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1.  Activity of ampicillin-sulbactam and oxacillin in experimental endocarditis caused by beta-lactamase-hyperproducing Staphylococcus aureus. 
Using a rat model of aortic valve infective endocarditis, we previously found that oxacillin was equally effective against an oxacillin-susceptible strain of Staphylococcus aureus and a beta-lactamase-hyperproducing borderline oxacillin-susceptible strain of S. aureus; also, ampicillin-sulbactam was less effective than oxacillin against both isolates and at low doses was less effective against the borderline-susceptible strain than against the fully oxacillin-susceptible strain (C. Thauvin-Eliopoulos, L. B. Rice, G. M. Eliopoulos, and R. C. Moellering, Jr., Antimicrob. Agents Chemother. 34:728-732, 1990). In the present study, we extended this work, using alternative treatment schedules and additional bacterial strains. Extending treatment with low doses of ampicillin-sulbactam (500 and 250 mg/kg of body weight per day, respectively) to 6.5 days resulted in equalization of effectiveness against the previously studied strains BOSSA-1 and OSSA-1 (3.75 +/- 1.61 log10 and 4.71 +/- 1.79 log10 CFU of residual viable bacteria per g, respectively). Against the borderline oxacillin-susceptible strain BOSSA-1, increasing the sulbactam dosage from 500 to 2,000 mg/kg/day while maintaining a fixed dose of ampicillin (1,000 mg/kg/day) by continuous infusion resulted in lower bacterial counts (4.93 +/- 1.84 log10 versus 3.65 +/- 1.26 log10 CFU of residual viable bacteria per g, respectively), but this difference was of only borderline significance; differences in efficacy between the low-dose and high-dose sulbactam regimens were exaggerated when intermittent intravenous administration was used (6.19 +/- 1.90 log10 versus 3.37 +/- 1.41 log10 CFU/g, respectively; P < 0.001). However, for any individual sulbactam dosage, the model of administration (continuous versus intermittent infusion) did not affect the activity of the regimen. When additional strains were used in the model, oxacillin and ampicillin-sulbactam (1,000 plus 2,000 mg/kg/day) were equally effective against both oxacillin-susceptible and borderline oxacillin-resistant strains of S. aureus. These results support the predictions that oxacillin would be clinically effective in the treatment of infections caused by borderline oxacillin-susceptible strains of S. aureus and that, except at very low doses, ampicillin-sulbactam would also be as effective against borderline-susceptible strains as against fully oxacillin-susceptible strains of S. aureus.
PMCID: PMC187700  PMID: 8460919
2.  Influence of erythromycin resistance, inoculum growth phase, and incubation time on assessment of the bactericidal activity of RP 59500 (quinupristin-dalfopristin) against vancomycin-resistant Enterococcus faecium. 
Antimicrobial Agents and Chemotherapy  1997;41(12):2749-2753.
RP 59500, a mixture of two semisynthetic streptogramin antibiotics (quinupristin and dalfopristin), is one of a few investigational agents currently in clinical trials with inhibitory activity against multiple-drug-resistant strains of Enterococcus faecium. We evaluated the bactericidal activity of this antimicrobial against 30 recent clinical isolates of vancomycin-resistant E. faecium, including 23 erythromycin-resistant (MIC, >256 microg/ml) and 7 erythromycin-intermediate (MIC, 2 to 4 microg/ml) strains. All isolates were inhibited by RP 59500 at 0.25 to 1.0 microg/ml. The bactericidal activity of RP 59500 was markedly influenced by the erythromycin susceptibility of the strains and by several technical factors, such as inoculum growth phase and time of incubation of counting plates. As determined by time-kill methods, RP 59500 at a concentration of 2 or 8 microg/ml failed to kill erythromycin-resistant organisms under any conditions. Bactericidal activity was observed against all seven erythromycin-intermediate isolates when log-phase inocula were used and the cells were counted after 48 h of incubation (mean reductions in viable bacteria for RP 59500 at concentrations of 2 and 8 microg/ml, 3.45 and 3.50 log10 CFU/ml, respectively), but killing was diminished when the plates were examined at 72 h (mean killing, 3.06 and 2.95 log10, CFU/ml, respectively). No bactericidal activity was observed when stationary-phase cultures were used. On the basis of these data, we expect that bactericidal activity of RP 59500 against the multiple-drug-resistant E. faecium strains currently encountered would be distinctly uncommon.
