Resistance to antibacterial agents.
Explore the source record for details and available documents.
Anti-Bacterial Agents↗
Biomedical subjects
C C Sanders
Publications and source records attributed to C C Sanders.
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.
Anti-Bacterial Agents↗
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.
Ampicillin↗
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.
Base Sequence↗
Fluoroquinolone resistance in staphylococci: new challenges.
Staphylococci show only marginal susceptibility to the newer fluoroquinolones. Minimum inhibitory concentrations (MICs) for susceptible strains usually range from 0.25 to 2.0 mg/l. As a single mutational event involving the gyrase target or permeability diminishes fluoroquinolone susceptibility fourfold on average, such a mutation in staphylococci would lead to a clinical level of resistance. Therefore, it is not surprising that in some institutions, the use of fluoroquinolones has been quickly followed by greatly increased prevalence of fluoroquinolone-resistant staphylococci. The greatest increase in resistance has been seen among methicillin-resistant staphylococci although increased prevalence of resistance among Staphylococcus saprophyticus and other methicillin-susceptible staphylococci has also been reported. Clinical isolates of staphylococci recovered since the introduction of the fluoroquinolones fall into three fluoroquinolone susceptibility groups: susceptible (MIC < 0.5 mg/l), moderately resistant (MIC 0.5 to 4 mg/l) and highly resistant (MIC > 4 mg/l). The first group represents wild type strains while the second and third groups represent single- and multiple-step mutants, respectively. To prevent increasing prevalence of isolates in the second and third groups, it would be prudent to avoid use of quinolones whenever possible. However, when it is necessary, a fluoroquinolone, which achieves serum/tissue levels eight times the MIC of the infecting strain, should be used.
Anti-Infective Agents↗
USA resistance patterns among UTI pathogens.
The fluoroquinolones are a new, potent class of antimicrobials which are heavily prescribed in the United States. Resistance to these agents has developed primarily in organisms that are inherently less sensitive, such as Staphylococcus spp. and Pseudomonas spp., but also, in some centres, in more sensitive organisms, such as members of the Enterobacteriaceae. Because the fluoroquinolones are a valuable class of broad-spectrum antibiotics, it is desirable that their usefulness be conserved by adopting measures to prevent or minimize the development of resistance. One obvious approach to this is to restrict their use, preventing overuse or misuse. The therapy of urinary tract infections is a major area in which fluoroquinolone usage could be reduced or rationalized. Although these agents are highly efficacious in the therapy of urinary tract infections, so too are older, less expensive agents such as nitrofurantoin, co-trimoxazole, sulphonamides and amoxycillin. From considerations of both economy and minimizing the development of resistance there appears to be little justification for using fluoroquinolones routinely to treat urinary tract infections, except where other oral agents may not be well tolerated or are unlikely to be effective.
Anti-Infective Agents↗
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.
Anti-Infective Agents↗
Imipenem resistance in Enterobacter.
Blood cultures obtained on two separate occasions from a 37-year-old male who received multiple antibiotics (including imipenem) for treatment of repeated episodes of intraabdominal abscesses and bacteremia yielded two isolates of Enterobacter with reduced susceptibility to imipenem, extended-spectrum cephalosporins, penicillins and aztreonam. Both isolates were unstable, giving rise to different colony types, each of which produced a single, non-inducible Bush group 1 beta-lactamase (pI = 9.6) that hydrolyzed imipenem. Outer membrane proteins were analyzed but no differences were detected between strains with different levels of imipenem resistance. Three-dimensional tests performed in conjunction with disk diffusion susceptibility tests provided a rapid and convenient means of detecting the production of imipenem-hydrolyzing enzymes by the Enterobacter strains. These isolates provided additional evidence that overproduction of the group 1 cephalosporinase of Enterobacter can contribute to resistance to imipenem.
Adult↗
Failure of the Vitek AutoMicrobic system to detect beta-lactam resistance in Aeromonas species.
