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1.  In vitro antagonism of beta-lactam antibiotics by cefoxitin. 
We assessed the extent and mechanisms of antagonism of beta-lactam antibiotics by cefoxitin. In tests with 41 gram-negative isolates, cefoxitin antagonized cephalothin, cefamandole, cefsulodin, cefotaxime, moxalactam, ampicillin, carbenicillin, piperacillin, mezlocillin, and azlocillin, but not cephalexin, mecillinam, or N-formimidoyl thienamycin. The extent of antagonism varied with the beta-lactam and genus studied. However, antagonism occurred most often with strains possessing inducible cephalosporinases. Antagonism of cephalothin and cefamandole correlated closely with the induction of beta-lactamases capable of inactivating these drugs. Although antagonism of the remaining drugs occurred more often with strains possessing inducible beta-lactamases, these enzymes did not inactivate the drugs. Morphological studies revealed that cefoxitin inhibited filamentation and lysis produced by various beta-lactam drugs. Results of this investigation suggest that cefoxitin antagonizes beta-lactams via (i) induction of drug-inactivating beta-lactamases, and (ii) the induction of beta-lactamases that cannot inactivate the drug but serve as barriers against access to target proteins. This barrier appears most efficient for drugs that bind to penicillin-binding proteins 1 and 3.
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PMCID: PMC182054  PMID: 6981376
3.  β-Lactamases Responsible for Resistance to Expanded-Spectrum Cephalosporins in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis Isolates Recovered in South Africa 
Although resistance to the expanded-spectrum cephalosporins among members of the family Enterobacteriaceae lacking inducible β-lactamases occurs virtually worldwide, little is known about this problem among isolates recovered in South Africa. Isolates of Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis resistant to expanded-spectrum cephalosporins recovered from patients in various parts of South Africa over a 3-month period were investigated for extended-spectrum β-lactamase production. Antibiotic susceptibility was determined by standard disk diffusion and agar dilution procedures. Production of extended-spectrum β-lactamases was evaluated by using the double-disk test, and the β-lactamases were characterized by spectrophotometric hydrolysis assays and an isoelectric focusing overlay technique which simultaneously determined isoelectric points and general substrate or inhibitor characteristics. DNA amplification and sequencing were performed to confirm the identities of these enzymes. The P. mirabilis and E. coli isolates were found to produce TEM-26-type, SHV-2, and SHV-5 extended-spectrum β-lactamases. An AmpC-related enzyme which had a pI of 8.0 and which conferred resistance to cefoxitin as well as the expanded-spectrum cephalosporins was found in a strain of K. pneumoniae. This is the first study which has identified organisms producing different extended-spectrum β-lactamases from South Africa and the first report describing strains of P. mirabilis producing a TEM-26-type enzyme. The variety of extended-spectrum β-lactamases found among members of the family Enterobacteriaceae isolated from major medical centers in South Africa is troubling and adds to the growing list of countries where these enzymes pose a serious problem for antimicrobial therapy.
PMCID: PMC105602  PMID: 9624474
4.  Structure-activity studies of quinolone-penems in genetically defined strains of Escherichia coli. 
Antimicrobial Agents and Chemotherapy  1997;41(11):2570-2572.
Quinolonyl-beta-lactam antimicrobial agents (QLAs) contain quinolones chemically linked to beta-lactams, although the impact of linkage is poorly understood. Genetically defined Escherichia coli strains were used to determine structure-activity characteristics of three quinolone-penem QLAs. Results suggest that the leaving group resulting from beta-lactam hydrolysis may not be free quinolone.
PMCID: PMC164166  PMID: 9371371
5.  Occurrence and detection of extended-spectrum beta-lactamases in members of the family Enterobacteriaceae at a veterans medical center: seek and you may find. 
Journal of Clinical Microbiology  1997;35(10):2593-2597.