PMCID: PMC164201  PMID: 9420051
3.  In vitro activity of RU 64004, a new ketolide antibiotic, against gram-positive bacteria. 
The comparative in vitro activity of RU 64004 (also known as HMR 3004), a new ketolide antibiotic, was tested by agar dilution against approximately 500 gram-positive organisms, including multiply resistant enterococci, streptococci, and staphylococci. All streptococci were inhibited by < or = 1 microg of RU 64004 per ml. The ketolide was more potent than other macrolides against erythromycin A-susceptible staphylococci and was generally more potent than clindamycin against erythromycin A-resistant strains susceptible to this agent. Clindamycin-resistant staphylococci (MIC, > 128 microg/ml) proved resistant to the ketolide, but some erythromycin A- and clindamycin-resistant enterococci remained susceptible to RU 64004.
PMCID: PMC163882  PMID: 9145901
4.  Efficacies of piperacillin-tazobactam and cefepime in rats with experimental intra-abdominal abscesses due to an extended-spectrum beta-lactamase-producing strain of Klebsiella pneumoniae. 
The in vivo activities of piperacillin-tazobactam and cefepime were compared with those of ticarcillin-clavulanate, ceftazidime, cefotaxime, and imipenem in a rat model of intra-abdominal abscess with a strain of Klebsiella pneumoniae elaborating an extended-spectrum beta-lactamase (TEM-26). With the exception of ceftazidime, all of the antimicrobial agents significantly reduced bacterial counts within abscesses at the end of therapy compared with those in untreated controls. Residual viable cell counts (mean +/- standard deviation in log10 CFU/gram) were as follows: control, 8.76 +/- 0.97; ceftazidime, 8.00 +/- 0.76; piperacillin-tazobactam, 3.87 +/- 1.72; ticarcillin-clavulanate, 3.74 +/- 1.34; cefepime, 3.15 +/- 1.19; cefotaxime, 2.61 +/- 0.77; imipenem, 2.41 +/- 0.93. Imipenem was more effective than either of the inhibitor combinations (P < 0.05). Cefotaxime was unexpectedly effective given its poor in vivo activity against this organism in our earlier studies, which used a different dose and total duration of therapy (L. B. Rice, J. D. C. Yao, K. Klimm, G. M. Eliopoulos, and R. C. Moellering, Jr., Antimicrob. Agents Chemother. 35:1243-1244, 1991). These observations suggest that the effectiveness of cephalosporins in the treatment of experimental infections caused by extended-spectrum beta-lactamase-producing K. pneumoniae may be highly dependent on dosing regimens, even for a specific organism and site of infection.
PMCID: PMC163849  PMID: 9145868
5.  In vitro activities in new oxazolidinone antimicrobial agents against enterococci. 
The comparative in vitro activities of two new oxazolidinone antimicrobial agents, U-100592 and U-100766, against 180 isolates of enterococci representing several resistance profiles were examined by using an agar dilution technique. The two oxazolidinones inhibited all isolates, including strains resistant to vancomycin, ampicillin, and minocycline, at concentrations between 1 and 4 micrograms/ml.
PMCID: PMC163410  PMID: 8807077
6.  Comparative in vitro activities of L-695,256, a novel carbapenem, against gram-positive bacteria. 
The in vitro activity of a prototype 2-aryl carbapenem, L-695,256, against gram-positive bacteria was examined. All streptococci and oxacillin-susceptible and -resistant staphylococci were inhibited at concentrations of < or = 0.125, < or = 0.125, and 4 micrograms/ml, respectively. The activity of L-695,256 was superior to that of imipenem against other organisms intrinsically resistant to beta-lactams.
