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Therapeutic options in an era of decreasing antimicrobial susceptibility.

Antimicrobial resistance among human pathogens has evolved to the multidrug-resistant phase. Consequently, preserving antimicrobial efficacy is now an important clinical consideration when selecting an agent for therapy. A new, in vitro measure of potency called the mutant prevention concentration (MPC) allows clinicians to select antibacterials on the basis of an agent's ability to restrict the selection of resistant mutants. With some pathogens, C-8-methoxy fluoroquinolones are expected to be quite effective at restricting the selection of resistance because the value of MPC is below the human serum drug concentration achieved with standard doses. Clinical trials are now needed to determine how well preclinical profiles of these drugs correlate with the prevention of resistance.

Anti-Bacterial Agents↗

European Committee on Antimicrobial Susceptibility Testing (EUCAST) Technical Notes on antimicrobial susceptibility testing.

The main objectives of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are to harmonise breakpoints for antimicrobial agents in Europe, and to act as the breakpoint committee for the European Medicines Agency (EMEA) during the registration of new antimicrobial agents. Detailed EUCAST procedures for harmonising and setting breakpoints for antimicrobial agents are available on the EUCAST website. Beginning with the current issue, a series of EUCAST Technical Notes will be published in CMI, based on the rationale documents produced by EUCAST for each of the antimicrobial agents studied, with the aim of highlighting important background information underlying decisions on breakpoints made by EUCAST.

Advisory Committees↗

In vitro evaluations of amikacin: an assessment of the currently used methods of disk diffusion and dilution susceptibility, antimicrobial synergy, and the measurement of amikacin concentrations.

The amikacin antimicrobial susceptibility tests were reviewed and found to be acceptable for clinical laboratory use. The early change from the 10-micrograms to the 30-micrograms diagnostic disk concentrations has resulted in reasonable accuracy, according to data from surveys of the College of American Pathologists, and acceptable discrimination between susceptible and resistant microorganisms. Similarly, standardized dilution susceptibility methods have proven acceptable, but great care must be exercised to select an agar medium in which performance was evaluated by the criteria of the National Committee for Clinical Laboratory Standards. Breakpoint concentrations selected as susceptible for amikacin (equal to or less than 16 micrograms/ml) were based on infected patient pharmacokinetics and previously correlated with patient bacteriologic outcome. Amikacin serum levels have been accurately measured by numerous procedures, including gas-liquid chromatography, radioimmunoassay, radioenzymatic assay, bioassay, and latex agglutination tests. Recent surveys of the College of American Pathologists support the earlier suspicions of lower accuracy and specificity with the bioassay method. Care must be taken to rapidly and appropriately process specimens from patients receiving concurrent high doses of antipseudomonal penicillins because of documented inactivation of some aminoglycosides by these penicillins. Amikacin is less affected by these beta-lactams. Evaluations of the antibacterial activity of amikacin in combination with other antimicrobial agents, principally the beta-lactams, continue to show high rates of enhanced killing or synergy. Although the methods for assessment of synergy have not been standardized, remarkably favorable and similar results between laboratories have been reported.

Amikacin↗

Respiratory tract pathogens isolated from patients hospitalized with suspected pneumonia: frequency of occurrence and antimicrobial susceptibility patterns from the SENTRY Antimicrobial Surveillance Program (United States and Canada, 1997).

Thirty-seven sentinel hospitals (29 in the United States [US]; eight in Canada) collected bacterial isolates from hospitalized patients with a diagnosis of pneumonia. The antimicrobial susceptibility patterns of these pathogens were determined to more than 60 agents (40 reported) using the reference broth microdilution method described by the National Committee for Clinical Laboratory Standards. The five most frequently recorded species among the 2757 isolates collected during the study were (no. tested/%): Staphylococcus aureus (632/22.9%), Pseudomonas aeruginosa (498/18. 1%), Haemophilus influenzae (284/10.3%), Klebsiella spp. (240/8.7%), and Streptococcus pneumoniae (213/7.7%). There was a significant difference in the susceptibility to antimicrobials between the US and Canada for S. aureus to oxacillin (50.1% versus 93.8% susceptible, respectively), gentamicin (78.7% versus 97.8%), and fluoroquinolones (49.5 to 53.0% versus 89.8 to 94.9%). Amikacin (92. 8% susceptible) was the most active antimicrobial agent against P. aeruginosa, and meropenem was the most potent beta-lactam. Against H. influenzae, most drugs retained a high level of activity, whilst against the S. pneumoniae, only the newer fluoroquinolones (gatifloxacin, levofloxacin, sparfloxacin) remained highly effective in vitro. Only two antimicrobial agents (imipenem and meropenem) were >99% active against the Klebsiella spp. and Enterobacter spp. isolated in this survey (possess extended spectrum beta-lactamases or hyperproduction of Amp C cephalosporins); cefepime (95.6-100.0% susceptible) was significantly more active than other cephalosporins tested. Clonal, epidemic outbreaks of multiply resistant strains were very rare in monitored hospitals. In conclusion, important differences exist between the US and Canada in the susceptibility patterns of some respiratory tract pathogens to commonly used antimicrobial agents with Canadian strains generally being more susceptible to currently available antimicrobial agents.

