ABSTRACT
Since its inaugural issue nearly half a century ago, Antimicrobial Agents and Chemotherapy has served as a premier source for reports on scientific and clinical advances in the field of antimicrobial chemotherapy. As a follow-up to the previous "History of Antimicrobial Agents and Chemotherapy from 1972 to 1998" written by George A. Jacoby (Antimicrob Agents Chemother 43:999-1002, 1999, https://doi.org/10.1128/AAC.43.5.999), we herein highlight the further evolution of this comprehensive and authoritative journal in response to changing science, demographics, and information technology.
Subject(s)
Anti-Infective Agents , Anti-Bacterial Agents , History, 20th CenturyABSTRACT
Apramycin, an aminocyclitol aminoglycoside, was rapidly bactericidal against Acinetobacter baumannii In a neutropenic murine thigh infection model, treatment-associated A. baumannii CFU reductions of >4 log10 per thigh were observed for all exposures for which area under the curve (AUC)/MIC ratio was >50 and maximum concentration of drug in serum (Cmax)/MIC was ≈10 or higher. Based on these findings, we suggest that apramycin deserves further preclinical exploration as a repurposed therapeutic for multidrug-resistant Gram-negative pathogens, including A. baumannii.
Subject(s)
Acinetobacter baumannii/drug effects , Acinetobacter baumannii/pathogenicity , Anti-Bacterial Agents/therapeutic use , Nebramycin/analogs & derivatives , Thigh/microbiology , Animals , Anti-Bacterial Agents/pharmacology , Drug Resistance, Multiple, Bacterial/genetics , Mice , Microbial Sensitivity Tests , Nebramycin/pharmacology , Nebramycin/therapeutic useABSTRACT
Increasing resistance among Gram-negative uropathogens limits treatment options, and susceptibility data for multidrug-resistant isolates are limited. We assessed the activity of five oral agents against 91 multidrug-resistant Gram-negative urine isolates that were collected from emergency department/hospitalized patients. Fosfomycin and nitrofurantoin were most active (>75% susceptibility). Susceptibilities to sulfamethoxazole-trimethoprim, ciprofloxacin, and ampicillin were ≤40%; empirical use of these agents likely provides inadequate coverage in areas with a high prevalence of multidrug-resistant uropathogens.
Subject(s)
Anti-Bacterial Agents/pharmacology , Ampicillin/pharmacology , Ciprofloxacin/pharmacology , Drug Resistance, Multiple, Bacterial/genetics , Fosfomycin/pharmacology , Microbial Sensitivity Tests , Nitrofurantoin/pharmacology , Trimethoprim, Sulfamethoxazole Drug Combination/pharmacology , Urinary Tract Infections/microbiologyABSTRACT
The genetic mechanisms that contribute to reduced susceptibility to vancomycin in Staphylococcus aureus are complex and heterogeneous. In addition, debate is emerging as to the true effect of reduced susceptibility to vancomycin on staphylococcal virulence. To investigate this, comparative genomics was performed on a collection of vancomycin-exposed isogenic S. aureus pairs (14 strains in total). Previously described mutations were observed in genes such as vraG, agrA, yvqF, and rpoB; however, a new mechanism was identified involving a serine/threonine phosphatase, Stp1. After constructing an stp1 deletion mutant, we showed that stp1 is important in vancomycin susceptibility and cell wall biosynthesis. Gene expression studies showed that stp1 also regulates virulence genes, including a hemolysin, superantigen-like protein, and phenol-soluble modulin, and that the deletion mutant is attenuated in virulence in vivo. Stp1 provides a new link between vancomycin susceptibility and virulence in S. aureus.
