Biomedical subjects

Michael J Rybak

Publications and source records attributed to Michael J Rybak.

At least 19 recordsLinked to original sources

PubMed2007

Antimicrobial activities of ceragenins against clinical isolates of resistant Staphylococcus aureus.

The rise in the rates of glycopeptide resistance among Staphylococcus aureus isolates is concerning and underscores the need for the development of novel potent compounds. Ceragenins CSA-8 and CSA-13, cationic steroid molecules that mimic endogenous antimicrobial peptides, have previously been demonstrated to possess broad-spectrum activities against multidrug-resistant bacteria. We examined the activities of CSA-8 and CSA-13 against clinical isolates of vancomycin-intermediate S. aureus (VISA), heterogeneous vancomycin-intermediate S. aureus (hVISA), as well as vancomycin-resistant S. aureus (VRSA) and compared them to those of daptomycin, linezolid, and vancomycin by susceptibility testing and killing curve analysis. We also examined CSA-13 for its concentration-dependent activity, inoculum effect, postantibiotic effect (PAE), and synergy in combination with various antimicrobials. Overall, the MICs and minimal bactericidal concentrations of CSA-13 were fourfold lower than those of CSA-8. Time-kill curve analysis of the VRSA, VISA, and hVISA clinical isolates demonstrated concentration-dependent bactericidal killing. An inoculum effect was also observed when a higher starting bacterial density was used, with the time required to achieve 99.9% killing reaching 1 h with a 6-log10-CFU/ml starting inoculum, whereas it was>or=24 h with a 8- to 9-log10-CFU/ml starting inoculum with 10x the MIC (P<or=0.001). A concentration-dependent PAE was demonstrated with CSA-13, nearly doubling from 2x to 4x the MIC (P=0.03). With respect to the CSA-13 antimicrobial combinations, time-kill curve analysis showed no difference in the log10 CFU/ml at 24 h for the majority of the organisms tested. However, early synergy at 4 to 8 h was detected against the VRSA Pennsylvania strain (2002) when CSA-13 was tested in combination with gentamicin, while early additivity was demonstrated against all of the other organisms.

Anti-Bacterial Agents↗

PubMed2007

Antimicrobial susceptibility and staphylococcal chromosomal cassette mec type in community- and hospital-associated methicillin-resistant Staphylococcus aureus.

STUDY OBJECTIVE: To differentiate the characteristics of community-associated methicillin-resistant Staphylococcus aureus (MRSA) and hospital-associated MRSA isolates on the basis of their susceptibility profiles, induction of clindamycin resistance, and staphylococcal chromosomal cassette (SCC) mec types. DESIGN: In vitro molecular and susceptibility study of isolates obtained from December 2004-January 2006 as part of a large, ongoing clinical study. SETTING: Level I trauma center in Detroit, Michigan. BACTERIAL STRAINS: Three hundred eight MRSA isolates randomly collected from patients; 130 were classified as community-associated, and 178 were classified hospital-associated by using definitions from the Centers for Disease Control and Prevention (CDC). INTERVENTION: Minimum inhibitory concentrations were tested on the basis of current guidelines from the Clinical and Laboratory Standards Institute. MEASUREMENTS AND MAIN RESULTS: All tested MRSA isolates were susceptible to daptomycin, linezolid, and vancomycin. In addition, community-associated MRSA isolates were significantly (all p < or = 0.05) more susceptible to trimethoprim-sulfamethoxazole (99%), clindamycin (96%), and a fluoroquinolone (76%) than hospital-associated MRSA isolates. Inducible resistance to clindamycin was demonstrated in 8.4% of community-associated MRSA isolates versus 50% of hospital-associated MRSA isolates (p < or = 0.001). Of interest, 35% of the MRSA isolates collected from hospitalized patients (> 48 hrs after admission and according to the CDC definition) possessed SCCmec type IV. CONCLUSION: Overall, inducible clindamycin resistance occurred at significantly higher rates in the hospital-associated MRSA isolates, susceptibility differed significantly between community- and hospital-associated MRSA, and most of the hospital isolates contained SCCmec type IV.

Anti-Bacterial Agents↗

PubMed2006

Evaluation of accessory gene regulator (agr) group and function in the proclivity towards vancomycin intermediate resistance in Staphylococcus aureus.