Anti-Bacterial Agents↗

The Meropenem Yearly Susceptibility Test Information Collection antimicrobial susceptibility program in Spain: a 5-year analysis.

The Meropenem Yearly Susceptibility Test Information Collection program is a global study providing in vitro surveillance data on antimicrobial susceptibility in centers prescribing meropenem. This study summarizes data on the activity of meropenem and 5 comparators against 4022 clinical isolates from 7 centers in Spain (1999-2003). Those bacteria intrinsically resistant to meropenem were excluded. Among Enterobacteriaceae, 100% of Enterobacter spp., Citrobacter spp., and Serratia spp. were susceptible to meropenem. Escherichia coli and Klebsiella pneumoniae susceptibilities to carbapenems were 100% and > or =98%, respectively. Extended-spectrum beta-lactamase-producing Enterobacteriaceae were 3.8% of isolates, and all of them were susceptible to meropenem. Ciprofloxacin resistance in E. coli was around 20%. Meropenem and piperacillin/tazobactam were the most active agents against Pseudomonas aeruginosa. Acinetobacter baumannii were 61-90% susceptible to carbapenems, but only 6-21% susceptible to ciprofloxacin. In this period, around 100% of oxacillin-susceptible staphylococci were susceptible to meropenem. There was no significant decrease in susceptibility to the carbapenems throughout the 5-year period. The clinical use of meropenem in 7 Spanish centers did not increase bacterial resistance to this agent in the microorganisms evaluated.

Academic Medical Centers↗

Clinical evaluation of the Abbott MS-2 antimicrobial susceptibility testing system.

Antimicrobial susceptibilities were determined for 845 clinical isolates by the standardized Bauer-Kirby disk diffusion method and the automated Abbott Ms-2 system. There was an overall correlation of 90% between the two methods. The Abbott MS-2 susceptibility instrument offers a rapid and accurate method for the antimicrobial susceptibility testing of bacteria.

Anti-Bacterial Agents↗

Antimicrobial susceptibility of flavobacteria.

Antimicrobial susceptibility patterns of 28 clinical isolates of Flavobacterium sp. were determined by standard disk diffusion technique and by antimicrobial dilution in agar. Rifampin, clindamycin, trimethoprim-sulfamethoxazole, cefoxitin, and vancomycin are among the antimicrobial agents which may be clinically useful to treat infections caused by flavobacteria. All 28 isolates were resistant to erythromycin with minimal inhibitory concentrations of 32 mug/ml or more. Currently recommended interpretive zones of inhibition by disk diffusion did not reliably predict antimicrobial susceptibility of the 28 flavobacteria isolates when compared with the agar dilution technique, and, therefore, a more direct measurement of minimal inhibitory or bactericidal concentration is recommended.

Anti-Bacterial Agents↗

Interpretive criteria and quality control limits for ceftibuten disk susceptibility tests. Collaborative Antimicrobial Susceptibility Testing Group.

In vitro studies were undertaken to evaluate susceptibility tests with 30-micrograms ceftibuten disks. The following interpretive criteria were proposed: less than or equal to 17 mm for resistance (MIC, greater than or equal to 32 micrograms/ml) and greater than or equal to 21 mm for susceptibility (MIC, less than or equal to 8.0 micrograms/ml). A multilaboratory quality control study led to the conclusion that Escherichia coli ATCC 25922 should provide zones 29 to 35 mm in diameter.

