ABSTRACT
Oritavancin exhibited in vitro activity against 169 strains of vancomycin-susceptible, methicillin-resistant Staphylococcus aureus (MRSA) with MICs ranging from 0.03 to 1 µg/ml and against vancomycin-intermediate MRSA (VISA; n = 29), heterogeneous vancomycin-intermediate MRSA (hVISA; n = 5), and vancomycin-resistant MRSA (n = 5) strains, with MICs ranging from 0.12 to 4 µg/ml. For 10 MRSA isolates comprising 5 VISA and 5 hVISA strains, synergy between oritavancin and gentamicin, linezolid, or rifampin was observed against most of the strains tested using a time-kill method.
Subject(s)
Anti-Bacterial Agents/pharmacology , Glycopeptides/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Drug Synergism , Lipoglycopeptides , Microbial Sensitivity TestsABSTRACT
The past decade has seen an alarming confluence of circumstances antithetical to development of new antibacterials, and most of the very few new drugs under development have problems with their microbiology, toxicity, or pharmacokinetics and pharmacodynamics. Most large pharmaceutical companies have divested themselves of their antibiotic portfolios, and the promise that start-up companies would fill the niche has not been fulfilled. What is left of the field is being stifled by bureaucratic regulations, problems with approval, lack of expertise and a general lack of understanding of how serious the situation is. In paediatrics, in particular, there is no sign of any new antibacterial in the foreseeable future. Waiting for initiatives and deliberations will probably take too long, and a vigorous and deliberate effort to educate the public-who in their turn can apply the needed pressure--seems to be the only way of achieving a rapid turnaround of this most dangerous situation.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacterial Infections/epidemiology , Bacterial Infections/microbiology , Drug Resistance, Bacterial , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/mortality , Drug Approval , Drug Discovery/trends , Humans , Incidence , Treatment FailureABSTRACT
Among 10 coagulase-negative staphylococci, telavancin, quinupristin/dalfopristin, and tigecycline were the most potent antimicrobials. Telavancin exhibited bactericidal effect to 9 strains out of 10 tested at 4× MIC after 24 h of exposure similar to those of vancomycin and daptomycin. By contrast, linezolid was mainly bacteriostatic and teicoplanin was bactericidal to 7 strains tested at 4× MIC after 24 h.
Subject(s)
Aminoglycosides/pharmacology , Anti-Bacterial Agents/pharmacology , Microbial Viability/drug effects , Staphylococcus/drug effects , Coagulase/metabolism , Humans , Lipoglycopeptides , Microbial Sensitivity Tests , Staphylococcus/enzymology , Time FactorsABSTRACT
OBJECTIVES: To characterize the mechanisms responsible for elevated MICs of ceftaroline for methicillin-resistant Staphylococcus aureus (MRSA). METHODS: During the 2008 Assessing Worldwide Antimicrobial Resistance Evaluation ('AWARE') surveillance programme, four S. aureus collected from separate patients in Athens, Greece, demonstrated ceftaroline MICs of 4 mg/L. These isolates were clonally related and one strain (13101) was selected for further characterization. Two strains (4981 and 4977) displaying ceftaroline MICs of 1 and 2 mg/L, respectively, were included for comparison. All strains originated from the same hospital. Penicillin-binding protein (PBP) affinities for ceftaroline and comparators were determined. Strains were typed by single-locus typing (i.e. spa typing), multilocus sequence typing ('MLST') and by multiple-locus variable-number tandem repeat fingerprinting (MLVF). The presence of Pantone-Valentine leucocidin and the staphylococcal cassette chromosome mec types was assessed. We also performed nucleotide sequencing of the mecA (encoding PBP2a) promoter and ribosomal binding site (rbs) regions and mecR1. RESULTS: Ceftaroline demonstrated the highest PBP2a affinity with strain 4981 (ST5-MRSA-II) (IC(50) 0.06 mg/L; MIC 1 mg/L). Strains 4977 and 13101 (both ST239-MRSA-III) showed indistinguishable MLVF profiles. Ceftaroline PBP2a binding affinity in strains 4977 (IC(50) 0.25 mg/L; MIC 2 mg/L) and 13101 (IC(50) 1 mg/L; MIC 4 mg/L) was 4- and 16-fold lower than 4981, respectively. Strain 4981 contains a wild-type PBP2a, while strains 4977 and 13101 have N(146)K and E(150)K alterations in the non-penicillin-binding domain. Additionally, 13101 has one substitution (H(351)N) in the transpeptidase domain. Alterations in the mecR1, mecA promoter or rbs regions were not observed. CONCLUSIONS: Increased ceftaroline MICs were associated with decreased PBP2a binding affinity and reflected alterations in PBP2a.
