High doses of cefotaxime in treatment of adult meningitis due to Streptococcus pneumoniae with decreased susceptibilities to broad-spectrum cephalosporins.

We treated nine patients (10 episodes) with meningitis caused by Streptococcus pneumoniae isolates with decreased susceptibilities to broad-spectrum cephalosporins with high doses of cefotaxime (300 mg/kg of body weight per day; maximum dose, 24 g/day). Early adjunctive therapy with dexamethasone was also administered. Cefotaxime MICs were 0.5 (three episodes), 1 (five episodes), and 2 (two episodes) micrograms/ml, and MBCs ranged from 1 to 4 micrograms/ml. Therapy was well tolerated, and all patients experienced prompt clinical improvement. One patient died 8 days after the end of therapy, the central nervous system infection had already been cured, and the remaining patients recovered without relapses.     

Clindamycin therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant Streptococcus pneumoniae.

Although penicillin resistance among Streptococcus pneumoniae strains is increasing in many areas, resistance to clindamycin remains low. In our well-characterized rabbit meningitis model, we conducted experiments to evaluate the bacteriologic efficacy of clindamycin after a penicillin- and cephalosporin-resistant S. pneumoniae strain was intracisternally inoculated. Animals received a loading intravenous dose of 30 mg of clindamycin per kg of body weight and then two doses of 20 mg/kg given 5 h apart. In addition to clindamycin, some animals received dexamethasone (DXM) with or without ceftriaxone. The concentrations of clindamycin in cerebrospinal fluid were from 8.9 to 12.8% of the concomitant concentrations in serum and were unaffected by DXM administration. Mean changes in CFU (log10 per milliliter) at 10 and 24 h were -3.7 and -6.1, respectively, for clindamycin-treated rabbits, -3.6 and -6.3 for clindamycin-DXM-treated rabbits, -3.9 and -5.8, respectively, for clindamycin-ceftriaxone-treated rabbits, and -5.0 and -6.7, respectively, for clindamycin-ceftriaxone-DXM-treated rabbits. By 24 h all but one of the cultures of cerebrospinal fluid (that from a clindamycin-DXM-treated rabbit) were sterile. Because of the potential risk for clindamycin-treated rabbits to develop macrolide-lincosamide resistance, we attempted, unsuccessfully, to induce clindamycin resistance in vitro in two S. pneumoniae strains. Although clindamycin therapy might be effective in selected patients with multiple-drug-resistant pneumococcal meningitis who have failed conventional treatments, clinical experience is necessary before it can be recommended.     

Comparative serum bactericidal activities of ceftizoxime and cefotaxime against intermediately penicillin-resistant Streptococcus pneumoniae.

In a randomized crossover study involving 12 healthy volunteers, 1 g of ceftizoxime or cefotaxime was administered intravenously every 12 h for a total of three doses on two separate weekends. The duration of serum bactericidal titers (SBTs) greater than 1:2 and the time serum drug concentrations remained above the MIC (T > MIC) were determined against three clinical isolates of Streptococcus pneumoniae with intermediate resistance to penicillin. The duration of SBTs and T > MIC for both antimicrobial agents exceeded 50% of the dosing interval for all isolates. Ceftizoxime's T > MIC was statistically greater than that of cefotaxime, indicating that its longer half-life in serum (1.7 h) compared with that of cefotaxime (approximately 1 h) compensates for its slightly lower microbiologic activity against the penicillin-resistant pneumococci tested in this study.     

Antibiotic surveillance of Streptococcus pneumoniae in Mississipi.

