection, the use of chemoprophylaxis, and the indications for vaccinations are included.

Penicillin- and cephalosporin-resistant Streptococcus pneumoniae. Emerging treatment for an emerging problem.

The global emergence of pneumococci resistant to antimicrobial therapy has led to dilemmas in the management of pneumococcal infections. The principles of pharmacodynamics predict that penicillin and cephalosporin therapy of pneumonia will be successful against pneumococci with minimum inhibitory concentrations of penicillin up to 4 micrograms/ml. These predictions are supported by the observations of a number of recent clinical studies. Otitis media therapy is influenced by penicillin-resistance and current recommendations are that amoxicillin is the drug of choice for this infection, given at a double dose of 80 to 90 mg/kg/day. For the therapy of meningitis, cefotaxime or ceftriaxone in maximal doses is recommended and vancomycin may be added if cephalosporin-resistant strains are encountered with reasonable frequency in the population. The new fluoroquinolones with excellent antipneumococcal activity may be considered for use in the setting of pneumonia caused by highly resistant pneumococci and are under evaluation for the management of meningitis.

Pharmacodynamics of gatifloxacin in cerebrospinal fluid in experimental cephalosporin-resistant pneumococcal meningitis.

The purpose of this study was to evaluate the cerebrospinal fluid (CSF) pharmacodynamics of a new fluoroquinolone, gatifloxacin (AM-1155), in experimental pneumococcal meningitis. The penetration of gatifloxacin into CSF, calculated as the percentage of the area under the concentration-time curve (AUC) in CSF over the AUC in blood, was 46 to 56%. Gatifloxacin showed linear pharmacokinetics in CSF, and 1 h after intravenous dosages of 7.5, 15, or 30 mg/kg of body weight, peak CSF concentrations were 0.46 +/- 0.08 (mean +/- standard deviation), 0.94 +/- 0.16, and 1.84 +/- 0.5 microg/ml, respectively. The elimination half-life of gatifloxacin in CSF was 3. 8 to 5.6 h (compared with 2.7 to 3.2 h in blood). There was a significant interrelationship among the highest measured values of gatifloxacin in blood and CSF/minimal bactericidal concentration (Cpeak/MBC), the time antibiotic concentrations exceeded the MBC (T > MBC), and AUC/MBC (r = 0.94); in single-dose experiments, each correlated significantly with the bacterial killing rate. Divided-dose regimens, resulting in greater T > MBC values but lower Cpeak/MBC ratios, were more effective in terms of bacterial clearance compared with corresponding single-dose regimens. Gatifloxacin therapy was as effective as currently recommended regimens (e.g., a combination of ceftriaxone and vancomycin) against this highly cephalosporin-resistant pneumococcal strain. The bactericidal activity of gatifloxacin in CSF was closely related to the AUC/MBC ratio, but maximal activity was achieved only when drug concentrations exceeded the MBC for the entire dosing interval.

In vivo efficacy of cefotaxime and amoxicillin against penicillin-susceptible, penicillin-resistant and penicillin---cephalosporin-resistant strains of Streptococcus pneumoniae in a mouse pneumonia model.

OBJECTIVE: To compare cefotaxime (CTX) to amoxicillin (AMO) (usually considered the definitive therapy for penicillin-susceptible Streptococcus pneumoniae infections) in an immunocompromised mouse pneumonia model. METHODS: Three S. pneumoniae clinical isolates were used: two serotype 19 strains, a penicillin-susceptible (Ps) strain (penicillin MIC=0.03 microg/mL) and a highly penicillin-resistant (Pr) strain (penicillin MIC=4 microg/mL), and one serotype 23F strain, a penicillin---cephalosporin-resistant (CFTR) strain (CTX MIC=4 microg/mL). RESULTS: CTX activity in this mouse model of pneumonia induced by the highly penicillin-resistant strain of S. pneumoniae was lower than expected from its low MIC against this organism. Furthermore, AMO had greater efficacy than CTX against a CFTR S. pneumoniae strain. CONCLUSION: Our data suggest that there is no major difference in the in vivo efficacy of the two agents, cefotaxime and amoxicillin, against penicillin-resistant and penicillin---cephalosporin-resistant S. pneumoniae.