A total of 907 consecutive isolates of members of the family Enterobacteriaceae recovered during a 20-week period were tested for production of extended-spectrum beta-lactamases (ESBLs) by the double-disk (DD) potentiation method. Of 84 DD-positive isolates, 83 (9.2%) produced ESBLs based on isoelectric focusing. SHV-derived ESBLs and several TEM-derived ESBLs were present in nine species, including the first isolate of Citrobacter koserii and Morganella morganii known to harbor an SHV-derived ESBL. Results of testing 58 nonrepeat isolates for ESBL production by several recommended methods were as follows (percent detected in parentheses): DD method with aztreonam (95), ceftazidime (79), ceftriaxone (88), or cefpodoxime (90); broth microdilution method with ceftazidime (86) or cefotaxime (91) alone or in combination with clavulanate; and the standard disk diffusion method with new breakpoints and standard concentrations of aztreonam (78), ceftazidime (79), ceftriaxone (83), or cefpodoxime (98) or a novel concentration (5 microg) of ceftazidime (88). In three instances during an extended part of the study, an ESBL-producing isolate and a non-ESBL-producing isolate of the same species were recovered from a single blood culture bottle. These data indicate that ESBLs occur in several species of Enterobacteriaceae and at a relatively high incidence at our institution and that the standard disk diffusion method with cefpodoxime and the DD method with several beta-lactams are practical and cost-effective methods for detecting ESBL-producing isolates of Enterobacteriaceae.
PMCID: PMC230016  PMID: 9316913
6.  Rationale behind high-dose amoxicillin therapy for acute otitis media due to penicillin-nonsusceptible pneumococci: support from in vitro pharmacodynamic studies. 
To evaluate whether increased doses of amoxicillin should be used to treat acute pneumococcal otitis media, an in vitro pharmacokinetic model was used to evaluate the killing of pneumococci by amoxicillin when middle ear pharmacokinetics were simulated. Logarithmic-phase cultures were exposed to peak concentrations of 3, 6, and 9 microg of amoxicillin per ml every 12 h, and an elimination half-life of 1.6 h was simulated. Changes in viable bacterial counts were measured over 36 h. All three doses rapidly decreased the viable bacterial counts of penicillin-susceptible strains below the 10-CFU/ml limit of detection by 6 to 10 h and maintained counts below this limit through 36 h. The 3-microg/ml peak dose was much less effective against two of three strains with intermediate penicillin resistance and all three penicillin-resistant strains, with bacterial counts approaching those in drug-free control cultures by 12 h. The 6-microg/ml peak dose completely eliminated two of three strains with intermediate penicillin resistance and maintained viable counts of the other nonsusceptible strains at 1.5 to 2 logs below the initial inoculum through 36 h. The 9-microg/ml peak dose was most effective, completely eliminating all three strains with intermediate penicillin resistance and maintaining the viable counts of the resistant strains at 3 to 4 logs below the original inoculum. The pharmacodynamics observed in this study suggest that peak concentrations of amoxicillin of 6 to 9 microg/ml may be sufficient for the elimination of penicillin-nonsusceptible pneumococcal strains causing otitis media, especially those with intermediate resistance to amoxicillin. In vivo pharmacokinetic studies are needed to determine if these levels can be achieved in middle ear fluid with amoxicillin at 70 to 90 mg/kg/day divided into two daily doses. If these levels are reliably achieved, then clinical studies are warranted.
PMCID: PMC164037  PMID: 9303386
7.  Comparison of screening methods for detection of extended-spectrum beta-lactamases and their prevalence among blood isolates of Escherichia coli and Klebsiella spp. in a Belgian teaching hospital. 
Journal of Clinical Microbiology  1997;35(9):2191-2197.
Using a set of 33 well-defined extended-spectrum beta-lactamase (ESBL)-producing strains of Escherichia coli and Klebsiella pneumoniae, we compared three screening methods for ESBL detection: (i) a double-disk synergy test, (ii) a three-dimensional test (both the double-disk synergy test and the three-dimensional test were performed with ceftriaxone, ceftazidime, aztreonam, and cefepime), and (iii) the Etest ESBL screen (AB Biodisk, Solna, Sweden), based on the recognition of a reduction in the ceftazidime MIC in the presence of clavulanic acid. In the double-disk test, all four indicator antibiotics scored equally and 31 of the 33 reference strains were recognized. In the three-dimensional test, ceftriaxone was the only satisfactory indicator and 30 ESBL-positive strains were detected by this antibiotic. Both systems produced two false-positive results with cefepime. With the Etest ESBL screen, 15 of 16 TEM-related and 11 of 16 SHV-related ESBL-producing strains scored positive. In 10 cases the clavulanic acid on one end of the strip interfered with the MIC determination for ceftazidime, which was read on the opposite end. This MIC had to be determined with an extra ceftazidime-only strip. No false-positive results were noted. Eighty-six blood isolates of E. coli and Klebsiella species were screened for ESBL expression by the double-disk and three-dimensional tests, both with ceftriaxone. Six strains with suspicious antibiogram phenotypes also gave positive results by the double-disk test. One E. coli strain remained undetected by the three-dimensional test. Identification of the enzymes suspected of being ESBLs by isoelectric focusing (all strains) and DNA sequencing (1 strain) confirmed the screening test results except for one Klebsiella oxytoca strain, which proved to be a hyperproducer of its chromosomal enzyme and which also had a negative Etest score. The five true ESBL producers were all confirmed by the Etest ESBL screen. Pulsed-field gel electrophoresis proved that the E. coli strains were unrelated, but that two of the three K. pneumoniae strains were closely related.