Simulated therapeutic vancomycin exposures were evaluated against agr wild-type and knockout Staphylococcus aureus groups I, II, III, and IV using an in vitro pharmacodynamic model. All agr groups developed intermediate resistance to vancomycin after subtherapeutic exposure. The free unbound fraction of the area under the concentration-time curve (fAUC/MIC) required to suppress resistance was fourfold higher (P < 0.001) in agr dysfunctional strains (112 to 169) than that in parent wild-type strains (28).

Anti-Bacterial Agents↗

PubMed2006

Characteristics of patients with healthcare-associated infection due to SCCmec type IV methicillin-resistant Staphylococcus aureus.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) with the staphylococcal cassette chromosome mec (SCCmec) type IV allele is most commonly associated with community-acquired MRSA (CA-MRSA) infection; however, such organisms have also been identified in the healthcare setting. The objective of the present study was to characterize the epidemiology of and clinical outcomes associated with SCCmec-IV MRSA infection acquired in the healthcare setting, compared with infection caused by MRSA of other SCCmec types. DESIGN: We evaluated a cohort of 100 inpatients with MRSA infection that met the Centers for Disease Control and Prevention definition for healthcare-associated infection and compared the patients' demographic characteristics, the antimicrobial susceptibilities of the MRSA isolates, the infection types, and the associated clinical and microbiological outcomes. For each MRSA isolate, the SCCmec type and the presence of Panton-Valentine leukocidin (PVL) were determined by polymerase chain reaction methods. RESULTS: SCCmec-IV MRSA isolates were isolated from 53 patients (42% of these isolates were positive for PVL), and SCCmec-II or SCCmec-III MRSA was isolated from 47 patients (3% of these isolates were positive for PVL). No differences were noted between the patients in the SCCmec-II/III group and the patients in the SCCmec-IV group with respect to age (median, 55 vs 50 years); sex (77% vs 64% of patients were male); medical service (surgical service, 60% in both groups; ICU admission, 55% vs 53%), Acute Physiology and Chronic Health Evaluation II score (median, 8 vs. 7); infection type; or underlying comorbidities, except for presence of a burn wound (13% vs 2%; P < .04). Patients in the SCCmec-II/III group were more likely to have multiple sites of infection (P = .006) and a longer length of stay (LOS) prior to detection of MRSA than were patients in the SCCmec-IV group (median, 4 vs 1 days; P < .001). Total LOS was significantly greater for patients in the SCCmec-II/III, compared with those in the SCCmec-IV group (P = .006). Multiple logistic regression identified liver disease and longer LOS prior to detection of MRSA as predictors of infection with SCCmec-II/III MRSA. Rates of susceptibility to clindamycin, gentamicin, ciprofloxacin, levofloxacin, and tetracycline was significantly greater among SCCmec-IV MRSA isolates, compared with type II/III isolates (P < or = .05). Compared with SCCmec-IV isolates acquired in the community, the susceptibility rates among healthcare-associated SCCmec-IV isolates was significantly less for clindamycin, gentamicin, and levofloxacin, indicating that these organisms may quickly acquire resistance to non- beta -lactam antibiotics, as do SCCmec-II/III strains. CONCLUSIONS: SCCmec-IV MRSA appears to have become established in hospitals. The onset of infection caused by SCCmec-IV strains is earlier than the onset of infection with SCCmec-II/III strains; however, associated types of infection are similar. Infection with SCCmec-II/III MRSA is currently associated with an adverse impact on outcome, compared with infection with SCCmec-IV MRSA. Further research is warranted to determine the impact of SCCmec type IV strains in hospital settings.

Adult↗

PubMed2006

Comparative activity of the new lipoglycopeptide telavancin in the presence and absence of serum against 50 glycopeptide non-susceptible staphylococci and three vancomycin-resistant Staphylococcus aureus.