Subject(s)
Anti-Bacterial Agents/pharmacology , Cephalosporins/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Staphylococcal Infections/microbiology , Amino Acid Sequence , Bacterial Proteins/genetics , Bacterial Toxins/genetics , DNA Fingerprinting , Exotoxins/genetics , Genotype , Greece , Humans , Leukocidins/genetics , Methicillin-Resistant Staphylococcus aureus/classification , Methicillin-Resistant Staphylococcus aureus/genetics , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Microbial Sensitivity Tests , Molecular Sequence Data , Molecular Typing , Penicillin-Binding Proteins/metabolism , Protein Binding , Sequence Analysis, DNA , Sequence Homology, Amino Acid , Virulence Factors/genetics , CeftarolineABSTRACT
BACKGROUND: Emergence of multidrug-resistant Staphylococcus aureus has triggered a reassessment of fusidic acid (CEM-102, sodium fusidate). METHODS: Fusidic acid was examined for (1) activity against recent methicillin-resistant S. aureus (MRSA) isolates; (2) modulation of activity by acidic pH; and (3) accumulation by phagocytic cells and intracellular activity against methicillin-susceptible S. aureus (MSSA) and MRSA. RESULTS: About 96% of strains (N = 94) were susceptible (European Committee on Antimicrobial Susceptibility Testing breakpoint [≤ 1 mg/L]). Activity was enhanced at pH 5.5 (6 dilutions decrease for minimum inhibitory concentration) in parallel with an increase of drug bacterial accumulation (opposite effects for clindamycin; linezolid remained unaffected). Fusidic acid accumulated in THP-1 cells (about 5.5 fold), with further accumulation at pH 5.5 vs pH 7.4. The intracellular activity of Fusidic acid was similar to that of clindamycin and linezolid (maximal relative activity, 0.4-0.6 log(10) colony-forming unit decrease). No cross-resistance to vancomycin or daptomycin was observed. CONCLUSIONS: Fusidic acid is active against S. aureus in broth as well as intracellularly, with no cross-resistance to other antibiotics.
Subject(s)
Anti-Bacterial Agents/pharmacology , Fusidic Acid/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Monocytes/microbiology , Staphylococcal Infections/microbiology , Staphylococcus aureus/drug effects , Acetamides/pharmacology , Cell Line , Clindamycin/pharmacology , Colony Count, Microbial , Culture Media , Humans , Hydrogen-Ion Concentration , Linezolid , Methicillin/pharmacology , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Microbial Sensitivity Tests/standards , Monocytes/drug effects , Oxazolidinones/pharmacology , Staphylococcus aureus/growth & development , Staphylococcus aureus/isolation & purificationABSTRACT
ACHN-490 was tested alone and in combination with cefepime, doripenem, imipenem, or piperacillin-tazobactam in a synergy time-kill analysis against 25 Pseudomonas aeruginosa strains with different resistance phenotypes. Each combination was synergistic against most isolates at 24 h, and antagonism was not observed. Combinations of ACHN-490 with cefepime, doripenem, imipenem, or piperacillin-tazobactam yielded synergies in ≥70% and ≥80% of strains at 6 and 12 h, respectively, and in ≥68% at 24 h.
Subject(s)
Anti-Bacterial Agents/pharmacology , Carbapenems/pharmacology , Cephalosporins/pharmacology , Imipenem/pharmacology , Pseudomonas aeruginosa/drug effects , Cefepime , Doripenem , Microbial Sensitivity Tests , Penicillanic Acid/analogs & derivatives , Penicillanic Acid/pharmacology , Piperacillin/pharmacology , Piperacillin, Tazobactam Drug CombinationABSTRACT
We tested the MICs of fusidic acid (CEM-102) plus other agents against 40 methicillin-resistant Staphylococcus aureus (MRSA) isolates from cystic fibrosis patients and the activities of fusidic acid with or without tobramycin or amikacin against Pseudomonas aeruginosa, MRSA, and Burkholderia cepacia isolates from cystic fibrosis patients in a 24-h time-kill study. Fusidic acid was potent (MICs, 0.125 to 0.5 µg/ml; a single 500-mg dose of fusidic acid at 8 h averaged 8 to 12. 5 µg/ml with 91 to 97% protein binding) against all MRSA strains. No antagonism was observed; synergy occurred for one MRSA strain treated with fusidic acid plus tobramycin.