PMCID: PMC229938  PMID: 9276386
8.  Penicillin-binding proteins and induction of AmpC beta-lactamase. 
In competition assays for radiolabeled penicillin, penicillin-binding proteins (PBPs) 4, 7a, and 7b showed very high affinities for strong inducers of AmpC beta-lactamase. Loss of PBP 4 resulted in diminished inducibility. This suggests that if PBPs are involved in induction of AmpC beta-lactamase, there is probably a redundancy in function among the different PBPs.
PMCID: PMC164055  PMID: 9303404
9.  Importance of beta-lactamase inhibitor pharmacokinetics in the pharmacodynamics of inhibitor-drug combinations: studies with piperacillin-tazobactam and piperacillin-sulbactam. 
An in vitro pharmacokinetic model was used to study the pharmacodynamics of piperacillin-tazobactam and piperacillin-sulbactam against gram-negative bacilli producing plasmid-encoded beta-lactamases. Logarithmic-phase cultures were exposed to peak antibiotic concentrations observed in human serum after the administration of intravenous doses of 3 g of piperacillin and 0.375 g of tazobactam or 0.5 g of sulbactam. Piperacillin and inhibitor were either dosed simultaneously or piperacillin was dosed sequentially 0.5 h after dosing with the inhibitor. In studies with all four test strains, the pharmacodynamics observed after simultaneous dosing were similar to those observed with the sequential regimen. Since the ratio between piperacillin and tazobactam was in constant fluctuation after sequential dosing, these data suggest that the pharmacodynamics of the piperacillin-inhibitor combinations were not dependent upon maintenance of a critical ratio between the components. Furthermore, when regrowth was observed, the time at which bacterial counts began to increase was similar between the simultaneous and sequential dosing regimens. Since the pharmacokinetics of the inhibitors were the same for all regimens, these data suggest that the length of time that the antibacterial activity was maintained over the dosing interval with these combinations was dictated by the pharmacokinetics of the beta-lactamase inhibitor in the combination. The antibacterial activity of the combination appeared to be lost when the amount of inhibitor available fell below some critical concentration. This critical concentration varied depending upon the type and amount of enzyme produced, as well as the specific inhibitor used. These results indicate that the antibacterial activity of drug-inhibitor combinations, when dosed at their currently recommended ratios, is more dependent on the pharmacokinetics of the inhibitor than on those of the beta-lactam drug.
PMCID: PMC163782  PMID: 9087477
10.  Enterobacter spp.: pathogens poised to flourish at the turn of the century. 
Clinical Microbiology Reviews  1997;10(2):220-241.
Knowledge of the genus Enterobacter and its role in human disease has expanded exponentially in recent years. The incidence of infection in the hospital and the community has increased. New clinical syndromes have been recognized. Enterobacter spp. have also been implicated as causes of other syndromes that traditionally have been associated almost exclusively with more easily treatable pathogens, such as group A streptococci and staphylococci. Rapid emergence of multiple-drug resistance has been documented in individual patients during therapy and in populations and environments with strong selective pressure from antimicrobial agents, especially the cephalosporins. Therapeutic options for patients infected with multiply resistant strains have become severely limited. Carbapenems or, alternatively, fluoroquinolones are the most predictively active options, although resistance to both classes has been observed on rare occasions. Enterobacter spp. appear well adapted for survival and even proliferation as the turn of the century approaches.