PMCID: PMC162669  PMID: 7786011
7.  In vitro activity of A-86719.1, a novel 2-pyridone antimicrobial agent. 
This study evaluated the in vitro activity of A-86719.1, a novel 2-pyridone antimicrobial agent. The drug inhibited all tested members of the family Enterobacteriaceae at < or = 0.5 microgram/ml and all tested Pseudomonas aeruginosa, Burkholderia (Pseudomonas) cepacia, and Xanthomonas maltophilia strains at < or = 2 micrograms/ml. All but two strains of gram-positive bacteria were inhibited by < or = 1 microgram of the new drug per ml, including isolates highly resistant to ciprofloxacin.
PMCID: PMC162641  PMID: 7785983
8.  In vitro activities of two glycylcyclines against gram-positive bacteria. 
The glycylcyclines designated CL 329,998 and CL 331,002 are N,N-dimethylglycylamido derivatives of minocycline and 6-demethyl-6-deoxytetracycline, respectively. In vitro activities of these two antimicrobial agents were compared with those of tetracycline, minocycline, and seven other antimicrobial agents against 412 gram-positive organisms. Both new drugs were significantly more active than minocycline against methicillin-resistant Staphylococcus aureus (MICs for 90% of isolates tested, 0.25 and 0.5 microgram/ml versus 4 micrograms/ml). CL 329,998 inhibited all streptococci, lactobacilli, and Leuconostoc spp. at concentrations of < or = 0.5 microgram/ml, with CL 331,002 slightly less active against some species. All enterococci, including minocycline-resistant and multidrug-resistant isolates, were inhibited at < or = 0.5- and < or = 1.0-microgram/ml concentrations of the new drugs, respectively. Only bacteriostatic activity was evident by time-kill curves. The two glycylcyclines demonstrated activities in vitro that were superior to those of minocycline against several gram-positive bacterial species, and at relatively low concentrations, they inhibited isolates resistant to both tetracycline and minocycline.
PMCID: PMC284494  PMID: 8203851
9.  Activity of fleroxacin alone and in combination with clindamycin or metronidazole in experimental intra-abdominal abscesses. 
To assess the potential efficacy of fleroxacin in combination with clindamycin or metronidazole in mixed aerobic and anaerobic infections, we used a rat model of intra-abdominal abscesses in which the inoculum consisted of pooled rat feces mixed with BaSO4. Two hours after bacterial challenge, antimicrobial therapy was begun intravenously with regimens designed to stimulate human pharmacokinetics. A combination of clindamycin and gentamicin was included as an established treatment regimen. After 8.5 days of therapy, final bacterial counts in abscesses showed that fleroxacin alone or combined with metronidazole or clindamycin effectively eradicated Escherichia coli, with bacterial densities of < or = 2.84 +/- 0.1, < or = 2.9 +/- 0.1, and < or = 2.9 +/- 0.1 (mean +/- standard error of the mean) log10 CFU/g, respectively. The addition of either clindamycin or metronidazole to fleroxacin substantially enhanced the effectiveness of the regimens against Bacteroides fragilis, with bacterial counts of < or = 3.0 +/- 0.1 or < or = 2.9 +/- 0.1 log10 CFU/g, respectively, versus 9.2 +/- 0.2 log10 CFU/g for fleroxacin alone. The combination of metronidazole and fleroxacin also resulted in a significantly greater reduction of peptostreptococci and Bacteroides thetaiotaomicron than fleroxacin alone (< or = 2.9 +/- 0.1 versus 6.1 +/- 0.9 log10 CFU/g and 3.3 +/- 0.4 versus 8.3 +/- 0.1 log10 CFU/g, respectively). Except for those of B. fragilis, counts of other anaerobes were reduced to a greater extent by metronidazole plus fleroxacin than by clindamycin plus fleroxacin, although differences were not always significant. Metronidazole plus fleroxacin was at least as active a clindamycin plus gentamicin against all species and was significantly more active against Clostridium spp. No regimen effectively eradicated enterococci from the abscesses. These results suggest that the addition of either metronidazole or clindamycin would effectively enhance the spectrum of fleroxacin for treatment of mixed aerobic and anaerobic infections.