OBJECTIVE: A survey of antimicrobial resistance in S. pneumoniae isolates collected from representative geographic regions of Mississippi during two different respiratory seasons was conducted to determine rates and distribution of drug resistance. DESIGN: A total of 318 S. pneumoniae isolates was collected from July 1999 to March 2000, and 171 isolates were collected from July 2001 to March 2002. The minimum inhibitory concentration for 12 antibiotics was determined by the micro dilution method. SETTING: A total of 28 hospitals through out the state of Mississippi participated in the submission of S. pneumoniae isolates felt to be clinically relevant and reported to the attending physician. Specimens were transported to a central laboratory via state health department courier. PATIENT POPULATION: Isolates were obtained from hospital inpatients as well as outpatients seen in local clinics. MAIN OUTCOME MEASURES: Changes in the percentage of isolates resistant to the tested antibiotics and patient demographics were collected. RESULTS: Pediatric isolates accounted for 36% and 28%, respectively, in 2000 and 2002. The relative percentage of total respiratory isolates remained for each year. Resistance to penicillin increased in pediatric (58% vs. 71%) and adult (40% vs. 52%) as did resistance to ceftriaxone (pediatric 14% vs. 31%; adult 9% vs. 25%) from 2000 to 2002. The majority of isolates were resistant to multiple antibiotics in both years tested. CONCLUSION: The results of this study are comparable to those from other national studies of antimicrobial resistance in S. pneumoniae demonstrating increasing resistance to multiple classes of antibiotics quantitatively and qualitatively.     

Evolution of plasmid-coded resistance to broad-spectrum cephalosporins.

A clinical isolate of Klebsiella ozaenae with transferable resistance to broad-spectrum cephalosporins produces a beta-lactamase determined by plasmid pBP60. The beta-lactamase had the same isoelectric point as SHV-1 (7.6). From heteroduplex analysis, an extensive homology between the two bla genes could be deduced; therefore, the new beta-lactamase was designated SHV-2. Enzymatic studies revealed that SHV-2 was able to hydrolyze broad-spectrum cephalosporins due to an increased affinity of these compounds for the enzyme. The assumption that SHV-2 is a natural mutant of SHV-1 was strongly supported by the isolation of a laboratory mutant of SHV-1 that showed activities similar to those of SHV-2.     

Antimicrobial therapy of experimental meningitis caused by Streptococcus pneumoniae strains with different susceptibilities to penicillin.

The pharmacokinetics and bacteriological efficacies of penicillin G, ceftriaxone, vancomycin, and imipenem were determined in rabbits with experimental meningitis caused by Streptococcus pneumoniae strains with different penicillin susceptibilities. Drug dosages were adjusted to attain peak concentrations in serum that were similar to those observed in infants and children. In animals infected with a penicillin-susceptible (MBC, 0.008 micrograms/ml) pneumococcus, penicillin G and ceftriaxone reduced the number of organisms in cerebrospinal fluid (CSF) by greater than or equal to 4.14 log10 CFU/ml after single doses and after 9-h continuous infusions. A single large dose (50 mg/kg) of penicillin G was comparatively ineffective (-2.15 log10 CFU/ml) against a relatively penicillin-resistant (MBC, 0.5 micrograms/ml) strain, whereas ceftriaxone therapy resulted in a 3.66- and 4.77-log10 CFU/ml reduction after single doses and 9-h continuous infusions, respectively. In animals in which meningitis was caused by a penicillin-resistant (MBC, 8.0 micrograms/ml) pneumococcus, a single dose of penicillin (50 or 150 mg/kg) or of ceftriaxone failed to lower the number of organisms in CSF. Vancomycin and imipenem reduced the counts in CSF by at least 2.19 and 4.10 log10 CFU/ml after single doses and 9-h infusions, respectively. In all experiments, a bactericidal titer of greater than or equal to 1:8 in CSF was necessary to achieve a maximal bacteriological effect.     

Bactericidal activity against intermediately cephalosporin-resistant Streptococcus pneumoniae in cerebrospinal fluid of children with bacterial meningitis treated with high doses of cefotaxime and vancomycin.

Cerebrospinal fluid (CSF) was taken from 19 children with bacterial meningitis treated with cefotaxime (300 mg/kg of body weight/day) and vancomycin (60 mg/kg/day). Median levels of drugs in CSF were smaller than expected, as follows: 4.4 microg/ml for cefotaxime, 3.2 microg/ml for desacetylcefotaxime, and 1.7 microg/ml for vancomycin. The median CSF bactericidal titer against an intermediately cefotaxime-resistant pneumococcus was 1:4. Our data suggest at least an additive interaction between the drugs used in this study.     