Ceftibuten↗

Bacterial Pathogens Isolated from Patients with Bloodstream Infections in Latin America, 1997: Frequency of Occurrence and Antimicrobial Susceptibility Patterns from the SENTRY Antimicrobial Surveillance Program.

We report the antimicrobial susceptibility of 736 organisms isolated from bloodstream infections in 10 Latin American medical centers during the first six months of 1997. The data presented here is from the SENTRY Antimicrobial Surveillance Program, a comprehensive surveillance study involving 72 medical centers worldwide. The isolates ivere tested for in in vitro susceptibility to 35 antimicrobial agents by the broth microdilution method. The five most frequently isolated species were (n/%): Staphylococcus aureus (1 65/22.4%), Escherichia coli(118/16.0%), coagulase-negative staphylococci (CoNS - 115/15.6%), Pseudomonas aeruginosa (51/6.9%), Klebsiella spp. (46/ 6.3%). Susceptibility to oxacillin was 70.9% for S. aureus and only 33.9% for CoNS. Vancomycin was active against all of staphylococci, while teicoplanin was active against 99.4% of S. aureus and only 90.4% of CoNS. The new fluoroquinolones sparfloxacin, gatifloxacin, and trovafloxacin, and the streptogramin, quinupristin/dalfopristin, were very active against these species. Only one vancomycin-resistant enterococcus was detected; however, high-level aminoglycoside resistance rates were common (66.7%). E. coli and Klebsiella spp. showed low susceptibilities for cefotaxime (90.7% and 41.3%) and for cefoxitin (85.6% and 78.3% respectively), indicating a high frequency of isolates that produce ESBL and/or stably derepressed ampC enzymes. These strains, phenotypically consistent with extended-spectrum beta-lactamase (ESBL) production, were typed using ribotyping and pulsed-field gel electrophoresis. The most active compounds (M IC90 in µg/mL /% susceptibility) against P. aeruginosa were meropenem (2 /94.1%), followed by amikacin (>32 / 86.3%), and piperacillin alone or with tazobactam (128/84.3%). Ceftazidime and cefepime showed similar activity (70.6% susceptibility) and levofloxacin was the most active fluoroquinolone (MI C50 &lte; 0.5; 76.5% susceptibility) against this gram-negative species. These results show the unique pattern of bloodstream isolates for Latin America and they demonstrate the present utility of several classes of compounds against emerging antimicrobial-resistant species in this region.

Journal Article↗

[Consensus for antimicrobial susceptibility testing for Enterobacteriaceae. Subcommittee on Antimicrobials, SADEBAC (Argentinian Society of Clinical Bacteriology), Argentinian Association of Microbiology].

Taking into account previous recommendations from the National Committee for Clinical Laboratory Standards (NCCLS), the Antimicrobial Committee, Sociedad Argentina de Bacteriología Clínica (SADEBAC), Asociación Argentina de Microbiología (AAM), and the experience from its members and some invited microbiologists, a consensus was obtained for antimicrobial susceptibility testing and interpretation in most frequent enterobacterial species isolated from clinical samples in our region. This document describes the natural antimicrobial resistance of some Enterobacteriaceae family members, including the resistance profiles due to their own chromosomal encoded beta-lactamases. A list of the antimicrobial agents that should be tested, their position on the agar plates, in order to detect the most frequent antimicrobial resistance mechanisms, and considerations on which antimicrobial agents should be reported regarding to the infection site and patient characteristics are included. Also, a description on appropriate phenotypic screening and confirmatory test for detection of prevalent extended spectrum beta-lactamases in our region are presented. Finally, a summary on frequent antimicrobial susceptibility profiles and their probably associated resistance mechanisms, and some infrequent antimicrobial resistance profiles that deserve confirmation are outlined.

Anti-Bacterial Agents↗

Antimicrobial susceptibility of community and hospital acquired bacteria.