BACKGROUND: Telavancin, a new multifunctional lipoglycopeptide antibiotic, exhibits broad-spectrum Gram-positive activity against a variety of pathogens. We examined the effects of human serum and antimicrobial concentrations on the activity of telavancin against glycopeptide-intermediate staphylococcal species (GISS), heteroresistant GISS (hGISS) and three vancomycin-resistant Staphylococcus aureus (VRSA) compared with vancomycin, quinupristin/dalfopristin, linezolid and daptomycin. METHODS: MIC and MBCs were performed against all antimicrobials. Time-kill experiments were performed using two strains of GISS (Mu50; NJ992) and VRSA (VRSAMI; VRSAPA) at 1, 2, 4, 8, 16 and 32x MIC. Telavancin and daptomycin were evaluated in the presence and absence of serum. RESULTS: All GISS and hGISS were susceptible to the tested agents with telavancin and quinupristin/dalfopristin demonstrating the lowest MIC, followed by daptomycin, linezolid and vancomycin. Against VRSA, daptomycin and quinupristin/dalfopristin had the lowest MIC, followed by linezolid, telavancin and vancomycin. In the presence of serum, telavancin and daptomycin MICs increased 1- to 4-fold. Concentration-dependent activity was demonstrated by telavancin and daptomycin, in the presence and absence of serum. Telavancin and daptomycin were bactericidal against GISS and performed similarly in the presence of serum. Quinupristin/dalfopristin demonstrated bactericidal activity at clinically achievable concentrations, whereas linezolid was bacteriostatic. CONCLUSIONS: Telavancin demonstrated concentration-dependent bactericidal activity against GISS, hGISS and VRSA at concentrations equal to or above 4x MIC, which corresponds to therapeutic levels against GISS and clinically achieved concentrations against the VRSA. Similar to daptomycin, telavancin activity was diminished in the presence of serum but bactericidal activity was maintained. Further investigation with telavancin against GISS, hGISS and VRSA is warranted.

Aminoglycosides↗

PubMed2006

Susceptibility studies of piperazinyl-cross-linked fluoroquinolone dimers against test strains of Gram-positive and Gram-negative bacteria.

Susceptibility testing was used to evaluate potential spectrum of action for piperazinyl-cross-linked fluoroquinolone dimers against test strains of Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and vancomycin-resistant Enterococcus faecium (VRE) and to evaluate dimers against fluoroquinolone-resistant and fluoroquinolone-susceptible strains of streptococci. Individual dimers displayed equivalent or lowered MIC values compared with parent fluoroquinolone monomers against test strains of S. pneumoniae, S. pyogenes, E. coli, and VRE. Raised MIC values were observed for all dimers in comparison to monomers against test strains of P. aeruginosa and E. coli. In comparison to parent fluoroquinolones, all dimers displayed decreased percent inhibition of growth against M. tuberculosis. Structural requirements for activity of dimers and partial dimers against all organisms, including lower MICs against certain fluoroquinolone-resistant and fluoroquinolone-susceptible strains of streptococci, were consistent with requirements previously observed for dimers against fluoroquinolone-susceptible and fluoroquinolone-resistant strains of S. aureus. In contrast, the 10- to 100-fold lowering of MICs against wild-type and fluoroquinolone-resistant strains of S. aureus previously observed for individual cross-linked dimers was not observed with test strains of the various organisms used here.

Ciprofloxacin↗

PubMed2006

The pharmacokinetic and pharmacodynamic properties of vancomycin.

Vancomycin is one of only a few antibiotics available to treat patients infected with methicillin-resistant Staphylococcus aureus and methicillin-resistant, coagulase-negative Staphylococcus species. Therefore, understanding the clinical implications of the pharmacokinetic and pharmacodynamic properties of vancomycin is a necessity for clinicians. Vancomycin is a concentration-independent antibiotic (also referred to as a "time-dependent" antibiotic), and there are factors that affect its clinical activity, including variable tissue distribution, inoculum size, and emerging resistance. This article reviews the pharmacokinetic and pharmacodynamic data related to vancomycin and discusses such clinical issues as toxicities and serum concentration monitoring.

Animals↗

PubMed2006

Pharmacodynamics: relation to antimicrobial resistance.