Treatment of experimental endocarditis due to penicillin-resistant Streptococcus pneumoniae.

Using two strains of pneumococci for which MICs of penicillin were 1 and 4 micrograms/ml, those of cefotaxime were 0.01 and 0.5 micrograms/ml, and those of teicoplanin were 0.01 and 0.1 micrograms/ml, we studied the efficacy of different dosages of penicillin, cefotaxime, and teicoplanin in the treatment of experimental pneumococcal endocarditis in rabbits. Animals treated with dosages of penicillin G procaine needed to achieve levels in serum near the MIC for pneumococci showed a significant reduction in log10 CFU per gram of vegetation, as compared with the control (P < 0.001), although only 20% of the animals showed sterile vegetations. When levels of penicillin in serum were in the range of three- to fourfold the MIC, a greater reduction in log10 CFU per gram of vegetation was seen, and 88% of the animals showed sterile vegetations. Only the regimen of penicillin that provided concentrations in serum above the MIC throughout the interval between two doses provided constant sterilization of the cardiac vegetations. Dosages of cefotaxime and teicoplanin selected to achieve concentrations in serum equivalent to that obtained in humans during treatment resulted in levels of antimicrobial agents in serum hundreds or thousands of times higher than the MICs for the infecting strains. In terms of antimicrobial efficacy, cefotaxime and teicoplanin were equivalent to regimens with high dosages of penicillin.     

Failure of ceftazidime-amikacin therapy for bacteremia and meningitis due to Klebsiella pneumoniae producing an extended-spectrum beta-lactamase.

A multiple trauma patient failed treatment with ceftazidime and amikacin for bacteremia and meningitis due to a Klebsiella pneumoniae strain that produced a novel, plasmid-mediated beta-lactamase. Both pre- and posttreatment isolates were resistant to ceftazidime (MIC, greater than or equal to 64 micrograms/ml) and various penicillins but not to other expanded-spectrum cephalosporins. The beta-lactamase had a pI of 5.25 and was encoded on a conjugal plasmid of approximately 150 kilobases. DNA hybridization studies indicated that the enzyme was a TEM derivative.     

Novel plasmid-mediated beta-lactamase in clinical isolates of Klebsiella pneumoniae more resistant to ceftazidime than to other broad-spectrum cephalosporins.

Multiresistant Klebsiella pneumoniae strains isolated from three patients in the same intensive care unit were more resistant to ceftazidime than to cefotaxime and aztreonam but remained susceptible to moxalactam and imipenem. Resistance to beta-lactams, kanamycin, streptomycin, sulfonamides, and tetracyclines was transferable to Escherichia coli by conjugation and was lost en bloc after treatment with ethidium bromide. Agarose gel electrophoresis of wild types and transconjugants indicated that these resistances were mediated by a 150-kilobase plasmid, pCFF14. The strains constitutively produced a beta-lactamase with isoelectric point close to 5.6 and which had a higher Vmax for ceftazidime and cephalothin than for cefotaxime. The substrate profile and isoelectric point of this enzyme thus differ from those of other known plasmid-mediated beta-lactamases, including the broad-spectrum enzyme CTX-1. Hybridization studies support the derivation of the novel enzyme from a TEM-type beta-lactamase.     

Genetic analysis of clinical isolates of Streptococcus pneumoniae with high-level resistance to expanded-spectrum cephalosporins.