Subject(s)
Amikacin/pharmacology , Burkholderia cepacia/drug effects , Cystic Fibrosis/microbiology , Fusidic Acid/pharmacology , Pseudomonas aeruginosa/drug effects , Staphylococcus aureus/drug effects , Tobramycin/pharmacology , Drug Synergism , HumansABSTRACT
Ceftaroline, the active component of the prodrug ceftaroline fosamil, is a novel broad-spectrum cephalosporin with bactericidal activity against Gram-positive and -negative isolates. This study evaluated the potential for ceftaroline and comparator antibiotics to select for clones of Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, Staphylococcus aureus, and Enterococcus faecalis with elevated MICs. S. pneumoniae and S. pyogenes isolates in the present study were highly susceptible to ceftaroline (MIC range, 0.004 to 0.25 µg/ml). No streptococcal strains yielded ceftaroline clones with increased MICs (defined as an increase in MIC of >4-fold) after 50 daily passages. Ceftaroline MICs for H. influenzae and M. catarrhalis were 0.06 to 2 µg/ml for four strains and 8 µg/ml for a ß-lactamase-positive, efflux-positive H. influenzae with a mutation in L22. One H. influenzae clone with an increased ceftaroline MIC (quinolone-resistant, ß-lactamase-positive) was recovered after 20 days. The ceftaroline MIC for this isolate increased 16-fold, from 0.06 to 1 µg/ml. MICs for S. aureus ranged from 0.25 to 1 µg/ml. No S. aureus isolates tested with ceftaroline had clones with increased MIC (>4-fold) after 50 passages. Two E. faecalis isolates tested had ceftaroline MICs increased from 1 to 8 µg/ml after 38 days and from 4 to 32 µg/ml after 41 days, respectively. The parental ceftaroline MIC for the one K. pneumoniae extended-spectrum ß-lactamase-negative isolate tested was 0.5 µg/ml and did not change after 50 daily passages.
Subject(s)
Anti-Bacterial Agents/pharmacology , Cephalosporins/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Enterococcus faecalis/drug effects , Haemophilus influenzae/drug effects , Klebsiella pneumoniae/drug effects , Microbial Sensitivity Tests , Moraxella catarrhalis/drug effects , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Streptococcus pyogenes/drug effects , CeftarolineABSTRACT
Against 33 Gram-positive and -negative bacteria, NXL 103 MICs were 0.03 to 1 µg/ml. NXL 103 was bactericidal by 12 h at 2 × MIC against all 5 pneumococci and at 2 × MIC after 24 h against all 5 group A and B ß-hemolytic streptococci. NXL 103 was bactericidal against all 8 Haemophilus influenzae strains at 2 × MIC and all 5 Moraxella catarrhalis strains at 4 × MIC after 24 h but was mainly bacteriostatic against 5 methicillin-resistant Staphylococcus aureus strains. After the exposure of one strain of each species to NXL 103 for 10 daily subcultures, the MICs remained within ± 1 dilution.
Subject(s)
Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Streptogramins/pharmacology , Haemophilus influenzae/drug effects , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effectsABSTRACT
BACKGROUND: Co-trimoxazole, clindamycin and linezolid are used to treat community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections, but little is known about intracellular activity. Moxifloxacin is active against intracellular methicillin-susceptible S. aureus (MSSA), but CA-MRSA has not been studied. METHODS: We used 12 clinical CA-MRSA, 1 MSSA overexpressing norA and 2 hospital-acquired MRSA (moxifloxacin MICs: 0.03 to 4 mg/L). Activity was assessed in broth and after phagocytosis by THP-1 macrophages or keratinocytes {concentration-dependent experiments [24 h of incubation] to determine relative potencies [EC(50)], static concentrations [C(s)] and maximal relative efficacies [E(max) (change in log(10) cfu compared with initial inoculum)] and time-dependent experiments [0-72 h] at human C(max)}. RESULTS: Concentration-dependent experiments: in broth, EC(50) and C(s) were correlated with the MIC for all antibiotics, but moxifloxacin achieved significantly (Pâ<â0.01) greater killing (more negative E(max)) than the comparators; and in THP-1 cells and keratinocytes, moxifloxacin acted more slowly but still reached a near bactericidal effect (2 to 3 log(10) cfu decrease) at 24 h with unchanged EC(50) and C(s) as long as its MIC was ≤0.125 mg/L (recursive partitioning analysis). Clindamycin and linezolid were static, and co-trimoxazole was unable to suppress the intracellular growth of CA-MRSA. At human C(max) in broth, moxifloxacin killed more rapidly and more extensively (≥5 log(10) cfu decrease at 10 h) than clindamycin (4 log(10) cfu at 48 h) or co-trimoxazole and linezolid (1-2 log(10) cfu at 72 h). CONCLUSIONS: Moxifloxacin is active against both extracellular and intracellular CA-MRSA if the MIC is low, and is more effective than clindamycin, co-trimoxazole and linezolid.
