Relapsing infection due to Enterobacter species: lessons of heterogeneity.
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Abscess↗
Biomedical subjects
A A Medeiros
Publications and source records attributed to A A Medeiros.
Evolution and dissemination of beta-lactamases accelerated by generations of beta-lactam antibiotics.
beta-Lactamases are the principal mechanism of bacterial resistance to beta-lactam antibiotics. In recent years the number and variety of new beta-lactamases detected has risen at an alarming rate, apparently in response to the clinical use of novel classes of beta-lactam antibiotics. This paper reviews the structure and evolution of beta-lactamases in an attempt to understand the pressures that have contributed to their emergence.
Anti-Bacterial Agents↗
Comparative susceptibility of clinical isolates producing extended spectrum beta-lactamases to ceftibuten: effect of large inocula.
BACKGROUND: Infections caused by Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) are a growing clinical problem. However, there is wide variation in the level of resistance to third generation beta-lactams conferred by these enzymes. METHODS: We studied 33 Klebsiella pneumoniae and 4 Escherichia coli isolates producing ESBLs obtained from outbreaks in 14 different hospitals and a nursing home in the United States. Microdilution testing with standard (10(4-5) colony-forming units/ml) and large (10(6-7) colony-forming units/ml) inocula, was used to compare the minimum inhibitory concentrations (MICs) of ceftibuten, a novel oral oxyimino beta-lactam, with those of other third generation beta-lactams (cefotaxime, ceftazidime, aztreonam, cefixime, cefpodoxime and cefoxitin). RESULTS: Twenty-seven of the clinical isolates had well-characterized ESBLs of 10 different types, 7 of which produced TEM-1; 1 isolate also produced LXA-1. Two strains produced more than 1 ESBL. The remaining 10 strains produced 8 as yet uncharacterized types of ESBL. With large inocula 73% tested susceptible to ceftibuten, whereas 8 to 22% tested susceptible to the other third generation beta-lactam antibiotics. Ceftibuten MICs increased with higher inocula when tested against strains producing SHV-4 or SHV-5 and, to a lesser extent, strains producing multiple beta-lactamases. Only cefoxitin showed a smaller inoculum effect. CONCLUSION: Ceftibuten merits clinical evaluation in infections caused by bacteria that produce ESBLs.
Anti-Bacterial Agents↗
Net effect of inoculum size on antimicrobial action of ampicillin-sulbactam: studies using an in vitro dynamic model.
To examine the predictable effect of inoculum size on the kinetics of the antimicrobial action of ampicillin-sulbactam, five TEM-1 beta-lactamase-producing Escherichia coli strains were studied in an in vitro dynamic model at two different initial inocula (N0S). All bacteria were exposed to ampicillin-sulbactam in a simulated system reflecting the pharmacokinetic profiles in human tissue after the administration of a single intravenous dose of ampicillin (2 g) plus sulbactam (1 g). Each strain was studied at low (4.0 to 5.2 log CFU/ml) and high (5.0 to 7.1 log CFU/ml) N0S. Despite pronounced differences in susceptibilities, the patterns of the killing curves observed with a given strain at different N0S were similar. As expected, viable bacterial counts increased with inoculum size. Striking visual contrasts in the respective curves for each organism were reflected by the area under the bacterial count-time curve (AUBC) but not by the difference between the N0 and the lowest bacterial counts (Nmin) at the nadir of the killing curve: the N0-associated changes in the AUBC on average were 75%, versus 2.5% for log N0--logNmin. To examine qualitative differences in antimicrobial effects at different N0S (i.e., the net effect of the inoculum), the difference in the high and low N0S was subtracted from each point on the killing curve obtained at the higher N0 for each strain. These adjusted curves were virtually superimposable on the observed killing curves obtained at the lower N0. Moreover, by using adjusted data, the AUBC values were similar at the two inocula, although slight (average, 11%) but systematic increases in the AUBC occurred at high N0S. Thus, there was only a weak net effect of inoculum size on the antibacterial effect of ampicillin-sulbactam. Due to similar slopes of the AUBC-log N0 plots, the antibacterial action at different N0S may be easily predicted by an approximate equation; the predicted AUBCs were unbiased and well correlated with the observed AUBCs (r = 0.997). Compiled data obtained with normalized AUBCs for different strains at different N0S yielded a positive correlation (r = 0.963) between the N0-normalized AUBC and the MIC of ampicillin-sulbactam. The adjustment and normalization procedure described might be a useful tool for revealing the net effect of the inoculum and to predict the inoculum effect if there are no qualitative differences in antimicrobial action at different inocula.
