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1.  The genome of the simian and human malaria parasite Plasmodium knowlesi 
Nature  2008;455(7214):799-803.
Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the ‘kra’ monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia1,2. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated3, and it has a close phylogenetic relationship to Plasmodium vivax​4, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or ‘hypnozoite’ in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone5) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome4 and other sequenced Plasmodium genomes6-8. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs9, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.
doi:10.1038/nature07306
PMCID: PMC2656934  PMID: 18843368
2.  Genome Evolution of Wolbachia Strain wPip from the Culex pipiens Group 
Molecular Biology and Evolution  2008;25(9):1877-1887.
The obligate intracellular bacterium Wolbachia pipientis strain wPip induces cytoplasmic incompatibility (CI), patterns of crossing sterility, in the Culex pipiens group of mosquitoes. The complete sequence is presented of the 1.48-Mbp genome of wPip which encodes 1386 coding sequences (CDSs), representing the first genome sequence of a B-supergroup Wolbachia. Comparisons were made with the smaller genomes of Wolbachia strains wMel of Drosophila melanogaster, an A-supergroup Wolbachia that is also a CI inducer, and wBm, a mutualist of Brugia malayi nematodes that belongs to the D-supergroup of Wolbachia. Despite extensive gene order rearrangement, a core set of Wolbachia genes shared between the 3 genomes can be identified and contrasts with a flexible gene pool where rapid evolution has taken place. There are much more extensive prophage and ankyrin repeat encoding (ANK) gene components of the wPip genome compared with wMel and wBm, and both are likely to be of considerable importance in wPip biology. Five WO-B–like prophage regions are present and contain some genes that are identical or highly similar in multiple prophage copies, whereas other genes are unique, and it is likely that extensive recombination, duplication, and insertion have occurred between copies. A much larger number of genes encode ankyrin repeat (ANK) proteins in wPip, with 60 present compared with 23 in wMel, many of which are within or close to the prophage regions. It is likely that this pattern is partly a result of expansions in the wPip lineage, due for example to gene duplication, but their presence is in some cases more ancient. The wPip genome underlines the considerable evolutionary flexibility of Wolbachia, providing clear evidence for the rapid evolution of ANK-encoding genes and of prophage regions. This host–Wolbachia system, with its complex patterns of sterility induced between populations, now provides an excellent model for unraveling the molecular systems underlying host reproductive manipulation.
doi:10.1093/molbev/msn133
PMCID: PMC2515876  PMID: 18550617
endosymbiont; Wolbachia; mosquito; cytoplasmic incompatibility; prophage; ankyrin
3.  Potential Impact of the VITEK 2 System and the Advanced Expert System on the Clinical Laboratory of a University-Based Hospital 
Journal of Clinical Microbiology  2001;39(7):2379-2385.
A study was designed to assess the impact of the VITEK 2 automated system and the Advanced Expert System (AES) on the clinical laboratory of a typical university-based hospital. A total of 259 consecutive, nonduplicate isolates of Enterobacteriaceae members, Pseudomonas aeruginosa, and Staphylococcus aureus were collected and tested by the VITEK 2 system for identification and antimicrobial susceptibility testing, and the results were analyzed by the AES. The results were also analyzed by a human expert and compared to the AES analyses. Among the 259 isolates included in this study, 245 (94.6%) were definitively identified by VITEK 2, requiring little input from laboratory staff. For 194 (74.9%) isolates, no inconsistencies between the identification of the strain and the antimicrobial susceptibility determined by VITEK 2 were detected by the AES. Thus, no input from laboratory staff was required for these strains. The AES suggested one or more corrections to results obtained with 65 strains to remove inconsistencies. The human expert thought that most of these corrections were appropriate and that some resulted from a failure of the VITEK 2 system to detect certain forms of resistance. Antimicrobial phenotypes assigned to the strains by the AES for β-lactams, aminoglycosides, quinolones, macrolides, tetracyclines, and glycopeptides were similar to those assigned by the human expert for 95.7 to 100% of strains. These results indicate that the VITEK 2 system and AES can provide accurate information in tests for most of the clinical isolates examined and remove the need for human analysis of results for many. Certain problems were identified in the study that should be remediable with further work on the software supporting the AES.
doi:10.1128/JCM.39.7.2379-2385.2001
PMCID: PMC88158  PMID: 11427542
4.  Ability of the VITEK 2 Advanced Expert System To Identify β-Lactam Phenotypes in Isolates of Enterobacteriaceae and Pseudomonas aeruginosa 
Journal of Clinical Microbiology  2000;38(2):570-574.