PMCID: PMC284436  PMID: 8192453
10.  Comparative activities of piperacillin and tazobactam against clinical isolates of Legionella spp. 
We evaluated the in vitro activity of piperacillin alone or in combination with the beta-lactamase inhibitor tazobactam against clinical isolates of Legionella species. At an inoculum of approximately 10(4) CFU, tazobactam, piperacillin, and the 8:1 combination had equivalent activities against Legionella spp. At an approximately 10-fold higher inoculum, the following results were obtained, expressed as MICs for 50 and 90% of strains tested (MIC range): piperacillin, 4 and 16 (0.25 to 32) micrograms/ml; tazobactam, 0.5 and 1 (0.125 to 2) micrograms/ml; and piperacillin-tazobactam (expressed in terms of MIC of piperacillin) 0.5 and 1 (0.03 to 2) micrograms/ml. Tazobactam alone and the combination with piperacillin were more active than piperacillin alone at the higher inoculum.
PMCID: PMC284412  PMID: 8141570
11.  In vitro activity of biapenem against clinical isolates of gram-positive and gram-negative bacteria. 
The in vitro activity of biapenem, a new carbapenem previously designated L-627, was compared with those of imipenem and several other antimicrobial agents against 771 clinical bacterial isolates. Against gram-positive organisms, biapenem was found to be approximately as active as imipenem, inhibiting 90% of isolates of most species at concentrations within one dilution of the MIC of imipenem for 90% of the isolates. Against gram-negative organisms and Bacteroides fragilis, biapenem was at least as active as and often more active than imipenem, with MICs for 90% of the isolates two- to eightfold lower than those of imipenem.
PMCID: PMC188112  PMID: 8239623
12.  A gene conferring resistance to vancomycin but not teicoplanin in isolates of Enterococcus faecalis and Enterococcus faecium demonstrates homology with vanB, vanA, and vanC genes of enterococci. 
We report the sequence of a 630-bp fragment of a gene associated with resistance to high levels of vancomycin in a clinical isolate of Enterococcus faecalis which retained susceptibility to teicoplanin. This gene was similar to the recently sequenced vanB and partially homologous with vanA, but it showed less-marked similarity to vanC. A DNA probe, derived from this polymerase chain reaction-amplified gene fragment, hybridized specifically with genomic DNA from Enterococcus faecium and E. faecalis isolates which were vancomycin resistant (MICs ranged from 8 to 512 micrograms/ml) but susceptible to teicoplanin. Curing of vancomycin resistance was associated with loss of DNA hybridization with the gene probe. Transfer of DNA which hybridized with the probe accompanied transfer of vancomycin resistance to a susceptible recipient strain. Neither curing nor transfer of vancomycin resistance was consistently related to loss or acquisition, respectively, of plasmid DNA.
PMCID: PMC188027  PMID: 8215270
13.  In vitro activity of ramoplanin against vancomycin-resistant gram-positive organisms. 
In vitro activity of ramoplanin, a cyclic lipoglycopeptide, against 92 vancomycin-resistant gram-positive organisms was evaluated. Ramoplanin demonstrated potent activity against many highly vancomycin-resistant organisms including enterococci (MICs for 90% of strains tested of 0.5 micrograms/ml) and against Lactobacillus spp., Leuconostoc spp., and Pediococcus spp., all of which were inhibited at concentrations of < or = 0.25 micrograms/ml. This drug or a derivative compound merits further investigation as a potential therapeutic agent for infections due to vancomycin-resistant enterococci.
PMCID: PMC187967  PMID: 8328787
14.  In vitro activity of RP59500, an injectable streptogramin antibiotic, against vancomycin-resistant gram-positive organisms. 