The ability of the Vitek AutoMicrobic system (AMS; Vitek, Inc., Hazelwood, MO) and disk-diffusion method to detect beta-lactam resistance was assessed with 25 strains from four species of Aeromonas. A very major error was indicated when a strain was shown to be susceptible by the AMS or disk-diffusion method but resistant by the agar dilution method. The rates for very major errors for disk diffusion and the AMS were 0% and 43%, respectively. The beta-lactam agents and numbers of very major errors for the AMS were as follows: ticarcillin, 17; mezlocillin, 3; piperacillin, 4; cephalothin, 9; cefazolin, 3; cefoxitin, 1; cefotetan, 2; and cefuroxime, 1. Thus, these data suggest that the AMS currently is not reliable for testing the resistance of Aeromonas to beta-lactam agents.
Aeromonas↗
Emergence of resistance to imipenem in Enterobacter isolates masquerading as Klebsiella pneumoniae during therapy with imipenem/cilastatin.
Clinical isolates identified as Klebsiella pneumoniae by the Vitek, Enterotube II, and API 20E systems were recovered from a patient undergoing therapy with imipenem/cilastatin. These isolates were resistant to multiple beta-lactam agents, and some were even resistant to imipenem. Analysis revealed a Bush group 1 beta-lactamase, and imipenem resistance corresponded to the loss of outer-membrane proteins in strains expressing high levels of this beta-lactamase. Further characterization efforts yielded abnormal but positive results of tests for ornithine decarboxylase production and motility, and chromosomal homology to an Enterobacter cloacae ampR, ampC probe was detected. These results suggested that the organisms were actually of an Enterobacter species, perhaps Enterobacter aerogenes. Cefoxitin resistance may be a useful marker for preventing this misidentification in the future; misidentification of such organisms poses a hazard, as it may lead to inappropriate beta-lactam therapy for infections caused by organisms that have the potential for resistance due to inducible group 1 cephalosporinases.
Aged↗
beta-Lactam resistance amongst Enterobacter species.
Following the introduction of extended-spectrum cephalosporins into clinical use, the prevalence of species belonging to the genus Enterobacter has increased because of their natural resistance to earlier cephalosporins and their ability to develop resistance rapidly to the newer drugs. beta-Lactam resistance in this genus is due, for the most part, to the presence of a Bush group 1 chromosomal cephalosporinase. This enzyme is normally inducible and resistance to older cephalosporins, cephamycins and aminopenicillins results from either the extreme lability of the drugs to the enzyme or from their inducer activities. Resistance to newer penicillins, cephalosporins and monobactams is attributable to the selection of mutants which express large amounts of the enzyme. Such mutants arise as the result of a spontaneous mutation in one of the regulatory genes responsible for suppressing enzyme expression. Since the enzyme has very high affinity for the newer cephalosporins, this, coupled with the slow penetration of the drugs into the cell, provides a very efficient mechanism of resistance. Recent surveys in the USA and elsewhere have shown that the increased prevalence of multi-beta-lactam-resistant strains of enterobacter is due to the increased use of the newer cephalosporins. Attempts to prevent these problems include the more judicious use of newer beta-lactam antibiotics and the development of enhanced-potency cephalosporins which are able to avoid resistance because they have lower enzyme affinity and permeate more rapidly into the cell.
Anti-Bacterial Agents↗
Use of a predictor panel to evaluate susceptibility test methods proposed for piperacillin-tazobactam.
A predictor panel of clinical isolates that produce a variety of types and amounts of beta-lactamases was used to assess the accuracy of dilution and disk diffusion susceptibility tests for piperacillin-tazobactam. Combinations of piperacillin-tazobactam with a fixed ratio of 8:1 and with tazobactam held constant at 4 micrograms/ml were examined in dilution tests performed in agar. In addition, disks containing 100 and 10 micrograms of piperacillin and tazobactam, respectively, were examined in diffusion tests. Three very major discrepancies between MICs determined with an 8:1 ratio and MICs determined with tazobactam held constant at 4 micrograms/ml were noted. These involved strains that appeared to be susceptible in tests with the 8:1 ratio but resistant when tazobactam was held constant at 4 micrograms/ml. However, the differences were only twofold. Error rate-bounded analysis with the disk containing 100 and 10 micrograms of piperacillin and tazobactam, respectively, revealed low error rates, regardless of whether MICs were determined with an 8:1 ratio or tazobactam held constant at 4 micrograms/ml. Thus, a predictor panel was useful in the identification of accurate susceptibility test for piperacillin-tazobactam.