OBJECTIVES: To study the antibiotic susceptibility of common community- and hospital-acquired bacteria in Thailand. MATERIAL AND METHOD: Eight common bacterial pathogens were studied in 24 hospitals across Thailand in 2002-2003. Isolates of clinically proven infections were tested for their susceptibility by agar-based disc diffusion method. RESULTS: A total of 9,091 isolates of target bacteria were studied. Community and hospital acquired bacteria accounted for 54.9% and 45.1% respectively. Community acquired Escherichia coli, Klebsiella pneumoniae, Acinetobacter spp., Enterobacter spp., Staphylococcus aureus were more susceptible to antimicrobials compared to hospital acquired strains. The difference in susceptibility of community-acquired vs hospital acquired Pseudomonas aeruginosa, Coagulase-negative staphylococci and Enterococcus spp. was less impressive indicating the spread of hospital strains into the community. Bacteria isolated from the blood stream were more susceptible to antimicrobials compared to those from the lower respiratory tract, urinary tract and surgical sites. Acinetobacter spp. and Enterococcus spp. were less susceptible to antimicrobials compared to others. CONCLUSION: Decreased susceptibility to antimicrobials was found in all bacteria tested. The susceptibility to commonly used antimicrobials of community-acquired bacteria decreased to a critical level indicating the widespread resistant bacteria to the community.

Anti-Bacterial Agents↗

Bacterial pathogens isolated from patients with bloodstream infection: frequencies of occurrence and antimicrobial susceptibility patterns from the SENTRY antimicrobial surveillance program (United States and Canada, 1997).

The SENTRY Program was established in January 1997 to measure the predominant pathogens and antimicrobial resistance patterns of nosocomial and community-acquired infections over a broad network of sentinel hospitals in the United States (30 sites), Canada (8 sites), South America (10 sites), and Europe (24 sites). During the first 6-month study period (January to June 1997), a total of 5,058 bloodstream infections (BSI) were reported by North American SENTRY participants (4,119 from the United States and 939 from Canada). In both the United States and Canada, Staphylococcus aureus and Escherichia coli were the most common BSI isolates, followed by coagulase-negative staphylococci and enterococci. Klebsiella spp., Enterobacter spp., Pseudomonas aeruginosa, Streptococcus pneumoniae, and beta-hemolytic streptococci were also among the 10 most frequently reported species in both the United States and Canada. Although the rank orders of pathogens in the United States and Canada were similar, distinct differences were noted in the antimicrobial susceptibilities of several pathogens. Overall, U.S. isolates were considerably more resistant than those from Canada. The differences in the proportions of oxacillin-resistant S. aureus isolates (26.2 versus 2.7% for U.S. and Canadian isolates, respectively), vancomycin-resistant enterococcal isolates (17.7 versus 0% for U.S. and Canadian isolates, respectively), and ceftazidime-resistant Enterobacter sp. isolates (30.6 versus 6.2% for U.S. and Canadian isolates, respectively) dramatically emphasize the relative lack of specific antimicrobial resistance genes (mecA, vanA, and vanB) in the Canadian microbial population. Among U.S. isolates, resistance to oxacillin among staphylococci, to vancomycin among enterococci, to penicillin among pneumococci, and to ceftazidime among Enterobacter spp. was observed in both nosocomial and community-acquired pathogens, although in almost every instance the proportion of resistant strains was higher among nosocomial isolates. Antimicrobial resistance continues to increase, and ongoing surveillance of microbial pathogens and resistance profiles is essential on national and international scales.

Anti-Bacterial Agents↗

[Antimicrobial susceptibility of Pseudomonas aeruginosa clinical isolates in Castellón, Spain].

A retrospective study of the susceptibility to antimicrobials (amikacin, tobramycin, gentamicin, ceftazidime, cefepime, piperacillin, piperacil-lin-tazobactam, imipenem, meropenem and ciprofloxacin) of 5,811 Pseudomonas aeruginosa isolates was performed in a general hospital over a period of 12 years. The majority of isolates was from respiratory samples (31.99%), followed by urine samples (26.36%) and ear samples (10.51%). There was a predominance of hospital strains (69.66%); 50.30% of those from medical services, 31.74% from critical care services (mainly ICU) and the remaining from surgical services. No antimicrobial included in our study showed an activity over all isolated strains. In health centers the majority of antimicrobials showed good activity, with a percentage of resistance less than 10%. However, hospital strains showed that only amikacin, piperacillin-tazobactam and meropenem had a percentage of resistance near or lower than 10%. In both environments, gentamicin presented with the highest percentage of resistance. Strains from patients hospitalized in critical care services showed an elevated resistance to tobramycin, imipenem and ceftazidime, while strains from patients in medical services showed resistance to ciprofloxacin. Similar studies published in Spain confirm the importance of conducting local studies in order to understand the antimicrobial susceptibility of P. aeruginosa in each region, and especially to carry out empirically based treatments.