Subject(s)
Phosphoprotein Phosphatases/metabolism , Staphylococcus aureus/enzymology , Vancomycin Resistance , Animals , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Disease Models, Animal , Female , Gene Deletion , Gene Expression Profiling , Hemolysis , Histocytochemistry , Liver/pathology , Liver Abscess/microbiology , Liver Abscess/mortality , Liver Abscess/pathology , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Phosphoprotein Phosphatases/genetics , Staphylococcal Infections/microbiology , Staphylococcal Infections/mortality , Staphylococcal Infections/pathology , Staphylococcus aureus/drug effects , Staphylococcus aureus/pathogenicity , Survival Analysis , Virulence , Virulence Factors/genetics , Virulence Factors/metabolismABSTRACT
Prokaryote-eukaryote interactions are ubiquitous and have important medical and environmental significance. Despite this, a paucity of data exists on the mechanisms and pathogenic consequences of bacterial-fungal encounters within a living host. We used the nematode Caenorhabditis elegans as a substitute host to study the interactions between two ecologically related and clinically troublesome pathogens, the prokaryote, Acinetobacter baumannii, and the eukaryote, Candida albicans. After co-infecting C. elegans with these organisms, we observed that A. baumannii inhibits filamentation, a key virulence determinant of C. albicans. This antagonistic, cross-kingdom interaction led to attenuated virulence of C. albicans, as determined by improved nematode survival when infected with both pathogens. In vitro coinfection assays in planktonic and biofilm environments supported the inhibitory effects of A. baumannii toward C. albicans, further showing a predilection of A. baumannii for C. albicans filaments. Interestingly, we demonstrate a likely evolutionary defense by C. albicans against A. baumannii, whereby C. albicans inhibits A. baumannii growth once a quorum develops. This counteroffensive is at least partly mediated by the C. albicans quorum-sensing molecule farnesol. We used the C. elegans-A. baumannii-C. albicans coinfection model to screen an A. baumannii mutant library, leading to the identification of several mutants attenuated in their inhibitory activity toward C. albicans. These findings present an extension to the current paradigm of studying monomicrobial pathogenesis in C. elegans and by use of genetic manipulation, provides a whole-animal model system to investigate the complex dynamics of a polymicrobial infection.
Subject(s)
Acinetobacter baumannii/physiology , Caenorhabditis elegans/microbiology , Candida albicans/physiology , Acinetobacter baumannii/drug effects , Acinetobacter baumannii/genetics , Acinetobacter baumannii/pathogenicity , Animals , Bacterial Proteins/metabolism , Bacterial Proteins/pharmacology , Biofilms/growth & development , Candida albicans/drug effects , Candida albicans/pathogenicity , Farnesol/pharmacology , Genetic Testing , Mutation , Virulence/geneticsABSTRACT
With the current high prevalence of infection caused by methicillin-resistant Staphylococcus aureus (MRSA) strains but in light of the general belief that beta-lactam antibiotics are more effective than vancomycin against infections caused by methicillin-susceptible S. aureus (MSSA) isolates, clinicians may utilize antistaphylococcal penicillins in combination with vancomycin for the empirical treatment of S. aureus infections. Vancomycin is considered to kill MSSA more slowly than oxacillin. Thus, we sought to evaluate the interaction of the combination of oxacillin and vancomycin on bacterial killing in vitro. Ten clinical isolates of MSSA isolated in the year 2000 were investigated. The killing observed at 24 h by vancomycin at 20 microg/ml, oxacillin at 16 microg/ml, or the combination did not differ (approximately 2.5 to 3.5 log10 CFU/ml). In a separate experiment, we assessed bacterial killing in a dynamic model simulating the free plasma concentration profiles expected following the administration of a combination of vancomycin at 1 g every 12 h and oxacillin at 1 g every 6 h. The time-kill profiles of these regimens against S. aureus ATCC 29213 were comparable to those observed in the fixed-concentration experiments. Using these methods, we found no evidence that vancomycin antagonized the bactericidal effect of oxacillin or that there was any benefit from use of the combination.