Efficacies of cefotaxime and ceftriaxone in a mouse model of pneumonia induced by two penicillin- and cephalosporin-resistant strains of Streptococcus pneumoniae

We previously demonstrated the efficacy of ceftriaxone (CRO), at 50 mg/kg of body weight every 12 h, against a highly penicillin-resistant (MIC, 4 micrograms/ml) Streptococcus pneumoniae strain with low-level resistance to CRO (MIC, 0.5 microgram/ml) in a leukopenic-mouse pneumonia model (P. Moine, E. Vallée, E. Azoulay-Dupuis, P. Bourget, J.-P. Bédos, J. Bauchet, and J.-J. Pocidalo, Antimicrob. Agents Chemother. 38:1953-1958, 1994). In the present study, we assessed the activity of CRO versus those of cefotaxime (CTX) and amoxicillin (AMO) against two highly penicillin- and cephalosporin-resistant S. pneumoniae strains (P40422 and P40984) (MICs of 2 and 8 for penicillin, 2 and 4 for AMO, and 4 and 8 for CRO or CTX, respectively). Against both strains, a greater than an 80% cumulative survival rate was observed with CRO at a dose of 100 or 200 mg/kg every 12 h (dose/MIC ratio, 25). With CTX, a high dosage of 400 mg/kg (dose/MIC ratio, 100 or 50) administered every 8 h (TID) was needed to protect 66 and 75% of the animals, respectively, with no statistically significant differences versus CRO. Against the P40422 strain, CRO (100 mg/kg) produced the greatest bactericidal effect, from the 8th to the 24th hour after a single injection (1.8-log-unit reduction over 24 h), and the fastest bacterial pulmonary clearance during treatment; with CTX, only multiple injections at a high dosage, i.e., 400 mg/kg TID, demonstrated a significant bactericidal effect. AMO in a high dosage, 400 mg/kg (dose/MIC ratio, 200) TID, showed good activity only against the P40422 strain. Despite the identical MICs of CTX and CRO, the longer time (3.6 to 4.6 h) that serum CRO concentrations remained above the MICs for the pathogens at a dose of 100 mg/kg resulted in greater efficacy versus CTX against highly penicillin- and cephalosporin-resistant S. pneumoniae strains.

Penicillin- and cephalosporin-resistant strains of Streptococcus pneumoniae causing sepsis and meningitis in children with sickle cell disease

Objective: We investigated the possibility that antimicrobial-resistant pneumococci were causing invasive disease in children with sickle-cell disease (SCD). Study design: Records of all children with SCD observed at the Mid-South Sickle Cell Center (MSSCC) at LeBonheur Children's Medical Center were reviewed from January 1990 to June 1994. Children with SCD and pneumococcal sepsis were identified. The Streptococcus pneumoniae isolates from these children were examined for serotype and antimicrobial susceptibilities. Two additional children not observed in the MSSCC had pneumococcal sepsis caused by penicillin-resistant isolates and were also included. Results: Antimicrobial susceptibility testing of the six penicillin-resistant isolates revealed that four were resistant to trimethoprim-sulfamethoxazole, two to erythromycin, and one to clindamycin. The two isolates that were resistant to ceftriaxone also were multiply resistant. From the MSSCC, 26 children had pneumococcal sepsis during the 4 1/2-year period studied. Five of these children (19%) died. Four (15%), including one who died, were infected with penicillin-resistant strains. Conclusion: Pneumococcal sepsis, meningitis, and infections of other foci in children with SCD may be caused by S. pneumoniae that is resistant to one or more antimicrobial agents, including penicillin. The addition of vancomycin to the antibiotics currently used for initial management should be considered in areas where the antibiotic resistance of S. pneumoniae is prevalent. (J P EDIATR 1995;127: 526-32)

Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.

Penicillin-resistant strains of Streptococcus pneumoniae are now found worldwide, and strains with resistance to cephalosporin are being reported. The appropriate antibiotic therapy for pneumococcal pneumonia due to resistant strains remains controversial. To examine the effect of resistance to penicillin and cephalosporin on mortality, we conducted a 10-year, prospective study in Barcelona of 504 adults with culture-proved pneumococcal pneumonia. Among the 504 patients, 145 (29 percent) had penicillin-resistant strains of S. pneumoniae (minimal inhibitory concentration [MIC] of penicillin G, 0.12 to 4.0 micrograms per milliliter), and 31 patients (6 percent) had cephalosporin-resistant strains (MIC of ceftriaxone or cefotaxime, 1.0 to 4.0 micrograms per milliliter). Mortality was 38 percent in patients with penicillin-resistant strains, as compared with 24 percent in patients with penicillin-sensitive strains (P = 0.001). However, after the exclusion of patients with polymicrobial pneumonia and adjustment for other predictors of mortality, the odds ratio for mortality in patients with penicillin-resistant strains was 1.0 (95 percent confidence interval, 0.5 to 1.9; P = 0.84). Among patients treated with penicillin G or ampicillin, the mortality was 25 percent in the 24 with penicillin-resistant strains and 19 percent in the 126 with penicillin-sensitive strains (P = 0.51). Among patients treated with ceftriaxone or cefotaxime, the mortality was 22 percent in the 59 with penicillin-resistant strains and 25 percent in the 127 with penicillin-sensitive strains (P = 0.64) The frequency of resistance to cephalosporin increased from 2 percent in 1984-1988 to 9 percent in 1989-1993 (P = 0.002). Mortality was 26 percent in patients with cephalosporin-resistant S. pneumoniae and 28 percent in patients with susceptible organisms (P = 0.89). Among patients treated with ceftriaxone or cefotaxime, mortality was 22 percent in the 18 with cephalosporin-resistant strains and 24 percent in the 168 with cephalosporin-sensitive organisms (P = 0.64). Current levels of resistance to penicillin and cephalosporin by S. pneumoniae are not associated with increased mortality in patients with pneumococcal pneumonia. Hence, these antibiotics remain the therapy of choice for this disease.