Streptococcus pneumoniae CS109 and CS111 were isolated in the United States in 1991 and have high levels of resistance to expanded-spectrum cephalosporins (MICs of 8 and 32 micrograms of cefotaxime per ml, respectively). CS109, but not CS111, also showed high-level resistance to penicillin. As both strains expressed the serotype 23F capsule, were very closely related in overall genotype, and possessed identical or closely related mosaic pbp1a, pbp2x, and pbp2b genes, it is likely that they have arisen from a recent common ancestor. High-level resistance to expanded-spectrum cephalosporins was entirely due to alterations of penicillin-binding proteins (PBPs) 1a and 2x, since a mixture of the cloned pbp1a and pbp2x genes from the resistant strains could transform the susceptible strain R6 to the full level of cephalosporin resistance of the clinical isolates. Both PBP1a and PBP2x of these strains were more resistant to inhibition by cephalosporins than those of typical highly penicillin-resistant isolates. The pbp1a genes of CS109 and CS111 were identical in sequence, and the fourfold difference in their levels of resistance to cephalosporins was due to a Thr-550-->Ala substitution at the residue following the conserved Lys-Ser-Gly motif of PBP2x. This substitution was also the major cause of the 16-fold-lower resistance of CS111 to penicillin. The pbp2x gene of CS111, in an appropriate genetic background, could provide resistance to 16 micrograms of cefotaxime per ml but only to 0.12 microgram of benzylpenicillin per ml. Removal of the codon 550 mutation resulted in a pbp2x gene that provided resistance to 4 microgram of cefotaxime per ml and 4 microgram of benzylpenicillin per ml. The Thr-550-->Ala substitution in CS111 therefore appears to provide increased resistance to expanded-spectrum cephalosporins but a loss of resistance to penicillin.     

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.     

Severe infection due to Streptococcus pneumoniae in asplenic renal transplant patients.

The medical records of 293 patients who underwent renal transplantation were analyzed for the occurrence of Streptococcus pneumoniae and Haemophilus influenzae infections in relation to splenectomy. Splenectomy was done in 236 (81%) graft recipients before or concomitant with transplantation. Bacteremia developed in five and fulminant sepsis in two from 3 to 32 months after splenectomy. No serious infections with these organisms occurred in the nonsplenectomy group. These results suggest that asplenia may be an additional factor predisposing transplant patients to serious infection. Prevention of these serious pneumococcal infections may be possible with polyvalent pneumococcal vaccine.     

Antibiotic susceptibility and serotypes of Streptococcus pneumoniae isolates from Hungary

OBJECTIVE: Hungary has reported one of the highest incidences of penicillin resistance in Streptococcus pneumoniae in Europe since the 1970s and is still cited accordingly. However, since the end of the 1990s the resistance of pneumococci in Hungary has not been investigated. In this study we assessed the current situation, particularly to establish whether the incidence of resistance is increasing and if this could be related to the spread of specific strain types. METHODS: Isolates of S. pneumoniae (n = 304) were collected by five diagnostic laboratories in Hungary in 2000-2002. Their identity was confirmed and their susceptibilities to 16 antibiotics were determined by the agar dilution method according to NCCLS guidelines. Representative strains were serotyped (n = 112). RESULTS AND CONCLUSIONS: We found significantly lower resistance rates for penicillin compared with the data previously reported from Hungary, but the intermediate resistance was high, at 37%. Macrolide resistance was a bigger problem ( approximately 40% for erythromycin), although there was full susceptibility to telithromycin. The strains with the highest MICs were isolated from carriers and young children. The fluoroquinolones were very effective, especially moxifloxacin and gatifloxacin. There was full susceptibility to vancomycin and linezolid. We found inconsistencies with previous reports in the survey of the resistance and identification of S. pneumoniae in the country. The serotype distribution of the isolates showed a much greater diversity than had previously been reported; however, there was correlation between serotype and resistance.     