Subject(s)
Anti-Bacterial Agents/pharmacology , Aza Compounds/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Quinolines/pharmacology , Acetamides/pharmacology , Cell Line , Clindamycin/pharmacology , Community-Acquired Infections/microbiology , Fluoroquinolones , Humans , Linezolid , Macrophages/microbiology , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Microbial Sensitivity Tests , Microbial Viability/drug effects , Moxifloxacin , Oxazolidinones/pharmacology , Phagocytosis , Staphylococcal Infections/microbiology , Trimethoprim, Sulfamethoxazole Drug Combination/pharmacologyABSTRACT
OBJECTIVES: Several methods have been introduced for detection of vancomycin-non-susceptible Staphylococcus aureus [heterogeneous vancomycin-intermediate S. aureus (hVISA) and vancomycin-intermediate S. aureus (VISA)]. However, the limitations of these methods can delay appropriate therapy for the patient. This study evaluated the spiral gradient endpoint (SGE) technique for detection of hVISA/VISA. METHODS: The SGE method was evaluated for intra-batch, inter-batch and inter-observer reproducibility in comparison with MICs determined by agar dilution. Three media, Mueller-Hinton agar, brain heart infusion agar and brain heart infusion agar with 5% glucose, were evaluated. The SGE method was compared with agar dilution for correlation of MIC and susceptibility category using control strains, clinical isolates and induced vancomycin-non-susceptible strains. RESULTS: The SGE method had good reproducibility and there was excellent correlation of MICs generated by SGE using brain heart infusion agar with those by agar dilution (r(2)â=0.950), with no difference in resistance categories generated by the two methods. All VISA isolates were correctly identified and the method allowed easy identification of hVISA by means of the trailing endpoint. CONCLUSIONS: SGE offers a simple, rapid and cost-effective alternative method for the detection of hVISA/VISA for the routine laboratory. Early recognition of vancomycin-non-susceptible strains can allow the change to appropriate antibiotics, resulting in potentially better patient outcomes.
Subject(s)
Staphylococcus aureus/drug effects , Vancomycin Resistance , Culture Media/chemistry , Humans , Microbial Sensitivity Tests/methods , Reproducibility of ResultsABSTRACT
We investigated emergence of linezolid resistance among coagulase-negative staphylococci at our tertiary care center in 2007. All 17 cases were healthcare associated, and prior administration of linezolid was documented Subject(s)
Acetamides/pharmacology
, Anti-Infective Agents/pharmacology
, Cross Infection/epidemiology
, Drug Resistance, Bacterial
, Molecular Epidemiology
, Oxazolidinones/pharmacology
, Staphylococcal Infections/epidemiology
, Staphylococcus/drug effects
, Staphylococcus/genetics
, Cross Infection/microbiology
, Electrophoresis, Gel, Pulsed-Field
, Humans
, Linezolid
, Microbial Sensitivity Tests
, Mutation
, RNA, Ribosomal, 23S/genetics
, Staphylococcal Infections/microbiology
, Staphylococcus/classification
, Staphylococcus epidermidis/classification
, Staphylococcus epidermidis/drug effects
ABSTRACT
OBJECTIVES: Increasing antibiotic resistance and interest in matching antibiotic therapy with pharmacokinetic/pharmacodynamic characteristics of isolates has led to increasing demands for determination of MICs. This can lead to increased costs for the laboratory. The spiral gradient endpoint (SGE) technique, a low-cost method of MIC determination, was developed some years ago. Although the technique showed good correlation with reference methods, it was not widely employed, mainly due to the introduction of alternative methods. We have revisited this technique and evaluated it for the determination of MICs for fastidious organisms. METHODS: The SGE method was first optimized for fastidious organisms using Haemophilus influenzae. Intra-batch and inter-batch reproducibility was determined for