The in vitro activity of RP59500, a streptogramin antibiotic, against 146 clinical isolates of vancomycin-resistant gram-positive bacteria was examined. Five strains of the species Enterococcus casseliflavus and Enterococcus gallinarum, for which the MIC of vancomycin was 8 micrograms/ml, were also studied. Twenty-eight vancomycin-susceptible strains of Enterococcus faecalis and Enterococcus faecium were included for comparison. The drug was highly active against Leuconostoc spp., Lactobacillus spp., and Pediococcus spp. (MICs, < or = 2 micrograms/ml). RP59500 was more active against vancomycin-susceptible strains of E. faecium than E. faecalis (MICs for 90% of the strains [MIC90s], 1.0 versus 32 micrograms/ml). Vancomycin-resistant strains of E. faecalis were as resistant to RP59500 as vancomycin-susceptible strains (MIC90, 32 micrograms/ml), but some vancomycin-resistant E. faecium strains were relatively more resistant to the new agent (MIC90, 16; MIC range, 0.5 to 32 micrograms/ml) than were vancomycin-susceptible organisms of this species.
PMCID: PMC187713  PMID: 8460927
15.  In vitro activity of CP-99,219, a new fluoroquinolone, against clinical isolates of gram-positive bacteria. 
The in vitro activity of the fluoroquinolone CP-99,219 against gram-positive bacteria was compared with those of five other antimicrobial agents. Against ciprofloxacin-susceptible staphylococci and against streptococci, MICs were < or = 0.12 and < or = 0.5 microgram/ml, respectively. CP-99,219 was also more active than ciprofloxacin against ciprofloxacin-resistant staphylococci, most enterococci, Leuconostoc spp., and lactobacilli.
PMCID: PMC187672  PMID: 8452372
16.  Influence of high-level gentamicin resistance and beta-hemolysis on susceptibility of enterococci to the bactericidal activities of ampicillin and vancomycin. 
Antimicrobial Agents and Chemotherapy  1992;36(11):2526-2528.
The bactericidal activities of ampicillin and vancomycin against 40 recent isolates of Enterococcus faecalis were examined by kill-kinetic studies at concentrations of 4 x the MIC and 20 micrograms/ml. Greater killing was seen with ampicillin (3.57 +/- 0.87 and 2.50 +/- 1.09 log10 CFU/ml, respectively; mean +/- standard deviation) than with vancomycin (1.23 +/- 0.65 and 1.05 +/- 0.57 log10 CFU/ml, respectively). Highly gentamicin-resistant strains showed a tendency toward reduced susceptibility to killing; beta-hemolytic strains were more susceptible than nonhemolytic strains when exposed to ampicillin at 20 micrograms/ml. Within each group, individual isolates demonstrated great variability in susceptibility to killing by the drugs.
PMCID: PMC284366  PMID: 1489198
17.  Absence of synergistic activity between ampicillin and vancomycin against highly vancomycin-resistant enterococci. 
Antimicrobial Agents and Chemotherapy  1992;36(10):2201-2203.
The emergence of clinical enterococcal isolates resistant to both ampicillin and vancomycin is a cause of great concern, as there are few therapeutic alternatives for treatment of infections caused by such organisms. We evaluated the effects of the combination of ampicillin with vancomycin against vancomycin-resistant clinical enterococcal isolates. Using both the checkerboard technique and time-kill curves, we examined 28 strains of enterococci (17 Enterococcus faecalis and 11 Enterococcus faecium strains) with different levels of resistance to vancomycin. Of these, 15 strains were also highly gentamicin resistant, and 9 demonstrated resistance to ampicillin. Only seven strains of E. faecalis were inhibited synergistically by the combination of vancomycin with ampicillin, and even then, the concentrations of vancomycin at which synergism was demonstrated were above levels achievable in serum. None of the ampicillin-resistant isolates (all E. faecium) were inhibited synergistically at any concentration of the drugs. In no instance was bactericidal synergism observed, and in most cases the combination resulted in less killing than with ampicillin alone. Antagonism was not observed at clinically relevant concentrations. The results of this study suggest that the combination of vancomycin with ampicillin has little to offer against these emerging pathogens.