Antibiotic pharmacodynamics (PD) describes the impact of an antimicrobial agent on a target pathogen and is based on the drug's pharmacokinetics (PK) and microbiologic activity toward that pathogen, together with the pathogen's susceptibility to the drug. Patient or host factors play an important role in antibiotic PD by affecting drug PK and patient susceptibility to infection. The 3 PD parameters commonly used to predict antibiotic efficacy are (1) the ratio of maximum serum concentration to the minimum inhibitory concentration (MIC) (Cmax/MIC); (2) the ratio of the area under the plasma concentration versus time curve (AUC) versus MIC (AUC/MIC) and (3) the duration of the dosing interval that plasma concentrations exceed the MIC (T>MIC). The Cmax/MIC ratio has been shown to predict aminoglycoside efficacy, AUC/MIC best describes fluoroquinolone, glycopeptide, and ketolide efficacy, and T>MIC best describes the efficacy of beta-lactams and macrolides. Traditionally, PK and PD (PK/PD) parameters have been used to predict antibiotic efficacy, but there is now increasing interest in trying to use PK/PD parameters to minimize development of resistance. With respect to fluoroquinolone resistance, the "mutant selection window" hypothesis has been developed to describe how drug exposures below the mutant prevention concentration may create conditions for the selection of resistant bacterial strains. The AUC/MIC ratio has also been used to describe fluoroquinolone drug exposures associated with either increased or decreased risk of resistance emergence. The accessory gene regulator (agr) locus in Staphylococcus aureus-and particularly agr group II-has been associated with reduced susceptibility or resistance of S aureus to vancomycin. Recent experiments suggest that the AUC/MIC ratio may be used to identify vancomycin exposures associated with emergence of resistance in S aureus. More generally, AUC/MIC ratios may be additive, and combination therapies may represent 1 approach to lowering the emergence rate of bacterial resistance associated with antibiotic therapy. But, further work needs to be done before this conclusion can be verified.

Animals↗

PubMed2006

Pharmacodynamics: relation to antimicrobial resistance.

Antibiotic pharmacodynamics (PD) describes the impact of an antimicrobial agent on a target pathogen and is based on the drug's pharmacokinetics (PK) and microbiologic activity toward that pathogen, together with the pathogen's susceptibility to the drug. Patient or host factors play an important role in antibiotic PD by affecting drug PK and patient susceptibility to infection. The 3 PD parameters commonly used to predict antibiotic efficacy are (1) the ratio of maximum serum concentration to the minimum inhibitory concentration (MIC) (C(max)/MIC); (2) the ratio of the area under the plasma concentration versus time curve (AUC) versus MIC (AUC/MIC) and (3) the duration of the dosing interval that plasma concentrations exceed the MIC (T>MIC). The C(max)/MIC ratio has been shown to predict aminoglycoside efficacy, AUC/MIC best describes fluoroquinolone, glycopeptide, and ketolide efficacy, and T>MIC best describes the efficacy of beta-lactams and macrolides. Traditionally, PK and PD (PK/PD) parameters have been used to predict antibiotic efficacy, but there is now increasing interest in trying to use PK/PD parameters to minimize development of resistance. With respect to fluoroquinolone resistance, the "mutant selection window" hypothesis has been developed to describe how drug exposures below the mutant prevention concentration may create conditions for the selection of resistant bacterial strains. The AUC/MIC ratio has also been used to describe fluoroquinolone drug exposures associated with either increased or decreased risk of resistance emergence. The accessory gene regulator (agr) locus in Staphylococcus aureus--and particularly agr group II--has been associated with reduced susceptibility or resistance of S aureus to vancomycin. Recent experiments suggest that the AUC/MIC ratio may be used to identify vancomycin exposures associated with emergence of resistance in S aureus. More generally, AUC/MIC ratios may be additive, and combination therapies may represent 1 approach to lowering the emergence rate of bacterial resistance associated with antibiotic therapy. But, further work needs to be done before this conclusion can be verified.

Animals↗

PubMed2006

Etest synergy testing of clinical isolates of Staphylococcus aureus demonstrating heterogeneous resistance to vancomycin.

In search for potential synergistic antimicrobial combinations against Staphylococcus aureus isolates, which display heterogeneous resistance to vancomycin, we evaluated the activities of 21 various combinations involving ampicillin/sulbactam, daptomycin, gentamicin, linezolid, quinupristin/dalfopristin, rifampin, and vancomycin by Etest and time-kill methods. A number of combinations demonstrated either synergistic or additive effects against hGISA SA118 and GISA SA179. Agreement between the Etest and time-kill methods for detecting antimicrobial synergy ranged from 66.6% to 71.4%. The Etest method appears promising, and further investigations are warranted.

Anti-Bacterial Agents↗

PubMed2006

Pulsatile delivery of clarithromycin alone or in combination with amoxicillin against Streptococcus pneumoniae.