The Advanced Expert System (AES) was used in conjunction with the VITEK 2 automated antimicrobial susceptibility test system to ascertain the β-lactam phenotypes of 196 isolates of the family Enterobacteriaceae and the species Pseudomonas aeruginosa. These isolates represented a panel of strains that had been collected from laboratories worldwide and whose β-lactam phenotypes had been characterized by biochemical and molecular techniques. The antimicrobial susceptibility of each isolate was determined with the VITEK 2 instrument, and the results were analyzed with the AES to ascertain the β-lactam phenotype. The results were then compared to the β-lactam resistance mechanism determined by biochemical and molecular techniques. Overall, the AES was able to ascertain a β-lactam phenotype for 183 of the 196 (93.4%) isolates tested. For 111 of these 183 (60.7%) isolates, the correct β-lactam phenotype was identified definitively in a single choice by the AES, while for an additional 46 isolates (25.1%), the AES identified the correct β-lactam phenotype provisionally within two or more choices. For the remaining 26 isolates (14.2%), the β-lactam phenotype identified by the AES was incorrect. However, for a number of these isolates, the error was due to remediable problems. These results suggest that the AES is capable of accurate identification of the β-lactam phenotypes of gram-negative isolates and that certain modifications can improve its performance even further.
PMCID: PMC86150  PMID: 10655347
5.  Cefepime-Aztreonam: a Unique Double β-Lactam Combination for Pseudomonas aeruginosa 
An in vitro pharmacokinetic model was used to determine if aztreonam could enhance the pharmacodynamics of cefepime or ceftazidime against an isogenic panel of Pseudomonas aeruginosa 164, including wild-type (WT), partially derepressed (PD), and fully derepressed (FD) phenotypes. Logarithmic-phase cultures were exposed to peak concentrations achieved in serum with 1- or 2-g intravenous doses, elimination pharmacokinetics were simulated, and viable bacterial counts were measured over three 8-h dosing intervals. In studies with cefepime and cefepime-aztreonam against the PD strain, samples were also filter sterilized, assayed for active cefepime, and assayed for nitrocefin hydrolysis activity before and after overnight dialysis. Against WT strains, the cefepime-aztreonam combination was the most active regimen, but viable counts at 24 h were only 1 log below those in cefepime-treated cultures. Against PD and FD strains, the antibacterial activity of cefepime-aztreonam was significantly enhanced over that of each drug alone, with 3.5 logs of killing by 24 h. Hydrolysis and bioassay studies demonstrated that aztreonam was inhibiting the extracellular cephalosporinase that had accumulated and was thus protecting cefepime in the extracellular environment. In contrast to cefepime-aztreonam, the pharmacodynamics of ceftazidime-aztreonam were not enhanced over those of aztreonam alone. Further pharmacodynamic studies with five other P. aeruginosa strains producing increased levels of cephalosporinase demonstrated that the enhanced pharmacodynamics of cefepime-aztreonam were not unique to the isogenic panel. The results of these studies demonstrate that aztreonam can enhance the antibacterial activity of cefepime against derepressed mutants of P. aeruginosa producing increased levels of cephalosporinase. This positive interaction appears to be due in part to the ability of aztreonam to protect cefepime from extracellular cephalosporinase inactivation. Clinical evaluation of this combination is warranted.