PMCID: PMC245476  PMID: 1444300
18.  Antimicrobial susceptibility changes in Enterococcus faecalis following various penicillin exposure regimens. 
Penicillin-"virgin" strains of Enterococcus faecalis collected from a population of individuals with no previous antibiotic exposure were subjected in vitro to penicillin delivered as repeated pulses, stepwise increasing concentrations, or sustained levels of a single concentration. Changes in resistance to penicillin were assessed by determination of MICs, and time-kill studies were performed to evaluate changes in tolerance to the bactericidal effects of penicillin. Isogenic clones, derived from various exposure regimens, which exhibited changes in either resistance or tolerance were further examined for changes in penicillin-binding proteins. Exposure to repeated pulses of penicillin resulted in the development of tolerance to penicillin without changes in the level of resistance. Clones derived from a regimen of stepwise increases in the penicillin concentration acquired both increased penicillin resistance and tolerance. Clones selected after prolonged continuous exposure to a fixed concentration of penicillin displayed minimally increased resistance to penicillin, but they retained the lytic, nontolerant response to the bactericidal effect of penicillin. Clones which acquired tolerance to the bactericidal effect of penicillin without changes in penicillin resistance exhibited a penicillin-binding protein pattern identical to that of the parental strain. Increased labeling of several penicillin-binding proteins accompanied the development of increased penicillin resistance in both penicillin-tolerant and nontolerant strains. Exposure of E. faecalis to penicillin in repeated pulses of brief duration, for prolonged periods at a constant concentration, or in stepwise graded concentrations can result in the selection of clones with increased resistance to the inhibitory or bactericidal effects of penicillin, or both. These observations may be relevant to the selection of dosing regimes for penicillin in the treatment of enterococcal infections, when bactericidal synergism cannot be achieved with penicillin-aminoglycoside combinations.
PMCID: PMC189238  PMID: 1590676
19.  Increasing resistance to beta-lactam antibiotics among clinical isolates of Enterococcus faecium: a 22-year review at one institution. 
Antimicrobial Agents and Chemotherapy  1991;35(11):2180-2184.
To identify any change in the antibiotic resistance of Enterococcus faecium, we examined the antibiotic susceptibilities of clinical strains (n = 84) isolated at one institution during the 22 years since 1968. A significant increase in resistance to penicillin was observed during the study period: the MICs of penicillin for 50 and 90% of isolates tested were 16 and 64 micrograms/ml, respectively, from 1969 to 1988 (n = 48; geometric mean MIC, 14 micrograms/ml) , whereas they were 256 and 512 micrograms/ml, respectively, from 1989 to 1990 (n = 36; geometric mean MIC, 123 micrograms/ml) (P less than 0.001). A comparable increase in resistance to ampicillin was also noted (P less than 0.001). No strains produced detectable beta-lactamase. In contrast, susceptibilities to vancomycin, teicoplanin, and ciprofloxacin remained stable. High-level resistance to gentamicin was observed in none of 48 isolates from 1969 to 1988, but was present in 22 of 36 strains (61%) from 1989 to 1990 (P less than 0.001) and was significantly associated with resistance (MIC, greater than or equal to 128 micrograms/ml) to penicillin (P less than 0.001). To assess the potential evolution of antibiotic resistance in this species, clinical isolates (n = 24) were compared with strains isolated in 1968 from a human population in the Solomon Islands that was never exposed to antibiotics. Solomon Island isolates were significantly more susceptible than all clinical strains to penicillin, ampicillin, and vancomycin (P less than 0.001 for each), but they exhibited no differences in susceptibility to teicoplanin or ciprofloxacin. The penicillin-binding affinity of penicillin-binding protein 5 (PBP 5) in penicillin-resistant clinical strains (MIC, 512 micrograms/ml) was notably lower than that in strains with more typical susceptibilities, suggesting an alteration in this PBP as a possible mechanism for increased penicillin resistance. Solomon Island strains most susceptible to penicillin demonstrated a prominent PBP 5* and the absence of PBP 5. These changes in the antibiotic resistance of E. faecium emphasize the importance of identifying this species in patients with serious enterococcal infections and the necessity of assessing its susceptibility to both beta-lactams and aminoglycosides if effective therapy is to be identified.