Antibiotic susceptibility in relation to penicillin-binding protein genes and serotype distribution of Streptococcus pneumoniae strains responsible for meningitis in Japan, 1999 to 2002

The antibiotic susceptibilities, genotypes of penicillin (PEN)-binding protein genes (pbp), and serotype distributions of Streptococcus pneumoniae isolates from meningitis patients were investigated by a nationwide surveillance group in Japan between 1999 and 2002. We analyzed 146 isolates from children (/=18 years old). Isolates with or without abnormal pbp1a, pbp2x, or pbp2b genes identified by PCR were classified into six genotype patterns and 90% MIC (MIC(90)) values for PEN: (i) strains with three normal genes (17.2% of isolates; MIC(90), 0.031 micro g/ml); (ii) strains with abnormal pbp2x (22.1%, 0.063 micro g/ml); (iii) strains with abnormal pbp2b (1.0%, 0.125 micro g/ml); (iv) strains with abnormal pbp2x and pbp2b (7.4%, 0.25 micro g/ml); (v) strains with abnormal pbp1a and pbp2x (12.7%, 0.25 micro g/ml); and (vi) strains with three abnormal PBP genes (39.7%, 4 micro g/ml), which are termed genotypic PEN-resistant S. pneumoniae (gPRSP). Panipenem, a carbapenem, showed an excellent MIC(90) (0.125 micro g/ml) against gPRSP, followed by meropenem and vancomycin (0.5 micro g/ml), cefotaxime and ceftriaxone (1 micro g/ml), and ampicillin (4 micro g/ml). Strains of gPRSP were significantly more prevalent in children (45.2%) than in adults (27.4%). The most frequent serotypes were 6B, 19F, 23F, 6A, and 14 in children and 23F, 22, 3, 10, 6B, and 19F in adults. Serotypes 6B, 6A, 19F, 23F, and 14 predominated among gPRSP. In children, 7- and 11-valent pneumococcal conjugate vaccines would cover 76.2 and 81.3% of isolates, respectively, although coverage would be lower in adults (43.9 and 56.0%, respectively). These findings suggest the need for early introduction of pneumococcal conjugate vaccines and continuous bacteriological surveillance for meningitis.     

Treatment of experimental pneumonia due to penicillin-resistant Streptococcus pneumoniae in immunocompetent rats.

A model of pneumonia due to Streptococcus pneumoniae resistant to penicillin was developed in immunocompetent Wistar rats and was used to evaluate the efficacies of different doses of penicillin, cefotaxime, cefpirome, and vancomycin. Adult Wistar rats were challenged by intratracheal inoculation with 3 x 10(9) CFU of one strain of S. pneumoniae resistant to penicillin (MICs of penicillin, cefotaxime, cefpirome, and vancomycin, 2, 1, 0.5, and 0.5 microg/ml, respectively) suspended in brain heart broth supplemented with 0.7% agar. The rats experienced a fatal pneumonia, dying within 5 days and with peak mortality (70 to 80%) occurring 48 to 72 h after infection, and the bacterial counts in the lungs persisted from 8.87 +/- 0.3 log10 CFU/g of lung at 24 h of the infection to 9.1 +/- 0.3 log10 CFU/g at 72 h. Four hours after infection the animals were randomized into the following treatment groups: (i) control without treatment, (ii) penicillin G at 100,000 IU/kg of body weight every 2 h, (iii) penicillin G at 250,000 IU/kg every 2 h, (iv) cefotaxime at 100 mg/kg every 2 h, (v) cefpirome at 200 mg/kg every 2 h, and (vi) vancomycin at 50 mg/kg every 8 h. Two different protocols were used for the therapeutic efficacy studies: four doses of beta-lactams and one dose of vancomycin or eight doses of beta-lactams and two doses of vancomycin. Results of the therapy for experimental pneumonia caused by penicillin-resistant S. pneumoniae showed that initially, all the antimicrobial agents tested had similar efficacies, but when we prolonged the treatment, higher doses of penicillin, cefotaxime, and cefpirome were more effective than penicillin at lower doses in decreasing the residual bacterial titers in the lungs. Also, when we extended the treatment, vancomycin was more efficacious than penicillin at lower doses but was less efficacious than higher doses of penicillin or cefpirome. The model that we have developed is simple and amenable for inducing pneumonia in immunocompetent rats and could be used to explore the pathophysiology and to evaluate optimal therapy of this infection in the immunocompetent host.