PMCID: PMC105655  PMID: 9660993
6.  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
7.  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
8.  Decimal assay for additivity of drugs permits delineation of synergy and antagonism. 
Although there are many in vitro tests for drug interactions, few possess a linear, predictable dose-dependent end point or have a precise definition for additivity. Therefore, a new test with both of these features, the decimal assay for additivity, was developed. This test is based on a disk diffusion assay and the strict linear relationship between drug mass and size of the inhibition zone. When the decimal assay for additivity was applied to combinations known on a mechanistic basis to be additive, synergistic, or antagonistic, results of the new test always reflected the expected drug interaction. For example, synergy between trimethoprim and sulfamethoxazole was detected in tests with Escherichia coli and Haemophilus influenzae, as was antagonism between cefoxitin and cefotaxime in tests with Enterobacter cloacae. Quinolones plus chloramphenicol appeared to be antagonistic. In addition to correctly identifying the drug interaction, the decimal assay for additivity identified the drug ratio producing the maximal drug interaction. These results suggest that the decimal assay for additivity should prove very useful in future studies of drug interactions.
PMCID: PMC187649  PMID: 8452356
10.  Beta-lactamase production in members of the family Enterobacteriaceae and resistance to beta-lactam-enzyme inhibitor combinations. 
Recent reports that members of the family Enterobacteriaceae that produce high levels of certain beta-lactamases are often resistant to ticarcillin-clavulanate prompted this study to assess the relationship between type and amount of enzyme produced and susceptibility to ticarcillin-clavulanate, piperacillin-tazobactam, and cefoperazone-sulbactam. Agar dilution MICs were determined by using 73 strains of Enterobacteriaceae that produced a single beta-lactamase that had been characterized and quantified and a beta-lactamase-negative control strain of Escherichia coli. For E. coli and Klebsiella pneumoniae, MICs of each combination increased as levels of TEM, SHV-1, or class IV enzymes increased. However, the percentage of strains that were resistant was highest for ticarcillin-clavulanate (32%), with only 18 and 6% resistant to piperacillin-tazobactam and cefoperazone-sulbactam, respectively. Strains producing PSE-1, regardless of level, were resistant or moderately susceptible to ticarcillin-clavulanate but were susceptible to piperacillin-tazobactam and cefoperazone-sulbactam. HMS-1 and OHIO-1 beta-lactamases were associated with resistance to ticarcillin-clavulanate and piperacillin-tazobactam, respectively. High levels of class IV enzymes in Klebsiella oxytoca were associated with resistance to all three combinations. These results indicate that the level and type of beta-lactamase produced by members of the family Enterobacteriaceae are important determinants of susceptibility to beta-lactam-inhibitor combinations, especially ticarcillin-clavulanate.
PMCID: PMC171654  PMID: 2344169
11.  Heterogeneity of class I beta-lactamase expression in clinical isolates of Pseudomonas aeruginosa. 
Antimicrobial Agents and Chemotherapy  1988;32(12):1893-1895.
Expression of chromosomal beta-lactamase was examined in 85 clinical isolates of Pseudomonas aeruginosa. beta-Lactamase assays with and without cefoxitin induction revealed four phenotypes of enzyme expression: low basal, inducible; moderate basal, inducible; moderate basal, constitutive; and high basal, constitutive. The isoelectric points of the major beta-lactamase bands were 9.4, 9.2, and 8.4. These results indicate that there is a limited heterogeneity in expression of chromosomal beta-lactamase of P. aeruginosa.
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PMCID: PMC176040  PMID: 3149885
12.  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
13.  Leakage of beta-lactamase: a second mechanism for antibiotic potentiation by amdinocillin. 
Discrepancies were observed between results of different beta-lactamase induction tests with amdinocillin, which appeared to be a strong inducer in whole-cell assays but a weak inducer in assays with cell-free sonic extracts. Results of a nitrocephin-disk test with constitutive beta-lactamase producers indicated that the positive results obtained in whole-cell assays were due to drug-produced leakage of enzyme from the cell and not to induction. Imipenem was also found to cause leakage of beta-lactamase from a similar number of constitutive enzyme producers, while cefoxitin was much less likely to cause leakage. A split-dose regimen was employed to treat mice infected with a strain of Enterobacter cloacae which appeared to leak enzyme on exposure to amdinocillin. Results indicated that prior treatment with amdinocillin significantly enhanced (P less than 0.025) the efficacy of azlocillin, an enzyme-labile drug, but did not affect the efficacy of cefotaxime, a relatively enzyme-stable drug. Conversely, prior treatment with amdinocillin did not potentiate the efficacy of either azlocillin or cefotaxime in the treatment of mice infected with an Escherichia coli strain that was highly susceptible to all three drugs. Thus, it appears that amdinocillin may potentiate the activity of other beta-lactam drugs not only by binding to a complementary penicillin-binding protein but also by causing leakage of beta-lactamase from the cell. This effect may be related to its ability to bind to penicillin-binding protein 2 and subsequently produce changes in outer membrane permeability.