Subject(s)
Anti-Bacterial Agents/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Oxacillin/pharmacology , Vancomycin/pharmacology , Anti-Bacterial Agents/pharmacokinetics , Drug Antagonism , Drug Synergism , Microbial Sensitivity Tests , Oxacillin/pharmacokinetics , Vancomycin/pharmacokineticsABSTRACT
BACKGROUND: The Enterococcus faecium genogroup, referred to as clonal complex 17 (CC17), seems to possess multiple determinants that increase its ability to survive and cause disease in nosocomial environments. METHODS: Using 53 clinical and geographically diverse US E. faecium isolates dating from 1971 to 1994, we determined the multilocus sequence type; the presence of 16 putative virulence genes (hyl(Efm), esp(Efm), and fms genes); resistance to ampicillin (AMP) and vancomycin (VAN); and high-level resistance to gentamicin and streptomycin. RESULTS: Overall, 16 different sequence types (STs), mostly CC17 isolates, were identified in 9 different regions of the United States. The earliest CC17 isolates were part of an outbreak that occurred in 1982 in Richmond, Virginia. The characteristics of CC17 isolates included increases in resistance to AMP, the presence of hyl(Efm) and esp(Efm), emergence of resistance to VAN, and the presence of at least 13 of 14 fms genes. Eight of 41 of the early isolates with resistance to AMP, however, were not in CC17. CONCLUSIONS: Although not all early US AMP isolates were clonally related, E. faecium CC17 isolates have been circulating in the United States since at least 1982 and appear to have progressively acquired additional virulence and antibiotic resistance determinants, perhaps explaining the recent success of this species in the hospital environment.
Subject(s)
Ampicillin Resistance/genetics , Drug Resistance, Multiple, Bacterial/genetics , Enterococcus faecium/drug effects , Enterococcus faecium/genetics , Bacterial Typing Techniques , Cross Infection/microbiology , Gram-Positive Bacterial Infections , Humans , Microbial Sensitivity Tests , Sequence Analysis, DNA , United States , Vancomycin , Virulence/geneticsABSTRACT
BACKGROUND: Despite availability of ceftolozane-tazobactam (C/T) and ceftazidime-avibactam (CZA) for several years, the individual spectrum of activity of each agent may not be widely known. We compared the activity of C/T and CZA against convenience samples of 119 extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales and 60 ß-lactam-resistant Pseudomonas aeruginosa clinical isolates collected from three U.S. institutions. METHODS: Minimal inhibitory concentrations (MICs) for C/T and CZA were determined by broth microdilution. Molecular identification of nine ß-lactamase gene targets was conducted for Enterobacterales and P. aeruginosa isolates with increased MICs to C/T or CZA. RESULTS: More than 90% of Enterobacterales isolates demonstrated susceptibility to both C/T and CZA, in contrast to the other traditional ß-lactam agents tested, which were much less active. The MIC50/90 values were nearly equivalent between agents. The most common ß-lactamase genes identified in Enterobacterales isolates with MIC values ≥2 mg/L were the CTX-M-1 group (85%) and CMY-2-like (23%) ß-lactamases. Both agents were active against >80% of ß-lactam-resistant P. aeruginosa isolates tested, most of which had oprD mutations identified. One P. aeruginosa isolate was positive for a Klebsiella pneumoniae carbapenemase-type gene but remained meropenem-susceptible. The MIC50 values were four-fold lower in favour of C/T (1 mg/L vs. 4 mg/L) against P. aeruginosa. CONCLUSIONS: Our data suggest that either agent may be a reasonable choice for centres with a high proportion of ESBL producers; however, C/T may have improved activity against P. aeruginosa and may be preferred in institutions with a higher frequency of resistant pseudomonal isolates.
Subject(s)
Pseudomonas Infections , Pseudomonas aeruginosa , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Azabicyclo Compounds , Ceftazidime , Cephalosporins , Drug Combinations , Humans , Pseudomonas Infections/drug therapy , Pseudomonas aeruginosa/genetics , Tazobactam/pharmacology , beta-Lactamases/geneticsABSTRACT
BACKGROUND: Most cases of reduced vancomycin susceptibility in Staphylococcus aureus reported in the literature have been in methicillin-resistant strains. We report the development of reduced vancomycin susceptibility in a series of clonally related, methicillin-susceptible S. aureus (MSSA) clinical isolates. This isogenic series permitted us to determine whether the evolution of reduced vancomycin susceptibility in MSSA is similar to that seen in MRSA. METHODS: Differences in vancomycin population analysis profiles; chemical autolysis; vancomycin, oxacillin, and daptomycin minimum inhibitory concentrations; and bactericidal activities were examined. RESULTS: Progressive vancomycin resistance correlated with increasing daptomycin nonsusceptibility. Chemical autolysis and the bactericidal activity of vancomycin, oxacillin, and daptomycin were reduced in the final, vancomycin-intermediate S. aureus isolate, compared with the vancomycin-susceptible MSSA progenitor. CONCLUSIONS: Clinicians should recognize that reduced vancomycin susceptibility can occur in S. aureus irrespective of background methicillin susceptibility and that development of intermediate vancomycin susceptibility in MSSA may result in increased tolerance to several classes of anti-staphylococcal antibiotics.