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.

▾ Imipenem + cilastatin – a new type of antibiotic

Imipenem is the first of the carbapenems – a new class of β-lactam antibiotics. It is combined with cilastatin, a non-antibiotic enzyme inhibitor which prevents the breakdown of imipenem to nephrotoxic metabolites. The combination (Primaxin – MSD) is available only for intravenous use. Imipenem has an unusually wide spectrum of activity covering most Gram-positive and Gram-negative bacteria including cephalosporin-resistant strains and anaerobes. Empirical use as the sole antibiotic in severe infections and as definitive treatment of unusually resistant bacteria is tempting.

Antimicrobial activity of Ro 24-6778, a covalent bonding of desmethylfleroxacin and desacetylcefotaxime

A new “dual action” cephalosporin (Ro 24-6778), representing an ester-linked desacetylcefotaxime and desmethylfleroxacin was tested against 287 aerobic bacteria. Ro 24-6778 was found to be very active (minimal inhibitory concentrations [MIC 90], ⩽0.5 μg/ml) against Enterobacteriaceae, Streptococcus spp., and Aeromonas hydrophila. Moderate Ro 24-6778 activity (MIC 90, 1–8 μg/ml) was demonstrated against Bacillus spp., Staphylococcus spp. (including oxacillin-resistant strains), Flavobacterium spp., Enterococcus durans, and Acinetobacter anitratus. More Ro 24-6778-resistant strains (MIC 90, 16–>32 μg/ml) were usually found among the enterococci, Xanthomonas hydrophilia, Pseudomonas spp., and Achromobacter xyloxidans isolates. These preliminary Ro 24-6778 MIC test results show a spectrum superior (93.4% of strains susceptible at ⩽ 8 μg/ml) to the comparison drugs (cefotaxime or fleroxacin) and possible clinical utility for therapy of many fluoroquinolone- or cephalosporin-resistant strains.

New Antibacterial Agents: the Role of New Penicillins and Cephalosporins in the Management of Infection in Granulocytopenic Patients

The result of the introduction of the new acyl-penicillins and the new cephalosporins has not, so far, been a major breakthrough in the empirical therapy of febrile episodes and infections in granulocytopenic patients. It remains to be seen whether other cephalosporins such as cefoperazone and ceftazidime will perform better in the future. Ceftazidime alone or in combination with aminoglycosides shows very promising early results. My present recommendation for empirical therapy in febrile neutropenic patients is to use a combination of a penicillin or a cephalosporin active against P. aeruginosa with an aminoglycoside. Special attention should be paid to the emergence of penicillin- and/or cephalosporin-resistant strains. Empirical therapy should be with antibiotics to which resistance is as rare as possible. In this respect, the newer compounds may play a role in the future. It should also be emphasized that clinical information about new drugs is at present based on the study of relatively small groups of patients. Larger studies performed in more homogeneous groups are needed better to define the role of new agents.

Inactivation of cephalosporins by Bacteroides.

We investigated the relationship between beta-lactamases of Bacteroides fragilis organisms and their resistance to cephalosporins. Timed killing curves were used to study the in vitro activity of three cephalosporins, cephalothin, cefazolin, and cefamandole, and a semisynthetic cephamycin, cefoxitin. Measurements of residual antibiotic concentrations in culture supernatants were made, and they were compared with the beta-lactamase activity of the microorganism. A cephalosporin-susceptible strain was rapidly killed by cephalothin, cefazolin, cefamandole, and cefoxitin. Four cephalosporin-resistant strains were not killed by cephalothin, cefazolin, or cefamandole but were killed by cefoxitin. An inoculum effect was noted with cefazolin and not with cefoxitin. The resistant strains of Bacteroides inactivated the three cephalosporins, but there was no inactivation of cefoxitin. A constitutive beta-lactamase was detected in all the isolates of the B. fragilis group that were resistant to the cephalosporins. There was no distinction of the species based on isoelectric focusing of the enzyme. These data suggest that inactivation by beta-lactamase may be the mechanism for resistance of B. fragilis to the cephalosporins and would explain the enhanced in vitro activity of cefoxitin.