PMCID: PMC172917  PMID: 9105752
11.  Trovafloxacin, a new fluoroquinolone with potent activity against Streptococcus pneumoniae. 
An in vitro study of the activity of 15 antibacterial agents against 202 recent pediatric isolates of Streptococcus pneumoniae from urban and rural Nebraska and rural Kentucky identified trovafloxacin, ofloxacin, clindamycin, and vancomycin as the most active agents and equally active against both penicillin-susceptible and--resistant strains. In contrast, six beta-lactams, three macrolides, and trimethoprim-sulfamethoxazole were less active overall, especially against penicillin-intermediate and--resistant strains. Trovafloxacin inhibited all strains at a concentration of < or = 0.25 micrograms/ml and was 8- to 16-fold more potent than ofloxacin or ciprofloxacin.
PMCID: PMC163735  PMID: 9021213
12.  Beta-lactamases and detection of beta-lactam resistance in Enterobacter spp. 
Enterobacter spp. are becoming increasingly frequent nosocomial pathogens, and beta-lactam-resistant strains are on the increase, especially among isolates recovered from intensive care units. Therefore, a study was designed to characterize the beta-lactamases produced by 80 isolates of E. cloacae, E. aerogenes, E. taylorae, E. gergoviae, E. sakazakii, E. asburiae, and E. agglomerans by induction studies, spectrophotometric hydrolysis assays, and isoelectric focusing. The ability of broth microdilution and disk diffusion susceptibility tests to detect resistance to 16 beta-lactam antibiotics among these species was also assessed. All species except E. agglomerans, E. gergoviae, and some isolates of E. sakazakii were found to produce a Bush group 1 cephalosporinase that was expressed inducibly or constitutively at high levels. In addition, some strains also produced a Bush group 2 beta-lactamase. In comparisons of broth microdilution and disk diffusion tests, disk diffusion tests failed to detect resistance in 1 of 25 isolates resistant to aztreonam and 2 of 30 isolates resistant to ceftazidime. These results indicate that species of Enterobacter can possess a variety of beta-lactamases that are responsible for beta-lactam resistance in this genus and that the disk diffusion test may occasionally miss resistance in some strains.
PMCID: PMC163656  PMID: 8980751
13.  Detection of extended-spectrum-beta-lactamase-producing members of the family Enterobacteriaceae with Vitek ESBL test. 
Journal of Clinical Microbiology  1996;34(12):2997-3001.
A three-phase analysis of the Vitek ESBL test and a double-disk (2 disk) test was performed to assess their ability to detect extended-spectrum beta-lactamases (ESBLs) in members of the family Enterobacteriaceae. In the first two phases involving detection of ESBLs in 157 stains processing well-characterized beta-lactamases, sensitivity and specificity were found to be 99.5 and 100%, respectively, for the Vitek ESBl test and 98.1 and 99.4%, respectively, for the 2-disk test. In the third phase, in which the ability of each test to detect ESBLs in 295 clinical isolates was assessed, there was only one false positive (Vitek ESBL test). Across all three phases, the Vitek ESBL test was found to be much easier to perform than the 2-disk test. The latter also involved subjective interpretation of results. There were a total of 176 Escherichia coli and 157 Klebsiella pneumoniae isolates and less than 40 isolates of each of 14 other species evaluated. In a supplemental study of Klebsiella oxytoca, an organism possessing a chromosomal beta-lactamase similar to an ESBL, the Vitek ESBL test was found to be capable of detecting hyperproduction of this enzyme in strains of this species as well. These data indicate that the Vitek ESBL test is reliable for the detection of ESBLs in E. coli and K. pneumoniae, the two species in which ESBLs are most common, and of hyperproduction of the K. oxytoca beta-lactamase, a situation which engenders a level of resistance to this species similar to that seen with ESBLs.
PMCID: PMC229448  PMID: 8940437
14.  Efficacy of ampicillin-sulbactam is not dependent upon maintenance of a critical ratio between components: sulbactam pharmacokinetics in pharmacodynamic interactions. 
Antimicrobial Agents and Chemotherapy  1996;40(11):2468-2477.