Subject(s)
Anti-Bacterial Agents/pharmacology , Staphylococcus aureus/drug effects , Vancomycin Resistance , Vancomycin/pharmacology , Bacteriolysis , Colony Count, Microbial , Daptomycin/pharmacology , Humans , Microbial Sensitivity Tests , Microbial Viability , Octoxynol/toxicity , Oxacillin/pharmacology , Staphylococcal Infections/microbiology , Staphylococcus aureus/classification , Staphylococcus aureus/isolation & purificationSubject(s)
Microbiology/history , Anti-Infective Agents , History, 20th Century , History, 21st Century , HumansABSTRACT
Nonmammalian model systems of infection such as Galleria mellonella (caterpillars of the greater wax moth) have significant logistical and ethical advantages over mammalian models. In this study, we utilize G. mellonella caterpillars to study host-pathogen interactions with the gram-negative organism Acinetobacter baumannii and determine the utility of this infection model to study antibacterial efficacy. After infecting G. mellonella caterpillars with a reference A. baumannii strain, we observed that the rate of G. mellonella killing was dependent on the infection inoculum and the incubation temperature postinfection, with greater killing at 37 degrees C than at 30 degrees C (P = 0.01). A. baumannii strains caused greater killing than the less-pathogenic species Acinetobacter baylyi and Acinetobacter lwoffii (P < 0.001). Community-acquired A. baumannii caused greater killing than a reference hospital-acquired strain (P < 0.01). Reduced levels of production of the quorum-sensing molecule 3-hydroxy-C(12)-homoserine lactone caused no change in A. baumannii virulence against G. mellonella. Treatment of a lethal A. baumannii infection with antibiotics that had in vitro activity against the infecting A. baumannii strain significantly prolonged the survival of G. mellonella caterpillars compared with treatment with antibiotics to which the bacteria were resistant. G. mellonella is a relatively simple, nonmammalian model system that can be used to facilitate the in vivo study of host-pathogen interactions in A. baumannii and the efficacy of antibacterial agents.
Subject(s)
Acinetobacter baumannii/drug effects , Acinetobacter baumannii/pathogenicity , Host-Pathogen Interactions , Moths/microbiology , Acinetobacter Infections/drug therapy , Animals , Disease Models, Animal , Quorum Sensing , VirulenceABSTRACT
We examined sequential methicillin-susceptible Staphylococcus aureus isolates from a patient with mitral valve endocarditis recovered during persistent bacteremia on standard therapy and relapse after treatment with daptomycin. An isolate obtained after 5 days of antimicrobial therapy, but before exposure to daptomycin, showed subtle physiological changes in response to daptomycin, with significant regrowth in the daptomycin killing assay compared to the treatment-naive strain. Once daptomycin was started, the population became more heterogeneous and tested as nonsusceptible. These organisms were examined in a simulated-vegetation in vitro pharmacodynamic model, which confirmed progressive decreases in killing with daptomycin concentrations that simulate those attained in humans with 6-mg/kg of body weight daily dosing. Early surgical intervention or combination therapy or both might have prevented the loss of daptomycin susceptibility.