Ampicillin↗
Evolution of extended-spectrum beta-lactam resistance (SHV-8) in a strain of Escherichia coli during multiple episodes of bacteremia.
Nine isolates of Escherichia coli were recovered from seven blood cultures over a period of 3 months from a 19-month-old female with aplastic anemia. Initial isolates were susceptible to extended-spectrum cephalosporins, including ceftazidime (MIC, < or = 0.25 microgram/ml), but gradually became resistant to this drug (MICs, > or = 128 micrograms/ml) and other cephalosporins and the monobactam aztreonam. Molecular typing methods, including plasmid profile analysis, pulsed-field gel electrophoresis, and arbitrarily primed PCR, indicated that the nine isolates were derived from a common ancestor. Dot blot hybridization and PCR analysis of total bacterial DNA using blaSHV- and blaTEM-specific DNA probes and primers identified the presence of a blaTEM beta-lactamase gene in all of the isolates and a blaSHV gene in the isolates with elevated ceftazidime MICs. Isoelectric focusing analysis of crude lysates showed that all nine isolates contained an enzyme with a pI of 5.4 corresponding to the TEM-1 beta-lactamase, and those isolates containing an SHV-type beta-lactamase demonstrated an additional band with a pI of 7.6. The first of the ceftazidime-resistant isolates appeared to hyperproduce the SHV enzyme compared to the other resistant isolates. DNA sequencing revealed a blaSHV-1 gene in the first ceftazidime-resistant isolate and a novel blaSHV gene, blaSHV-8, with an Asp-to-Asn substitution at amino acid position 179 in the remaining four isolates. Three of the ceftazidime-resistant isolates also showed a change in porin profile. The patient had received multiple courses of antimicrobial agents during her illness, including multiple courses of ceftazidime. This collection of blood isolates from the same patient appears to represent the in vivo evolution of resistance under selective pressure of treatment with various cephalosporins.
Amino Acid Sequence↗
Predictors of effect of ampicillin-sulbactam against TEM-1 beta-lactamase-producing Escherichia coli in an in vitro dynamic model: enzyme activity versus MIC.
The clinical outcome in patients treated with ampicillin-sulbactam may not always be predictable by disc susceptibility testing or with the MIC as determined with a constant level (4 micrograms/ml) of the beta-lactamase inhibitor (MIC1). The enzyme activities (EA) and the MICs estimated at a constant ratio of ampicillin to sulbactam of 2:1 (MIC2) for 15 TEM-1 beta-lactamase-producing strains of Escherichia coli were examined as alternatives to MIC1 as predictors of the antibacterial effects of this combined drug as studied in an in vitro model which simulates ampicillin-sulbactam pharmacokinetic profiles observed in human peripheral tissues. Integral parameters describing the area under the bacterial count-time curve (AUBC), the area between the normal growth curve, and the killing curve of bacteria exposed to antibiotic (ABBC), and the second parameter expressed as a percentage of its maximal hypothetical value (ABBC/ABBCmax) were calculated. All three parameters correlated well with EA (AUBC, r = 0.93; ABBC, r = -0.88; ABBC/ABBCmax, r = -0.91) and with MIC2 (r = 0.94, -0.94, and -0.95, respectively) but not with MIC1. Both EA and MIC2 can be considered reliable predictors of the antibacterial effect of ampicillin-sulbactam in an in vitro model. These correlations suggest that in vitro kinetic-dynamic models might be useful to reexamine established susceptibility breakpoints obtained with data based on the MIC1 (MICs obtained with constant levels of beta-lactamase inhibitors). These data also suggest that quantitative determinations of bacterial beta-lactamase production and MICs based on the component concentration ratio observed in vivo might be useful predictors of the effect of ampicillin-sulbactam and other beta-lactam-inhibitor combinations.
Ampicillin↗
Characterization of IMI-1 beta-lactamase, a class A carbapenem-hydrolyzing enzyme from Enterobacter cloacae.