An in vitro pharmacokinetic model (IVPM) and a mouse model of lethal bacteremia were used to compare the pharmacodynamics of ampicillin-sulbactam when the two components were dosed simultaneously and in sequence against TEM-1-producing Escherichia coli. The challenge isolates included three strains of E. coli producing various levels of beta-lactamase. Human pharmacokinetics of ampicillin-sulbactam (1.5- and 3.0-g intravenous doses) were simulated in each model, and pharmacodynamic interactions were evaluated over one 6-h dosing interval. Against all three strains, the sequential dosing of sulbactam prior to ampicillin did not alter the pharmacodynamics of these combinations from comparison with results obtained with the simultaneous administration of the two components. Similar pharmacodynamics were observed for the two dosing regimens regardless of the ampicillin-sulbactam dose used or whether the bacteria were treated in an immunocompetent mouse or in the absence of immune defenses in the IVPM. When antibacterial activity was lost and regrowth of the inoculum was observed, viable bacterial counts increased in both the simultaneous and sequential regimens at a point when sulbactam levels fell below a critical concentration. These data suggest that the efficacy of ampicillin-sulbactam is not dependent upon the maintenance of a constant 2:1 ratio for the two components. Rather, the efficacy of ampicillin-sulbactam appears to be dependent upon the maintenance of one or both components above a critical concentration. Furthermore, the pharmacokinetics of sulbactam, specifically, how long sulbactam levels remain above a minimum critical concentration, appears to dictate how long antibacterial activity is maintained with the combination.
PMCID: PMC163559  PMID: 8913448
15.  Sequencing and analysis of four new Enterobacter ampD Alleles. 
Sequences of ampD genes from wild-type, temperature-sensitive, and stably derepressed mutants of the wild-type strain of Enterobacter cloacae 029 and the hyperinducible strain E. cloacae 1194E were determined and compared with the ampD gene of the wild-type strain E. cloacae 14. Seventy nucleotide differences were found between the wild-type sequences, resulting in 13 amino acid changes. The deduced amino acid changes do not correspond to published AmpC regulation mutations and expand the number of known mutations leading to altered AmpC beta-lactamase expression in members of the family Enterobacteriaceae.
PMCID: PMC163450  PMID: 8843314
16.  New variant of TEM-10 beta-lactamase gene produced by a clinical isolate of proteus mirabilis. 
A clinical isolate of Proteus mirabilis was found to produce a new variant of the TEM-10 beta-lactamase gene. This is the first report of TEM-10 production by P. mirabilis and the first report of extended-spectrum beta-lactamase production by an isolate of this species recovered in the United States.
PMCID: PMC162712  PMID: 7625817
17.  Comparison of ampicillin-sulbactam regimens simulating 1.5- and 3.0-gram doses to humans in treatment of Escherichia coli bacteremia in mice. 
A mouse model of bacteremia was used to compare the efficacies of 1.5- and 3.0-g intravenous doses of ampicillin-sulbactam. Seven strains of Escherichia coli producing various levels of TEM-1 beta-lactamase were used as the challenge isolates. These strains included six clinical isolates (MICs from 2/1 micrograms/ml [with 2 and 1 microgram/ml being the respective concentrations of ampicillin and sulbactam] to 32/16 micrograms/ml) with similar degrees of virulence in mice and a laboratory genetic transformant (E. coli AFE) which hyperproduces TEM-1 (MIC = 128/64 micrograms/ml). Human pharmacokinetics were simulated by injecting mice subcutaneously twice (1 h apart) with ampicillin-sulbactam at concentrations of 40 mg/kg of body weight (1.5 g) and 80 mg/kg (3.0 g). Against two clinical isolates for which ampicillin-sulbactam MICs were < or = 8/4 micrograms/ml, no difference was observed in either the rate or level of killing between the two doses, and both doses were 100% protective against lethal infection. Against the four clinical isolates for which ampicillin-sulbactam MICs were between 16/8 and 32/16 micrograms/ml, a slight delay in killing was noted with three of the strains. This delay was followed by a rapid 2- to 3-log drop in the level of bacteremia, and both doses of ampicillin-sulbactam were 100% protective against lethal septicemia. With strain AFE, no killing was observed with the 40-mg/kg dose compared with a 2-log killing with the 80-mg/kg dose. This difference in killing correlated with a decreased protective efficacy of the 40-mg/kg dose. These data suggest that the 1.5-g preparation of ampicillin-sulbactam is as effective as the 3.0-g dose in the treatment of experimentally induced E. coli bacteremia, as long as ampicillin-sulbactam MICs are 32/16 micrograms/ml or less.