Cross Infection↗

Molecular epidemiologic features and antimicrobial susceptibility profiles of various ribotypes of Pseudomonas aeruginosa isolated from humans and ruminants.

OBJECTIVES: To assess automated ribotyping for characterization of Pseudomonas aeruginosa isolates and to identify their type prevalence and geographic distribution. SAMPLE POPULATION: 39 human and 56 ruminant P aeruginosa isolates. PROCEDURES: Isolates were identified by use of bacteriologic techniques and automated Pvull-based ribotyping. Susceptibility to antimicrobials was tested in vitro. Data were analyzed for index of discrimination; prevalence ratio; geographic distribution of ribotypes found only in humans, only in cows, or only in goats (single-host ribotypes); and geographic distribution of ribotypes found in humans and ruminants (multihost ribotypes). RESULTS: All isolates were typeable (45 ribotypes, 35 single-host ribotypes). Ribotyping index of discrimination was 0.976. More isolates (45.3%) than expected yielded multihost ribotypes (22% of all ribotypes). Although 8.6% of single-host ribotypes were found in 4 or more isolates, 60% of multihost ribotypes were found in 4 or more isolates. Ninety percent of multihost ribotypes were isolated from different geographic areas, whereas 3.0% of single-host ribotypes were isolated from different geographic areas. All ruminant isolates were susceptible to gentamicin and polymyxin B. In contrast, antibiogram profiles differed for human isolates from different geographic areas. Susceptibility to antimicrobials differentiated 6 isolates not distinguished by ribotyping. CONCLUSIONS AND CLINICAL RELEVANCE: Automated ribotyping with Pvull discriminated more isolates than in vitro antimicrobial susceptibility. In combination, both tests provided more information than either test alone. Given the greater prevalence and geographic distribution of multihost ribotypes, immunocompromised humans and lactating ruminants may have a greater risk for disease if exposed to multihost P aeruginosa ribotypes, compared with single-host ribotypes.

Animals↗

Who defines resistance? The clinical and economic impact of antimicrobial susceptibility testing breakpoints.

Antimicrobial susceptibility test breakpoints are necessary for the correct clinical interpretation of quantitative or qualitative susceptibility test values of antibacterial agents. Breakpoints are selected by regulatory bodies or professional groups (eg, the National Committee for Clinical Laboratory Standards) based on an extensive review of the microbiological, pharmacokinetic, and clinical data applicable to each drug. No precise formula for selection of optimal breakpoints has been established. Instead, the process involves a review of all existing data and is influenced by the perspectives of the individuals charged with selecting the breakpoints. The interpretive breakpoints may differ somewhat by country with some antibiotics because of regional or national decisions on dosing regimens. Breakpoints also influence the selection of empiric therapy and development of local, regional, or national treatment guidelines by classifying the percentage of previously tested organisms that were susceptible to various antibiotics. Thus, antibiotic breakpoints affect the care of individual patients and provide epidemiologists and policy makers with data regarding trends in antibiotic resistance.

Anti-Bacterial Agents↗

History and development of antimicrobial susceptibility testing methodology.

Antimicrobial susceptibility testing (AST) is performed daily on bacterial isolates in clinical laboratories. The techniques employed are often taken for granted. This paper traces the history and development of some methods still in common use for routine AST, e.g. disc diffusion and agar dilution. It was quickly recognized by early investigators that there were many variables affecting the results of these tests. Consequently, there was recognition (as early as the late 1950s) that standardization of these techniques was required. This need has led to many organizations producing standardized AST methodologies. Although some disc diffusion techniques that generated results within 4-6 h were described, most relied on 18-24 h incubation before a result was available. The clinical and economic pressures for rapid methods with low labour input led to the development of semi-automated and automated AST methodologies in the 1970s. Until 10 years ago, AST techniques relied on phenotypically testing the bacteria isolated. However, to increase the speed and reliability of resistance testing, the use of a genotypic approach has been advocated. The limitations and benefits of this new approach are discussed.

History, 19th Century↗