PMCID: PMC245356  PMID: 1803989
20.  Comparison of Enterococcus raffinosus with Enterococcus avium on the basis of penicillin susceptibility, penicillin-binding protein analysis, and high-level aminoglycoside resistance. 
We reidentified our laboratories' collections of 57 enterococcal isolates previously classified as Enterococcus avium by the API Rapid Strep identification system (Analytab Products, Plainview, N.Y.) with the identification criteria recommended by Facklam and Collins (R. R. Facklam and M. D. Collins, J. Clin. Microbiol. 27: 731-734, 1989). Thirty isolates were identified as true E. avium, 25 isolates were identified as E. raffinosus, and 2 isolates were identified as E. pseudoavium. E. raffinosus could be differentiated from E. avium on the basis of penicillin susceptibility, as follows: MIC for 50% of E. raffinosus isolates tested (MIC50), 32 micrograms/ml; MIC90, 64 micrograms/ml (range, 4 to 64 micrograms/ml); E. avium MIC50, 1 microgram/ml; MIC90, 2 micrograms/ml (range, 0.5 to 2 micrograms/ml). No strains produced detectable beta-lactamase. Penicillin-binding protein (PBP) analysis of all E. raffinosus isolates demonstrated the unique pattern reported previously (M. D. Collins, R. R. Facklam, J. A. E. Farrow, and R. Williamson, FEMS Microbiol. Lett. 57:283-288, 1989); however, a number of newly identified PBPs were noted. Of 25 isolates, 13 had an additional PBP of 77 kDa (designated PBP 6*), while all isolates possessed a 52-kDa PBP (PBP 7) and a 46-kDa PBP (PBP 8). The presence or absence of PBP 6* did not correlate with penicillin susceptibility; however, PBP 7 demonstrated many features suggestive of low penicillin-binding affinity and may represent a possible mechanism for the relative resistance of this species to penicillin, although this hypothesis remains speculative since attempts to develop a penicillin-hypersusceptible E. raffinosus mutant were unsuccessful. E. raffinosus isolates were significantly more likely to exhibit high-level resistance to kanamycin than E. avium strains were (P < 0.001; chi-square); however, no strains demonstrated high-level resistance to gentamicin. No trend toward increasing penicillin resistance was noted among this collection of E. avium and E. raffinosus isolates collected over the past 35 and 14 years, respectively. Relative resistance to penicillin may be a helpful differentiating feature between E. avium and E. raffinosus when assessment of raffinose metabolism is not possible or is indeterminant.
PMCID: PMC245181  PMID: 1929301
21.  Chromosomally mediated beta-lactamase production and gentamicin resistance in Enterococcus faecalis. 
We have analyzed four distinct strains of multiply resistant, beta-lactamase-producing enterococci isolated during an outbreak of colonization with these strains on an infant-toddler surgical ward at The Children's Hospital in Boston, Mass. All four strains were resistant to erythromycin, penicillin, and tetracycline and to high levels of gentamicin and streptomycin. One strain was also resistant to chloramphenicol. Plasmid profiles revealed four different plasmid patterns, with the number of identified plasmids ranging from zero to three. The gene coding for beta-lactamase production could be transferred at low frequency (less than 10(-8)) to an enterococcal recipient from one strain in conjunction with all of the other resistance determinants. Probes derived from the staphylococcal beta-lactamase gene and gentamicin resistance gene failed to hybridize with any of the detectable plasmids, but both genes were present on restriction fragments of genomic DNA in all strains. Our results indicate that the beta-lactamase genes and gentamicin resistance genes in these strains are integrated into the bacterial chromosome. The cotransmissibility of the resistance determinants raises the possibility of their incorporation into a multiresistance transposable genetic element.
PMCID: PMC244990  PMID: 1902647
22.  Outbreak of ceftazidime resistance caused by extended-spectrum beta-lactamases at a Massachusetts chronic-care facility. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2193-2199.