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PMCID: PMC174897  PMID: 3498436
14.  Characterization of beta-lactamases in situ on polyacrylamide gels. 
An inhibitor-based characterization system which allowed the identification of beta-lactamases after isoelectric focusing on polyacrylamide gels was developed. This system, using potassium clavulanate and oxacillin, distinguished type I chromosomally mediated enzymes from other beta-lactamases of gram-negative bacteria.
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PMCID: PMC180628  PMID: 3492960
15.  Evidence for multiple forms of type I chromosomal beta-lactamase in Pseudomonas aeruginosa. 
The multiple stages of derepression of the type I chromosomal beta-lactamase in Pseudomonas aeruginosa were examined. Mutants partially and fully derepressed for beta-lactamase were selected from a wild-type clinical isolate. An analysis of the beta-lactamase produced by these mutants and the induced wild type revealed significant differences in the products of derepression at each stage. Beta-lactamase produced by the fully derepressed mutant showed a lower affinity (Km, 0.113 mM) for cephalothin than that produced by the partially derepressed mutant (Km, 0.049 mM). However, due to a very large Vmax, the former possessed a much greater hydrolytic efficiency. Differences in substrate profile were also noted. Only beta-lactamase from the fully derepressed mutant hydrolyzed cefamandole, cefoperazone, and cefonicid. The partially derepressed mutant possessed a single beta-lactamase band with a pI of 8.4. The fully derepressed mutant possessed this band and an additional major band with a pI of 7.5. Induction of the wild type with cefoxitin produced both bands. The changes in physiologic parameters of the enzymes produced in the different stages of derepression suggest a complex system for beta-lactamase expression in P. aeruginosa. This may involve at least two distinct structural regions, each of which is under control of the same repressor.
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PMCID: PMC180579  PMID: 3096196
16.  Role of beta-lactamases and outer membrane proteins in multiple beta-lactam resistance of Enterobacter cloacae. 
The chromosomal beta-lactamase and outer membrane proteins of Enterobacter cloacae were examined to determine their relative contributions to multiple antibiotic resistance in this organism. Mutants altered in beta-lactamase expression, whether derived in the laboratory or recovered from patients treated with one of the new beta-lactam antibiotics, were found to have no detectable alterations in outer membrane proteins. Derepression of beta-lactamase in these mutants was associated with high-level resistance to multiple beta-lactam antibiotics, while loss of inducible beta-lactamase (i.e., production of basal enzyme levels only) was associated with acquisition of susceptibility to many beta-lactam antibiotics, including cephalothin. In contrast, alteration in outer membrane proteins was associated with only moderate-level resistance to beta-lactam antibiotics. However, this included resistance to such drugs as amdinocillin and Sch 34343, which were unaffected by derepression of beta-lactamase. Resistance to chloramphenicol and tetracycline also accompanied changes in outer membrane proteins. Although the outer membrane proteins of various strains of E. cloacae were similar, there did appear to be some major strain-to-strain variations. Thus, it appears that alterations in both beta-lactamase and outer membrane proteins can affect the susceptibility of E. cloacae to many antibiotics. However, alterations in beta-lactamase alone are sufficient to produce high-level multiple beta-lactam resistance in this organism.
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PMCID: PMC180074  PMID: 3873897
17.  Selection of multiple antibiotic resistance by quinolones, beta-lactams, and aminoglycosides with special reference to cross-resistance between unrelated drug classes. 