PMCID: PMC162656  PMID: 7785998
18.  Development of test panel of beta-lactamases expressed in a common Escherichia coli host background for evaluation of new beta-lactam antibiotics. 
A test panel of 35 different beta-lactamases expressed in a common Escherichia coli host was created to compare the effect that each beta-lactamase had on susceptibility to various beta-lactam antibiotics. A comparison of the MICs obtained with this panel generally reflected differences in the substrate profiles of the various beta-lactamases examined. In addition, several strains of the panel were subjected to selection with porin-specific bacteriophages to obtain mutants lacking either the OmpC or OmpF porin protein. A mutation in either OmpC or OmpF did change the susceptibilities of certain strains expressing beta-lactamase to certain beta-lactam antibiotics. However, the loss of a single porin did not predictably alter susceptibility to any given beta-lactam drug. This panel of strains producing various beta-lactamases was found to be a useful tool for comparing the effects of different beta-lactamases and outer membrane permeability upon susceptibility to beta-lactam drugs.
PMCID: PMC162532  PMID: 7726487
20.  Resistance to ticarcillin-potassium clavulanate among clinical isolates of the family Enterobacteriaceae: role of PSE-1 beta-lactamase and high levels of TEM-1 and SHV-1 and problems with false susceptibility in disk diffusion tests. 
Thirty-four clinical isolates of the family Enterobacteriaceae from the University of Texas M. D. Anderson Cancer Center appeared resistant to ticarcillin-potassium clavulanate in agar dilution and broth macrodilution tests. Among those isolates producing a single non-class I beta-lactamase, resistance was due to production of high levels of TEM-1, SHV-1, or class IV enzymes. In five Escherichia coli isolates, production of low levels of PSE-1 was responsible for resistance which seemed due to rapid hydrolysis of ticarcillin rather than diminished susceptibility of PSE-1 to inhibition by potassium clavulanate. Comparisons of dilution and disk diffusion tests revealed major discrepancies, with 65% false susceptibility in the disk test. Revision of the interpretive criteria used for disk diffusion tests from less than or equal to 11 to less than or equal to 18 mm for resistance is proposed to resolve these discrepancies until clinical data are obtained which can be used to determine which in vitro test is most predictive of therapeutic outcome. These new criteria would diminish false susceptibility without introducing false resistance.
PMCID: PMC175869  PMID: 3143303
21.  Characterization of beta-lactamase induction in Enterobacter cloacae. 
The induction of beta-lactamase was studied in a strain of Enterobacter cloacae. A wide variety of beta-lactam compounds were found to induce beta-lactamase in this organism, and the degree of induction was directly related to the stability of the inducer to degradation by the enzyme. The kinetics of the induction process were consistent with a system normally under repressor control, suggesting a direct interaction of the beta-lactam compound with a repressor protein in the E. cloacae cells. Although these characteristics are common to many inducible systems in gram-negative organisms, the induction of beta-lactamase in this strain was not subject to catabolite repression with glucose and remained unaffected by exogenous cyclic AMP in the culture medium. This suggests that the organization and function of the beta-lactamase regulatory genes in E. cloacae are unlike those of other inducible gene systems, such as those composing the well-characterized lactose operon in Escherichia coli.
PMCID: PMC184623  PMID: 6402977
22.  Antagonism of carbenicillin and cefamandole by cefoxitin in treatment of experimental infections in mice. 
The ability of cefoxitin to antagonize the in vivo efficacy of cefamandole and carbenicillin as predicted by in vitro assays was analyzed in experimental infections in mice. Cefoxitin was administered in a nonprotective dose either at the time of challenge or simultaneously with the protective drug, 1 and 3.5 h postchallenge. In mice infected with Enterobacter cloacae, median 50% protective doses of cefamandole and carbenicillin were markedly increased by cefoxitin, especially when the latter was given at the time of challenge. The antagonistic effect was also associated with increased numbers of challenge bacteria present in animal heart blood within a 6.5-h period after infection. In infections with Pseudomonas aeruginosa, cefoxitin antagonized carbenicillin; however, the effect was less dramatic than that seen with E. cloacae. Antagonism in this model was pronounced with simultaneous administration of antagonizing and protective drugs. The antagonistic effects observed in all in vivo tests were not due to the selection of stable resistance to the protective drugs, but appeared to be due to a reversible induction of beta-lactamases by cefoxitin.