During a 4-month period in late 1988, we isolated ceftazidime-resistant strains of Klebsiella pneumoniae and other members of the family Enterobacteriaceae from 29 patients at a chronic-care facility in Massachusetts. Ceftazidime resistance resulted from two distinct extended-spectrum beta-lactamases of the TEM type which efficiently hydrolyzed the cephalosporin: YOU-1 with a pI of 5.57 and YOU-2 with a pI of 5.2. Genes encoding these enzymes were present on different but closely related high-molecular-weight, multiple antibiotic resistance plasmids of the H12 incompatibility group and were transferable by conjugation in vitro. Agarose gel electrophoresis of extracts from clinical isolates indicated that this outbreak arose from plasmid transmission among different strains of the family Enterobacteriaceae rather than from dissemination of a single resistant isolate. Isolation rates of ceftazidime-resistant organisms transiently decreased after use of this drug was restricted, but resistant isolates continued to be recovered 7 months after empiric use of ceftazidime ceased.
PMCID: PMC172022  PMID: 2073110
23.  In vitro activity of BAY v 3522, a new cephalosporin for oral administration. 
The activity of BAY v 3522 was tested against over 500 clinical bacterial isolates and compared with the activities of ampicillin, amoxicillin-clavulanate, cefaclor, cefixime, cefuroxime, cephalexin, and/or ciprofloxacin, erythromycin, and metronidazole. BAY v 3522 activity against staphylococci and streptococci equaled or exceeded those of the other agents. BAY v 3522 exhibited no significant advantage over cefaclor, cefuroxime, or cephalexin against gram-negative bacilli.
PMCID: PMC171947  PMID: 2285305
24.  Failure of trimethoprim-sulfamethoxazole therapy in experimental enterococcal endocarditis. 
To assess the potential efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) against serious enterococcal infections, we used a rat enterococcal endocarditis model comparing TMP-SMX therapy (500 mg of TMP plus 2,500 mg of SMX per kg of body weight per day given every 8 h by intragastric gavage) with intravenous ampicillin therapy (1,000 mg/kg per day). Despite concentrations of active drug in serum well in excess of the MIC and MBC, the mean residual vegetation bacterial titer in TMP-SMX-treated rats was similar to that in untreated controls (8.4 +/- 1.1 versus 8.6 +/- 1.3 log10 CFU/g) and significantly higher than that in the ampicillin-treated group (3.6 +/- 1.5 log10 CFU/g; P less than or equal to 0.001). This demonstrates discordance between in vitro activity and in vivo efficacy of TMP-SMX in serious enterococcal infection.
PMCID: PMC171927  PMID: 2126691
25.  Comparative in vitro activity of WIN 57273, a new fluoroquinolone antimicrobial agent. 
The in vitro activity of WIN 57273, a new fluoroquinolone antimicrobial agent, was evaluated against approximately 600 bacterial isolates. The new drug was 4- to 128-fold more active than ciprofloxacin against a broad range of gram-positive organisms, with the new drug inhibiting 90% of strains of each species except Enterococcus faecium at concentrations of less than or equal to 0.25 microgram/ml. WIN 57273 was four- to eightfold less active than ciprofloxacin against many members of the family Enterobacteriaceae, but the MICs of the new drug for 90% of strains tested (MIC90s) were less than or equal to 8 micrograms/ml (range, 0.25 to 8 micrograms/ml) for all species. Branhamella catarrhalis, Haemophilus influenzae, Neisseria gonorrhoeae, and Legionella spp. were highly susceptible (MIC90s, less than or equal to 0.06 microgram/ml). WIN 57273 demonstrated excellent activity against anaerobes (MIC90s, less than or equal to 0.25 microgram/ml), and the drug was also more active than ciprofloxacin against 30 strains of Mycobacterium avium-M. intracellulare (MIC, 0.1 to 1.0 microgram/ml). The activity of WIN 57273 against gram-positive organisms was minimally affected by pH and increased at low pH (5.4) against gram-negative organisms. The bactericidal activity of WIN 57273 was demonstrated by time-kill techniques against selected organisms. The frequencies of spontaneous resistance to the new agent were low, but resistant colonies could be selected after serial passage of initially susceptible organisms through incremental concentrations of the drug.
PMCID: PMC171776  PMID: 2393275

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