Subject(s)
Anti-Bacterial Agents/pharmacology , Daptomycin/pharmacology , Drug Resistance, Bacterial , Endocarditis, Bacterial/microbiology , Methicillin/pharmacology , Staphylococcal Infections/microbiology , Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/therapeutic use , Bacteremia/microbiology , Daptomycin/pharmacokinetics , Daptomycin/therapeutic use , Humans , Male , Microbial Sensitivity Tests , Microbial Viability , Staphylococcus aureus/classification , Staphylococcus aureus/isolation & purificationABSTRACT
The in vitro activity of apramycin was compared to that of amikacin, gentamicin, and tobramycin against multidrug-resistant, extensively drug-resistant, and pandrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Apramycin demonstrated an MIC50/MIC90 of 8/32µg/ml for A. baumannii and 16/32µg/ml for P. aeruginosa. Only 2% of A. baumannii and P. aeruginosa had an MIC greater than an epidemiological cutoff value of 64µg/ml. In contrast, the MIC50/MIC90 for amikacin, gentamicin, and tobramycin were ≥64/>256µg/ml for A. baumannii with 57%, 95%, and 74% of isolates demonstrating resistance, respectively, and the MIC50/MIC90 were ≥8/256µg/ml for P. aeruginosa with 27%, 50%, and 57% of strains demonstrating resistance, respectively. Apramycin appears to offer promising in vitro activity against highly resistant pathogens. It therefore may warrant further pre-clinical study to assess potential for repurposing as a human therapeutic and relevance as a scaffold for further medicinal chemistry exploration.
Subject(s)
Acinetobacter baumannii/drug effects , Amikacin/pharmacology , Anti-Bacterial Agents/pharmacology , Gentamicins/pharmacology , Nebramycin/analogs & derivatives , Pseudomonas aeruginosa/drug effects , Tobramycin/pharmacology , Acinetobacter baumannii/isolation & purification , Animals , Drug Resistance, Multiple, Bacterial , Humans , Microbial Sensitivity Tests , Nebramycin/pharmacology , Pseudomonas aeruginosa/isolation & purificationABSTRACT
For the past 2 decades, vancomycin has served as the cornerstone of therapy against serious methicillin-resistant Staphylococcus aureus infections. This role is increasingly challenged by questions of efficacy, including reduced efficacy against infections caused by glycopeptide-intermediate S. aureus strains. In an evaluation of clinical glycopeptide-intermediate S. aureus isolates and serial, clinical methicillin-resistant S. aureus isolates obtained from patients receiving vancomycin for the treatment of bacteremia, we found that loss of function of the accessory gene regulator operon may confer a survival advantage to S. aureus under vancomycin selection pressure, particularly in strains with the accessory gene regulator group II genotype. Other advantages in a nosocomial setting may include enhancement of biofilm formation and promotion of physiologic changes supporting colonization. We conclude that loss of accessory gene regulator function in methicillin-resistant S. aureus might, in part, explain the decreased efficacy of vancomycin in the therapy of methicillin-resistant S. aureus bacteremia, thus highlighting the need to reevaluate the criteria of susceptibility to vancomycin.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacterial Proteins/physiology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Trans-Activators/physiology , Vancomycin/therapeutic use , Adaptation, Biological/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/standards , Bacterial Proteins/genetics , Cross Infection/drug therapy , Cross Infection/microbiology , Genotype , Humans , Methicillin Resistance , Operon/genetics , Operon/physiology , Phenotype , Staphylococcal Infections/microbiology , Staphylococcus aureus/genetics , Trans-Activators/genetics , Vancomycin/pharmacology , Vancomycin/standards , Vancomycin Resistance/drug effects , Vancomycin Resistance/geneticsABSTRACT