The ability of three quinolones, two beta-lactams, and one aminoglycoside to select resistant mutants was examined in tests with 30 isolates of commonly encountered nosocomial pathogens. Ciprofloxacin and norfloxacin, two new quinolone derivatives, were no more likely to select resistant mutants than amikacin, whereas nalidixic acid, an older quinolone derivative, was the most likely of the six drugs examined to select resistant mutants. Mutational frequencies of 10(-7) to 10(-8) were observed in most instances. In general, the mutants were 8 to 16 times less susceptible to the drug used for selection. Although most quinolone-selected mutants were cross-resistant only to other drugs within this class, certain mutants of Klebsiella pneumoniae selected by nalidixic acid, ciprofloxacin, or norfloxacin were also less susceptible to beta-lactam antibiotics. This unusual pattern of multiple drug resistance was associated with changes in outer membrane proteins of the organism. Multiple drug resistance was also observed in beta-lactam-selected mutants of Enterobacter cloacae and Pseudomonas aeruginosa (beta-lactams), amikacin-selected mutants of Providencia stuartii and P. aeruginosa (aminoglycosides), and beta-lactam- or amikacin-selected mutants of Serratia marcescens (beta-lactams plus aminoglycosides). These results underscore the need to examine carefully the frequency with which resistance to any new antibiotic develops, as well as the patterns of multiple drug resistance which may occur simultaneously.
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PMCID: PMC180026  PMID: 6098219
18.  Evaluation of Sch 29,482 in the eradication of Neisseria meningitidis from nasopharyngeal carriers. 
Fifty-eight chronic carriers of Neisseria meningitidis were given 250 mg of Sch 29,482 or placebo orally every 6 h for 4 days. Although 22 of 29 subjects taking Sch 29,482 became culture negative while taking the drug, only five were culture negative 2 weeks posttherapy. There were no significant adverse reactions.
PMCID: PMC185560  PMID: 6732217
19.  Influence of clindamycin on derepression of beta-lactamases in Enterobacter spp. and Pseudomonas aeruginosa. 
Previous studies in this and other laboratories have shown that derepression of beta-lactamases in strains of Enterobacter and Pseudomonas spp. is responsible for the rapid development of resistance to a variety of beta-lactam antibiotics. The purpose of the current study was to evaluate the effects of clindamycin on derepression of beta-lactamases in these two genera. In tests with four strains of each genus, clindamycin diminished derepression in one isolate of each genus and completely prevented derepression in a second Enterobacter isolate (strain 55). Additional tests with strain 55 revealed that other inhibitors of macromolecular synthesis did not completely prevent derepression of beta-lactamase when tested at concentrations that did not inhibit replication. However, clindamycin did not affect synthesis of beta-lactamase that was constitutively produced in a mutant of this strain (55M). It also did not inhibit derepression of beta-galactosidase in either strain 55 or 55M. Clindamycin did not diminish the bactericidal effects of beta-lactam antibiotics against Enterobacter or Pseudomonas spp. However, it enhanced the bactericidal activity of cefamandole against strain 55. These in vitro effects of clindamycin on strain 55 that were related to prevention of derepression of beta-lactamase were confirmed in vivo with an animal model of infection. These results indicate that in some strains, clindamycin can specifically prevent derepression of beta-lactamases without inhibiting growth. Such a selective effect may provide a new approach for the enhancement of the antibacterial activity of certain beta-lactam antibiotics.
PMCID: PMC185103  PMID: 6414365
20.  Development and evaluation of a biochemical scheme for identification of endocervical lactobacilli. 
Journal of Clinical Microbiology  1982;16(5):926-934.
A biochemical scheme for the species identification of endocervical lactobacilli was developed and evaluated with 10 isolates obtained from the American Type Culture Collection (ATCC) and 106 endocervical isolates obtained from women reporting to a local venereal disease clinic and a local hospital clinic. The scheme consisted of two stages. Stage I included six tests and was tested and modified with results obtained with ATCC strains. From the modified stage I, stage II was developed. Tests to be performed in this stage were determined from expected characteristics of lactobacilli. Stage II was also tested with the ATCC strains. Of the 106 endocervical isolates, 78 (74%) were identified with the two-stage scheme as developed with the ATCC strains. Unexpected results were obtained in one or both stages with the other 28 isolates. For 10 isolates, the final species identified were not previously expected to be recovered. A "best-fit" method was used to determine the most likely identification of the remaining 18 isolates. In a few instances, the use of a third stage was necessary to reach an identification. The final identification scheme, although complicated in appearance, generated a species identification with a total of 12 tests with a range of 7 to 10 tests per isolate.