Drug Therapy, Combination↗
Use of a predictor panel to evaluate susceptibility testing methods for ampicillin-sulbactam.
A predictor panel of clinical isolates that produce a variety of types and amounts of beta-lactamases was used to assess the accuracies of a variety of susceptibility tests for ampicillin-sulbactam. Combinations of ampicillin-sulbactam in ratios of 1:1 and 2:1 and with sulbactam held constant at concentrations of 4 and 8 micrograms/ml were examined in dilution tests performed in agar and broth. In addition, disks containing 10/10, 20/10, 20/20, and 20/30 micrograms of ampicillin-sulbactam were examined in diffusion tests. The results indicated that the MICs obtained in broth microdilution tests performed with each of the four combinations differed, on average, less than twofold. Of the disks tested, the 20/10-micrograms ampicillin-sulbactam disk provided the best separation between susceptible and resistant strains when interpretive criteria for resistance was a zone size of < or = 16 mm and that for susceptibility was a zone size of > or = 21 mm. This disk also gave the highest overall agreement with MICs, regardless of the combination used in the broth microdilution test. Discrepancies between agar and broth microdilution MICs were greater than twofold, on average, and this necessitated recommendation of separate criteria for the two methods. Thus, a predictor panel was very useful in identifying the parameters of susceptibility tests that were most accurate in identifying strains that were susceptible and resistant to ampicillin-sulbactam.
Ampicillin↗
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.
4-Quinolones↗
Ceftazidime resistance in Hafnia alvei.
Two morphotypes of Hafnia alvei differed in their susceptibilities to beta-lactam antibiotics. Both produced an inducible Bush group 1 beta-lactamase. Hyperinducibility of this enzyme was associated with reduced susceptibility in one morphotype.
Aged↗
Cefepime: the next generation?
Cefepime is a new aminothiazolylacetamido cephalosporin with a wider spectrum and greater potency than many currently available cephalosporins. It appears that these characteristics result from multiple properties of the molecule. In contrast to older cephalosporins, cefepime more rapidly penetrates the gram-negative cell, targets multiple essential penicillin-binding proteins, and escapes the effects of many beta-lactamases due to the enzymes' low affinity for the drug. The latter characteristic is most apparent in studies of Bush group 1 beta-lactamases. Derepression of this class of beta-lactamases has less effect on the in vitro activity of cefepime than on that of other cephalosporins. The results of clinical trials should now be carefully analyzed to determine whether these advantages carry over into the clinical arena.
Animals↗
Problems with detection of beta-lactam resistance among nonfastidious gram-negative bacilli.
The single most important aspect of any susceptibility test is the accurate detection of resistance, because resistance carries a strong prediction of therapeutic failure. However, the accurate detection of resistance has been difficult in tests performed with gram-negative organisms producing certain beta-lactamases and in tests with the new beta-lactam drug/beta-lactamase inhibitor combinations. These problems are due to limitations in the design of studies performed to establish test parameters, and these problems can be avoided if a new predictor panel approach is used. This, coupled with the use of special tests to detect resistance mechanisms, could optimize the accurate identification of beta-lactam resistance in gram-negative bacteria.
Anti-Bacterial Agents↗
beta-Lactam resistance in gram-negative bacteria: global trends and clinical impact.
Microbial drug resistance is an inescapable consequence of the utilization of antimicrobial agents in a given environment. Nowhere is the importance of resistance more evident than among agents of the beta-lactam family. Trends toward increased resistance can be seen among fastidious gram-negative bacteria like Haemophilus influenzae, where ampicillin resistance varies from 1% to 64% globally. For Escherichia coli, ampicillin resistance has risen to > or = 50% in high-risk populations, and resistance to third-generation cephalosporins is now being seen in certain areas. Inducible beta-lactamases have been responsible for increasing multiple beta-lactam resistance among certain Enterobacteriaceae and Pseudomonas aeruginosa, and this has been associated with increased use of newer cephalosporins. Xanthomonas maltophilia with its two inducible beta-lactamases is becoming an increasingly important nosocomial pathogen, especially in areas of heavy imipenem utilization. Only through the recognition of factors associated with increasing resistance and the mechanisms responsible can strategies be designed for minimizing beta-lactam resistance.
Ampicillin Resistance↗