Fosfomycin is recommended as first-line treatment for acute uncomplicated cystitis in women. It has demonstrated in vitro activity against a variety of pathogens; however, a paucity of data are available from the USA. We determined the susceptibility of a collection of urine isolates to fosfomycin and compared multiple methods of susceptibility testing. Consecutive non-duplicate Enterobacteriaceae, enterococci and Pseudomonas aeruginosa isolates were collected from the clinical microbiology laboratory between August 2013 and January 2014. Isolates represented hospitalised or emergency department patients with monomicrobial bacteriuria. Fosfomycin MICs were determined in duplicate, on separate days, by Etest and disk diffusion and results were compared with agar dilution. Nitrofurantoin and ciprofloxacin were used as comparators. MIC results were categorised using Clinical and Laboratory Standards Institute interpretive criteria for Escherichia coli and Enterococcus faecalis. Correlation between the three testing methods was evaluated. Overall susceptibility to fosfomycin was 94.4%, 93.5% and 87.9% by agar dilution, disk diffusion and Etest, respectively. Five fosfomycin-resistant isolates were identified, including two Morganella morganii, one P. aeruginosa, one Proteus mirabilis and one Enterobacter aerogenes. Across all organisms, rates of essential agreement, categorical agreement, minor errors, major errors and very major errors for Etest/disk diffusion compared with agar dilution were 77.3%/NA, 89.5/93.8%, 7.1/5.0%, 3.6/1.3% and 0/0%, respectively. Fosfomycin displayed fairly consistent activity against a majority of isolates collected when using the susceptibility breakpoint of 64 µg/mL. MICs for E. coli were particularly low (≤2 µg/mL). These data lend support to current guidelines that recommend fosfomycin as empirical first-line therapy for uncomplicated UTI.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacteriuria/drug therapy , Cystitis/drug therapy , Enterobacteriaceae/drug effects , Enterococcus/drug effects , Fosfomycin/therapeutic use , Pseudomonas aeruginosa/drug effects , Bacteriuria/microbiology , Ciprofloxacin/therapeutic use , Drug Resistance, Bacterial , Enterobacteriaceae/isolation & purification , Enterococcus/isolation & purification , Female , Humans , Microbial Sensitivity Tests , Nitrofurantoin/therapeutic use , Pseudomonas aeruginosa/isolation & purification , Urinary Bladder/microbiologyABSTRACT
Daptomycin resistance (DAP(R)) in Staphylococcus aureus is associated with mutations in genes that are also implicated in staphylococcal pathogenesis. Using a laboratory-derived series of DAP exposed strains, we showed a relationship between increasing DAP MIC and reduced virulence in a Galleria mellonella infection model. Point mutations in walK and rpoC led to cumulative reductions in virulence and simultaneous increases in DAP MIC. A point mutation to mprF did not impact on S.aureus virulence; however deletion of mprF led to virulence attenuation and hyper-susceptibility to DAP. To validate our findings in G. mellonella, we confirmed the attenuated virulence of select isolates from the laboratory-derived series using a murine septicaemia model. As a corollary, we showed significant virulence reductions for clinically-derived DAP(R) isolates compared to their isogenic, DAP-susceptible progenitors (DAP(S)). Intriguingly, each clinical DAP(R) isolate was persistent in vivo. Taken together, it appears the genetic correlates underlying daptomycin resistance in S. aureus also alter pathogenicity.
Subject(s)
Anti-Bacterial Agents/pharmacology , Daptomycin/pharmacology , Staphylococcus aureus/drug effects , Staphylococcus aureus/pathogenicity , Aminoacyltransferases/genetics , Aminoacyltransferases/metabolism , Animals , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Drug Resistance, Multiple, Bacterial , Genotype , Larva/microbiology , Microbial Sensitivity Tests , Moths/microbiology , Phenotype , Point Mutation , Staphylococcus aureus/genetics , VirulenceABSTRACT
Quinolones are widely used in the treatment of respiratory infections, in large part because of their activity against Streptococcus pneumoniae and other commonly encountered respiratory tract pathogens. Pneumococcal isolates that are resistant to these "respiratory quinolones" have now begun to emerge. Resistance is attributable to mutations affecting the intracellular targets of these drugs, topoisomerase IV and DNA gyrase; drug efflux contributes to quinolone resistance in some isolates. Most commonly, strains fully resistant to the newer quinolones have one or more mutations affecting DNA gyrase and topoisomerase IV. Although various agents of this class exhibit selectivity in primarily targeting one or the other of these enzymes, the passage of isolates in the presence of any agent can result in selection of mutations affecting both enzymes. Quinolone resistance in S. pneumoniae has arisen in heterogeneous genetic backgrounds but, ominously, has now appeared in strains that are well adapted for regional and global transmission.