PMCID: PMC182053  PMID: 6921959
23.  Evaluation of single-dose ciprofloxacin in the eradication of Neisseria meningitidis from nasopharyngeal carriers. 
Antimicrobial Agents and Chemotherapy  1988;32(11):1740-1741.
The ability of a single oral 750-mg dose of ciprofloxacin to eradicate Neisseria meningitidis from persistent nasopharyngeal carriers was prospectively evaluated in a placebo-controlled, randomized, double-blinded study. Cultures of specimens taken from all 23 ciprofloxacin-dosed subjects 1 day postdose were negative; cultures from 96% of these subjects were negative at 7 and 21 days postdose, including a specimen from a subject colonized with a minocycline-resistant strain. Of 22 placebo recipients, 20 (91%) remained culture positive. Single-dose ciprofloxacin appears efficacious for meningococcal prophylaxis.
PMCID: PMC175963  PMID: 3252755
24.  Inhibition of Neisseria gonorrhoeae by aerobic and facultatively anaerobic components of the endocervical flora: evidence for a protective effect against infection. 
Infection and Immunity  1978;19(2):704-710.
The ability of aerobic and facultatively anaerobic endocervical flora to inhibit the growth of Neisseria gonorrhoeae in vitro was assayed. Factors influencing the occurrence of inhibitory components of the flora in vivo were evaluated. Endocervical swabs were obtained from 229 women at a local venereal disease clinic. Endocervical flora and N. gonorrhoeae were isolated and identified, and the ability of the flora to inhibit the growth of N. gonorrhoeae was determined by an agar overlay assay. Results revealed the most active inhibitors to be streptococci, staphylococci, and lactobacilli, in that order. Among only those women harboring inhibitory endocervical flora, inhibitory lactobacilli were recovered from fewer women infected with N. gonorrhoeae than uninfected women (P less than 0.05). Among women having contact with an infected partner, those who subsequently developed gonorrhea were less likely to have inhibitory lactobacilli than those who did not become infected (P less than 0.05). No other significant differences in the composition of the inhibitory flora were noted between infected and uninfected women. During the 2 weeks following menses, recovery of inhibitory lactobacilli on culture was highest, whereas recovery of N. gonorrhoeae was lowest. These observations suggest that the presence of certain lactobacilli may reduce risk of acquisition of N. gonorrhoeae following exposure to infected partners and that the potential protective effect may be greatest during the 2 weeks after menses.
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PMCID: PMC414137  PMID: 415983
25.  Dissociated resistance among fluoroquinolones. 
A panel of 190 clinical isolates of staphylococci, enterococci, Streptococcus pneumoniae, members of the family Enterobacteriaceae, and nonfermentative gram-negative bacilli were examined by agar dilution tests for susceptibility to five quinolones and six nonquinolone agents. Members of the family Enterobacteriaceae and staphylococci were divided into subgroups according to their ciprofloxacin susceptibilities and were analyzed for cross-resistance to OPC-17116, ofloxacin, and temafloxacin. Although the MICs of all quinolones increased with increasing ciprofloxacin resistance, the MICs of OPC-17116, ofloxacin, and temafloxacin tended to increase less than those of ciprofloxacin, indicating that these agents were less affected by the mechanisms of quinolone resistance. An exception to this was the activity of OPC-17116 against highly ciprofloxacin-resistant staphylococci (MIC, > or = 8 micrograms/ml). Some of these staphylococci were equally resistant to OPC-17116, while others were fourfold more susceptible to ciprofloxacin than to OPC-17116. This indicated that in some strains OPC-17116 was more affected than ciprofloxacin by certain mechanisms responsible for high-level resistance. This was paralleled in single-step mutational studies in which 7 of 19 staphylococcal mutants exhibited large decreases in susceptibility to OPC-17116 (128- to 256-fold) but only modest decreases in susceptibility (4- to 16-fold) to the other quinolones. Such mutants were selected only from strains moderately resistant to ciprofloxacin (MIC, > or = 1 microgram/ml). This heterogeneity in the resistance of staphylococci to fluoroquinolones has not been seen previously and suggests that certain mechanisms of resistance in staphylococci affect OPC-17116 to a much greater extent than other quinolones.
PMCID: PMC284690  PMID: 7811025

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