In 1984, a year prior to the U.S. approval of imipenem for clinical use, a wound isolate and a bile isolate of Enterobacter cloacae were obtained from two patients in a California hospital. These isolates were resistant to imipenem, penicillins, and inhibitor combinations; early cephalosporins such as cephalothin, cefamandole, and cefoxitin; and cefoperazone. However, they were susceptible (MICs, < 4 micrograms/ml) to cefotaxime, ceftriaxone, ceftazidime, and moxalactam. Both strains produced an apparent TEM-1 beta-lactamase; an inducible NmcA-type imipenem-hydrolyzing beta-lactamase, IMI-1, with a pl of 7.05; and an inducible beta-lactamase with a pI of 8.1, typical of an E. cloacae AmpC beta-lactamase. Purified IMI-1 hydrolyzed imipenem and benzylpenicillin at modest rates, but more slowly than cephaloridine. The enzyme was inhibited by clavulanic acid and tazobactam. EDTA did not inhibit the cephaloridine-hydrolyzing activity. The beta-lactamase gene encoding IMI-1, imiA1, was cloned from E. cloacae 1413B. Sequence analysis identified the imiA1 gene as encoding a class A serine beta-lactamase. Both the imiA1 DNA and encoded amino acid sequences shared greater than 95% identity with the NmcA gene and its encoded protein. DNA sequence analysis also identified a gene upstream of imiA1 that shares > 95% identity with nmcR and that may encode a regulatory protein. In conclusion, IMI-1, a carbapenem-hydrolyzing beta-lactamase inhibited by clavulanic acid, was identified as a group 2f, class A, carbapenem-hydrolyzing cephalosporinase.
Amino Acid Sequence↗
Meningitis due to ceftriaxone-resistant Streptococcus pneumoniae.
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Adult↗
The growing threat of antibiotic-resistant Streptococcus pneumoniae.
Resistance to penicillin has spread worldwide during the past 25 years. Strains resistant to alternative antibiotics have also emerged. Strains resistant to multiple antibiotics increasingly are isolated worldwide. Recently, isolates of penicillin-resistant S. pneumoniae resistant to cefotaxime and ceftriaxone have caused meningitis. As a result, recommendations for the empiric therapy of pneumococcal infections, especially meningitis, are changing.
Bacterial Vaccines↗
Controlling vancomycin-resistant enterococci.
After controlling an epidemic of vanB-type vancomycin-resistant Enterococcus faecium (VRE), we contained a subsequent vanA E faecium outbreak by using prospective laboratory-based surveillance, placing patients with VRE in private rooms, requiring the use of both gowns and gloves by all personnel entering the patients' rooms, and conducting prevalence surveys of patients on affected wards.
Anti-Bacterial Agents↗
A functional classification scheme for beta-lactamases and its correlation with molecular structure.
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Models, Molecular↗
IS6770, an enterococcal insertion-like sequence useful for determining the clonal relationship of clinical enterococcal isolates.
Enterococci expressing resistance to antimicrobial agents are increasingly important nosocomial pathogens. Effective strategies to prevent or abort outbreaks of resistant enterococcal infection will rely on an accurate understanding of the mechanisms by which these organisms spread. A 1065-bp insertion-like sequence (IS6770) is present in varying copy numbers in > 90% of enterococcal strains thus far examined. Hybridization patterns resulting from hybridization of enterococcal genomic DNA with an internal IS6770 probe vary considerably between unrelated strains and correlate well with results of pulsed-field gel electrophoresis and field-inversion gel electrophoresis in identifying clonal relationships among enterococcal isolates. IS6770 analysis of several outbreaks of resistant enterococci has confirmed the spread of single resistant clones rather than the emergence of resistance within the resident flora. These results suggest that IS6770 hybridization will be a useful tool for tracing the epidemiology of nosocomial enterococcal infections.
Amino Acid Sequence↗
Pharmacodynamics of piperacillin alone and in combination with tazobactam against piperacillin-resistant and -susceptible organisms in an in vitro model of infection.
The pharmacodynamics of dosage regimens of piperacillin alone or in combination with tazobactam against piperacillin-resistant or -susceptible bacteria were studied in an in vitro model of infection. Experiments were conducted by using a fixed daily exposure of 12 g of piperacillin, given as 3 g alone or in combination with tazobactam at 0.375 g every 6 h, or the same total dose of the combination given as 4 g of piperacillin plus 0.5 g of tazobactam every 8 h. The addition of tazobactam to piperacillin, irrespective of the dosing interval, did not alter the killing of piperacillin-susceptible organisms (Escherichia coli J53 and Pseudomonas aeruginosa ATCC 27853). In contrast, experiments with an isogenic TEM-3-containing transconjugant of E. coli J53 (E. coli J53.2-TEM-3) that was resistant to piperacillin (MIC, 128 micrograms/ml) showed that the addition of tazobactam resulted in bacterial killing similar to that observed with the wild-type strain. Although tazobactam concentrations fell to less than 4 mg/liter (the concentration associated with a reduction in the piperacillin MIC from 128 to 2 mg/liter) 2 to 3 h after a dose, a similar degree of bacterial killing was observed when the same total 24-h dose of piperacillin-tazobactam was fractionated into dosing intervals of every 6 or 8 h. Investigations with Staphylococcus aureus 7176 (piperacillin MIC, 128 micrograms/ml) showed that the addition of tazobactam, again irrespective of dosing interval, also resulted in net bacterial killing which was not seen with piperacillin alone. These data support the use of extended dosing intervals (every 8 h) of piperacillin-tazobactam in the treatment of infections caused by piperacillin-resistant bacteria.