Subject(s)
DNA Gyrase/genetics , DNA Topoisomerase IV/genetics , Drug Resistance, Bacterial/genetics , Quinolones/pharmacology , Streptococcus pneumoniae/drug effects , Anti-Infective Agents , DNA Gyrase/physiology , DNA Topoisomerase IV/physiology , Humans , Microbial Sensitivity Tests , Mutation , Streptococcus pneumoniae/isolation & purificationABSTRACT
Quinupristin-dalfopristin and linezolid demonstrate in vitro activity against a wide range of gram-positive bacteria, including many isolates resistant to earlier antimicrobials. Quinupristin-dalfopristin is inactive against Enterococcus faecalis but has been effective for treatment of infections due to vancomycin-resistant Enterococcus faecium associated with bacteremia. In comparative trials, linezolid proved to be equivalent to comparator agents, resulting in its approval for several clinical indications. The almost-complete bioavailability of linezolid permits oral administration. Each agent can cause adverse effects that may limit use in individual patients. Resistance to these drugs has been encountered infrequently among vancomycin-resistant E. faecium. Resistance to quinupristin-dalfopristin is rare among staphylococci in the United States, and resistance to linezolid is very rare. Whether there is any benefit to use of these agents in combination regimens, and whether there are circumstances in which they might be alternatives to cell-wall active antibiotics for treatment of bone or endovascular infections, are questions that deserve further study.
Subject(s)
Acetamides/therapeutic use , Bacteremia/drug therapy , Gram-Positive Bacterial Infections/drug therapy , Oxazolidinones/therapeutic use , Virginiamycin/therapeutic use , Animals , Anti-Bacterial Agents/therapeutic use , Drug Therapy, Combination/therapeutic use , Enterococcus faecium/drug effects , Humans , Linezolid , Microbial Sensitivity Tests , Vancomycin ResistanceABSTRACT
We studied methicillin-resistant Staphylococcus aureus (MRSA) isolates to determine if the group II polymorphism at the accessory gene regulator (agr) locus demonstrated any relationship with the clinical efficacy of vancomycin. One hundred twenty-two MRSA isolates from 87 patients treated with vancomycin were evaluated. Forty-five of 87 patients had no clinical or bacteriological response to vancomycin. Among the 36 clinically evaluable patients with the agr group II polymorphism, 31 had an infection that failed to respond to vancomycin, whereas only 5 had an infection that responded successfully to vancomycin. This finding is of interest in light of our previous findings that glycopeptide-intermediately resistant S. aureus (GISA) and hetero-GISA clinical isolates in the United States and Japan are enriched for the agr group II polymorphism, and it suggests a possible intrinsic survival advantage of some S. aureus clones with this genetic marker under vancomycin selective pressure.
Subject(s)
Bacterial Proteins/genetics , Methicillin Resistance/genetics , Polymorphism, Genetic , Staphylococcus aureus/genetics , Trans-Activators/genetics , Vancomycin Resistance/genetics , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Polymerase Chain Reaction , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Vancomycin/therapeutic useABSTRACT
BACKGROUND: Infections may complicate cardiovascular surgery or may require surgery as an adjunct to successful treatment. Staphylococci, which are among the major pathogenic bacteria causing such infections, can be resistant to many of the older antibiotics. METHODS: The properties of several newer antimicrobial agents, recently approved or still investigational, were reviewed, with an emphasis on in vitro activities against staphylococci. RESULTS: The 2 approved agents, linezolid and quinupristin-dalfopristin, and several investigational agents being developed demonstrate in vitro antimicrobial activity against staphylococci. Three of these agents, daptomycin, which was approved by the US Food and Drug Administration in September 2003, and oritavancin and dalbavancin, which are in advanced stages of clinical development, are discussed. CONCLUSIONS: Although clinical studies are required, the in vitro anti-staphylococcal activities of several agents suggest that these antimicrobial agents might be useful options for some infections in patients who are intolerant of older antibiotics or who are infected with organisms that are resistant to older agents.