H. influenzae, Streptococcus pneumoniae, Moraxella catarrhalis and Neisseria gonorrhoeae. The method was then evaluated by comparison of MICs for clinical isolates of these organisms determined by SGE with those determined with the reference method. RESULTS: Optimization of the technique resulted in a method with excellent reproducibility for all organisms tested [SD 0.10-0.337; coefficient of variation (CV) 8.59%-18.66%]. These SDs/CVs were lower than those of the reference methods (0.27-2.34; 31.0%-63.8%). There was excellent correlation of the MICs with the reference methods (0.908-0.930) and insignificant differences in numbers of strains in each resistance category, with no tendency for SGE to produce higher or lower MICs than the reference method (P > 0.05). CONCLUSIONS: SGE was shown to be reproducible and produced results that correlated well with standard techniques for fastidious organisms. The method offers a rapid, flexible, cost-effective alternative for smaller laboratories and for routine use in developing countries.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Microbial Sensitivity Tests/methods , Bacteria/isolation & purification , Bacterial Infections/microbiology , Humans , Microbial Sensitivity Tests/economics , Reproducibility of Results , Time FactorsABSTRACT
Radezolid is a novel biaryloxazolidinone in clinical development which shows improved activity, including against linezolid-resistant strains. In a companion paper (29), we showed that radezolid accumulates about 11-fold in phagocytic cells, with approximately 60% of the drug localized in the cytosol and approximately 40% in the lysosomes of the cells. The present study examines its activity against (i) bacteria infecting human THP-1 macrophages and located in different subcellular compartments (Listeria monocytogenes, cytosol; Legionella pneumophila, vacuoles; Staphylococcus aureus and Staphylococcus epidermidis, mainly phagolysosomal), (ii) strains of S. aureus with clinically relevant mechanisms of resistance, and (iii) isogenic linezolid-susceptible and -resistant S. aureus strains infecting a series of phagocytic and nonphagocytic cells. Radezolid accumulated to similar levels ( approximately 10-fold) in all cell types (human keratinocytes, endothelial cells, bronchial epithelial cells, osteoblasts, macrophages, and rat embryo fibroblasts). At equivalent weight concentrations, radezolid proved consistently 10-fold more potent than linezolid in all these models, irrespective of the bacterial species and resistance phenotype or of the cell type infected. This results from its higher intrinsic activity and higher cellular accumulation. Time kill curves showed that radezolid's activity was more rapid than that of linezolid both in broth and in infected macrophages. These data suggest the potential interest of radezolid for recurrent or persistent infections where intracellular foci play a determinant role.
Subject(s)
Anti-Bacterial Agents/pharmacology , Legionella pneumophila/drug effects , Listeria monocytogenes/drug effects , Oxazolidinones/pharmacology , Phagocytes/drug effects , Phagocytes/microbiology , Staphylococcus aureus/drug effects , Staphylococcus epidermidis/drug effects , Acetamides/administration & dosage , Acetamides/pharmacology , Animals , Anti-Bacterial Agents/administration & dosage , Cells, Cultured , Dose-Response Relationship, Drug , Drug Resistance, Bacterial , Humans , Linezolid , Microbial Sensitivity Tests , Oxazolidinones/administration & dosage , RatsABSTRACT
At 24 h, sub-MIC doripenem and levofloxacin showed synergy against 21 of 25 Pseudomonas aeruginosa strains, sub-MIC doripenem and amikacin against 22 isolates, and sub-MIC doripenem and colistin against 19 isolates. Of 25 Acinetobacter baumannii strains, sub-MIC doripenem and levofloxacin showed synergy against 11 strains at 24 h, sub-MIC doripenem and amikacin against 24 strains, and sub-MIC doripenem and colistin against all isolates.