PMCID: PMC272504  PMID: 7153342
21.  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
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.  In vitro studies with Win 42122-2: comparison with gentamicin, netilmicin, and amikacin. 
The in vitro activity of Win 42122-2 against gram-negative clinical isolates was compared in serial twofold broth dilution tests with gentamicin, netilmicin, and amikacin. Against 173 gentamicin-susceptible Enterobacteriaceae, the activity of Win 42122-2 was generally twofold less than those of gentamicin or netilmicin and similar to that of amikacin. Against 60 gentamicin-susceptible nonfermentative gram-negative bacilli, including P. aeruginosa, the activity of Win 42122-2 was four- to eightfold less than that of gentamicin or netilmicin and two- to fourfold less than that of amikacin. Minimal bacterial concentrations for Win 42122-2 were usually similar to minimal inhibitory concentrations. Win 42122-2 was not highly active against gentamicin-resistant bacteria. Win 42122-2 was as active as gentamicin against Mycobacterium tuberculosis but was less active than gentamicin or amikacin against atypical mycobacteria. Win 42122-2 interacted synergistically with penicillin G against enterococci, including strains highly resistant to streptomycin.
PMCID: PMC181672  PMID: 7283421
24.  Emergence of Resistance to Cefamandole: Possible Role of Cefoxitin-Inducible Beta-Lactamases 
Selection of resistance to cefamandole has been observed, and the drug has failed to protect animals lethally infected with certain Enterobacteriaceae that appeared to be highly susceptible in vitro. Using spectrophotometric assays, some of these organisms were found to produce beta-lactamases highly active against cefamandole. Cefoxitin, a poor enzyme substrate, was found to be superior to both cephalothin and cefamandole in induction of these enzymes. A simple disk induction test was developed and used to examine 147 Enterobacteriaceae for production of these beta-lactamases. The enzymes were found in 69% of cephalothin-resistant, cefamandole-susceptible strains and in only 3% of strains susceptible to both cephalothin and cefamandole. They were most prevalent among isolates of Enterobacter, indole-positive Proteus, and Serratia. Since selection of resistance and therapeutic failures have occurred most often among these genera, the relationship between presence of inducible enzymes and outcome of therapy should be examined further in humans.
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PMCID: PMC352760  PMID: 314270
25.  In Vitro Activity of Furazlocillin (Bay k 4999) Compared with Those of Mezlocillin, Piperacillin, and Standard Beta-Lactam Antibiotics 
The activity of furazlocillin (Bay k 4999) was compared with those of mezlocillin, piperacillin, and standard beta-lactam antibiotics against a number of gram-positive and gram-negative organisms. These new expanded-spectrum penicillins were less active than penicillin G against most gram-positive organisms. Furazlocillin, mezlocillin, and piperacillin showed activity comparable to ampicillin and penicillin G against Haemophilus influenzae and penicillin-susceptible neisseriae, respectively. None of the drugs tested was effective against penicillin-resistant gonococci. The activity of furazlocillin was greater than that of mezlocillin, piperacillin, ampicillin, or carbenicillin against many Enterobacteriaceae. However, certain beta-lactam-resistant strains among these organisms were not highly susceptible to any of the three new penicillins. Furazlocillin was less active than piperacillin against Pseudomonas aeruginosa but was more active than carbenicillin or mezlocillin. Inoculum effects and discrepancies between minimal inhibitory concentrations and minimal bactericidal concentrations were observed with furazlocillin, mezlocillin, and piperacillin against several genera. The kinetics of bacterial killing by the new penicillins were often slow and incomplete over 24 h, especially in tests with Enterobacter and P. aeruginosa. Synergy was demonstrated between furazlocillin and aminoglycosides against a variety of gram-negative bacilli and Streptococcus faecalis.
PMCID: PMC352759  PMID: 475364

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