Bacteria↗
Outbreak of multidrug-resistant Enterococcus faecium with transferable vanB class vancomycin resistance.
Enterococcus faecium strains resistant to ampicillin, high levels of gentamicin, and vancomycin but susceptible to teicoplanin (vanB class vancomycin resistance) were recovered from 37 patients during an outbreak involving a 250-bed university-affiliated hospital. Three isolates with vancomycin MICs ranging from 8 to 256 micrograms/ml all hybridized with a vanB probe. Restriction endonuclease analysis of chromosomal and plasmid DNA suggested that all isolates tested were derived from a single clone. Vancomycin resistance was shown to be transferable. Risk factors for acquiring the epidemic strain included proximity to another case patient (P, 0.0005) and exposure to a nurse who cared for another case patient (P, 0.007). Contamination of the environment by the epidemic strain occurred significantly more often when case patients had diarrhea (P, 0.001). Placing patients in private rooms and requiring the use of gowns as well as gloves by personnel controlled the outbreak. These findings suggest that multidrug-resistant E. faecium strains with transferable vanB class vancomycin resistance will emerge as important nosocomial pathogens. Because extensive environmental contamination may occur when affected patients develop diarrhea, barrier precautions, including the use of both gowns and gloves, should be implemented as soon as these pathogens are encountered.
Adult↗
Nosocomial outbreaks of multiresistant bacteria: extended-spectrum beta-lactamases have arrived in North America.
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Bacteria↗
Spread of methicillin-resistant Staphylococcus aureus in a hospital after exposure to a health care worker with chronic sinusitis.
A dramatic increase in the incidence of methicillin-resistant Staphylococcus aureus at a teaching hospital was documented to be due to three factors: a hospital-wide outbreak of 32 cases caused by an epidemic strain, an increase in the number of nosocomial cases caused by several other strains, and an increase in the number of patients admitted carrying strains acquired at other institutions. Case patients with the epidemic strain were significantly more likely than control patients to have had previous exposure to a respiratory therapist (P = .005) who had chronic sinusitis due to the epidemic strain. The plasmid DNA of isolates from the implicated respiratory therapist and affected patients yielded the same patterns on restriction endonuclease digestion. Implementation of general control measures and eradication of the respiratory therapist's sinusitis and nasal carriage terminated the epidemic. Establishing the importance of the infected health care worker by epidemiological methods led to control of the outbreak without the institution of wide-scale culture of specimens from personnel and the environment or other expensive and labor-intensive measures.
Aged↗
High rate of erythromycin and clarithromycin resistance among Streptococcus pneumoniae isolates from blood cultures from Providence, R.I.
Four (5%) of 81 recent isolates of Streptococcus pneumoniae from the blood of adult patients but no isolates from pediatric patients (n = 51) were resistant (MIC, > or = 1 microgram/ml) to erythromycin. The MICs of clarithromycin were slightly lower than those of erythromycin, but there was complete cross-resistance. Routine testing and surveillance are needed to determine whether erythromycin resistance among S. pneumoniae isolates is increasing throughout the United States.
Adult↗
Emergence and nosocomial transmission of ampicillin-resistant enterococci.
Between 1986 and 1988, the incidence of ampicillin-resistant enterococci increased sevenfold at a university-affiliated hospital. Forty-three patients acquired nosocomial infections with ampicillin-resistant enterococci, most of which were also resistant to mezlocillin, piperacillin, and imipenem. An analysis of plasmid and chromosomal DNAs of isolates revealed that the increase was due to an epidemic of 19 nosocomial infections that yielded closely related strains of Enterococcus faecium and to a significant increase in the incidence of nonepidemic, largely unrelated strains of ampicillin-resistant enterococci. The nonepidemic strains were identified as E. faecium, E. raffinosus, E. durans, and E. gallinarum. A logistic regression analysis revealed that patients with nonepidemic resistant strains were 16 times more likely than controls to have received preceding therapy with imipenem. In our institution, the increase in the incidence of ampicillin-resistant enterococci appears to be due to the selection of various strains of resistant enterococci by the use of imipenem and to the nosocomial transmission of E. faecium and E. raffinosus.
Adult↗