Subject(s)
Acinetobacter baumannii/drug effects , Anti-Bacterial Agents/pharmacology , Pseudomonas aeruginosa/drug effects , Acinetobacter Infections/microbiology , Acinetobacter baumannii/isolation & purification , Drug Synergism , Humans , Microbial Sensitivity Tests , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/isolation & purificationABSTRACT
We tested the propensities of four carbapenems to select for resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii mutants by determining the mutant prevention concentrations (MPCs) for 100 clinical strains with various ss-lactam phenotypes. Among the members of the Enterobacteriaceae family and A. baumannii strains, the MPC/MIC ratios were mostly 2 to 4. In contrast, for P. aeruginosa the MPC/MIC ratios were 4 to > or =16. The MPC/MIC ratios for beta-lactamase-positive K. pneumoniae and E. coli isolates were much higher (range, 4 to >16 microg/ml) than those for ss-lactamase-negative strains.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Carbapenems/administration & dosage , Genes, Bacterial , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/genetics , Mutation , Acinetobacter baumannii/drug effects , Acinetobacter baumannii/genetics , Doripenem , Drug Resistance, Bacterial/genetics , Ertapenem , Escherichia coli/drug effects , Escherichia coli/genetics , Gram-Negative Bacteria/enzymology , Gram-Negative Bacteria/isolation & purification , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/microbiology , Humans , Imipenem/administration & dosage , In Vitro Techniques , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/genetics , Meropenem , Microbial Sensitivity Tests , Phenotype , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/genetics , Thienamycins/administration & dosage , beta-Lactamases/genetics , beta-Lactamases/metabolism , beta-Lactams/administration & dosageABSTRACT
Synergy time-kill studies against 40 methicillin-resistant Staphylococcus aureus (MRSA) strains of differing resistance phenotypes were conducted. Subinhibitory concentrations of telavancin were combined with sub-MIC concentrations of other antimicrobial agents that might be used in combination with telavancin to provide Gram-negative coverage. The highest incidence of synergy was found after 24 h with gentamicin (90% of strains), followed by ceftriaxone (88%), rifampin and meropenem (each 65%), cefepime (45%), and ciprofloxacin (38%) for combinations tested at or below the intermediate breakpoint for each agent.
Subject(s)
Aminoglycosides/pharmacology , Anti-Bacterial Agents/pharmacology , Gentamicins/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Cefepime , Ceftriaxone/pharmacology , Cephalosporins/pharmacology , Ciprofloxacin/pharmacology , Drug Synergism , Lipoglycopeptides , Meropenem , Microbial Sensitivity Tests , Oxacillin/pharmacology , Rifampin/pharmacology , Thienamycins/pharmacology , Time FactorsABSTRACT
Synergy time-kill studies of 47 methicillin-resistant Staphylococcus aureus strains with differing resistance phenotypes showed that combinations of subinhibitory concentrations of ACHN-490 and daptomycin yielded synergy against 43/47 strains at 24 h, while the combination was indifferent against the remaining 4 strains. ACHN-490 and ceftobiprole showed synergy in 17/47 strains tested at 24 h, while 6/47 strains showed synergy for subinhibitory combinations of ACHN-490 and linezolid.
Subject(s)
Acetamides/pharmacology , Aminoglycosides/pharmacology , Daptomycin/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Oxazolidinones/pharmacology , Sisomicin/analogs & derivatives , Aminoglycosides/chemistry , Anti-Bacterial Agents/pharmacology , Cephalosporins/pharmacology , Drug Resistance, Bacterial/drug effects , Drug Synergism , Linezolid , Microbial Sensitivity Tests , Sisomicin/chemistry , Sisomicin/pharmacology , Time FactorsABSTRACT
We tested the propensity of three quinolones to select for resistant Streptococcus pneumoniae mutants by determining the mutant prevention concentration (MPC) against 100 clinical strains, some of which harbored mutations in type II topoisomerases. Compared with levofloxacin and gemifloxacin, moxifloxacin had the lowest number of strains with MPCs above the susceptibility breakpoint (P<0.001), thus representing a lower selective pressure for proliferation of resistant mutants. Only moxifloxacin gave a 50% MPC (MPC50) value (1 microg/ml) within the susceptible range.
Subject(s)
Anti-Bacterial Agents/pharmacology , Aza Compounds/pharmacology , Fluoroquinolones/pharmacology , Levofloxacin , Naphthyridines/pharmacology , Ofloxacin/pharmacology , Quinolines/pharmacology , Streptococcus pneumoniae/drug effects , DNA Topoisomerases, Type II/genetics , Drug Resistance, Bacterial/genetics , Gemifloxacin , Microbial Sensitivity Tests , Moxifloxacin , Mutation , Polymerase Chain Reaction , Streptococcus pneumoniae/geneticsABSTRACT
CEM-101 had MIC ranges of 0.002 to 0.016 microg/ml against macrolide-susceptible pneumococci and 0.004 to 1 microg/ml against macrolide-resistant phenotypes. Only 3 strains with erm(B), with or without mef(A), had CEM-101 MICs of 1 microg/ml, and 218/221 strains had CEM-101 MICs of