We evaluated pulsatile dosing of clarithromycin and amoxicillin alone or combined against Streptococcus pneumoniae with various susceptibilities. When combined, pulsatile amoxicillin with clarithromycin was superior to either 8- or 12-h dosing against the intermediate strain and was identical for the susceptible strain. Pulse dosing of antimicrobials warrants further investigation.

Amoxicillin↗

PubMed2006

Impact of Enterococcus faecalis on the bactericidal activities of arbekacin, daptomycin, linezolid, and tigecycline against methicillin-resistant Staphylococcus aureus in a mixed-pathogen pharmacodynamic model.

We inoculated an in vitro pharmacodynamic model simultaneously with clinical isolates of methicillin-resistant Staphylococcus aureus and an enterocin-producing enterococcus (vancomycin-resistant Enterococcus faecalis, ampicillin susceptible) at 7 log10 CFU/ml to examine enterocin effects and antimicrobial activity on staphylococci. The investigated antimicrobial regimens were 100 mg arbekacin every 12 h (q12h), 6 mg daptomycin per kg of body weight/day, 600 mg linezolid q12h, and 100 mg tigecycline q24h alone and in combination (daptomycin, linezolid, and tigecycline) with arbekacin. Simulations were performed in triplicate; bacterial quantification occurred over 48 h, and development of resistance was evaluated throughout. When we evaluated the impact of antimicrobial activity against S. aureus alone, daptomycin demonstrated bactericidal activity (>or=3 log10 CFU/ml kill), whereas arbekacin, linezolid, and tigecycline displayed bacteriostatic activities (<3 log10 CFU/ml kill). In the mixed-pathogen model, early and distinctive stunting of S. aureus growth was noted (1.5 log CFU/ml difference) in the presence of enterocin-producing E. faecalis compared to growth controls run individually (P=0.02). Most noteworthy was that in the presence of enterocin-producing E. faecalis, bactericidal activity was observed with arbekacin and tigecycline and with the addition of arbekacin to linezolid. Antagonism was noted for the combination of tigecycline and arbekacin against S. aureus in the presence of enterocin-producing E. faecalis. Our research demonstrates that the inhibitory effect of E. faecalis contributed significantly to its overall antimicrobial impact on S. aureus. This contribution was enhanced or improved compared to the activity of each antimicrobial alone. Further research is warranted to determine the impact of polymicrobial infections on antimicrobial activity.

Acetamides↗

PubMed2006

Tigecycline: first of a new class of antimicrobial agents.

Tigecycline is the first commercially available member of the glycylcyclines, a new class of antimicrobial agents. The glycylcyclines are derivatives of the tetracycline antibiotics, with structural modifications that allow for potent gram-positive, gram-negative, and anaerobic activity, including certain multidrug-resistant strains. The enhanced activity can be attributed to stronger binding affinity and enhanced protection against several mechanisms of resistance that affect other antibiotic classes such as tetracyclines. Tigecycline exhibits generally bacteriostatic action by reversibly binding to the 30S ribosomal subunit and inhibiting protein translation. In vitro activity has been demonstrated against multidrug-resistant gram-positive pathogens including methicillin-resistant and glycopeptide-intermediate and -resistant Staphylococcus aureus, as well as vancomycin-resistant enterococci. Multidrug-resistant gram-negative pathogens, such as Acinetobacter baumannii and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli, are typically highly susceptible to tigecycline. The drug also has displayed significant activity against many clinically important anaerobic organisms. This agent demonstrates a predictable pharmacokinetic profile and minimal drug interactions, and is generally well tolerated, with nausea being the most common adverse event. It was approved in June 2005 for the treatment of complicated skin and skin structure infections (SSSIs) and complicated intraabdominal infections. Currently, a limited number of broad-spectrum antimicrobials are available to combat multidrug-resistant organisms. The addition of new agents is essential to limiting the spread of these pathogens and improving outcomes in patients with these types of infections. Tigecycline has demonstrated promising results in initial in vitro and clinical studies for SSSIs and complicated intraabdominal infections; however, further clinical experience will clarify its role as a broad-spectrum agent.

Animals↗

PubMed2005

Evaluation of daptomycin activity against Staphylococcus aureus in an in vitro pharmacodynamic model under normal and simulated impaired renal function.

OBJECTIVES: Daptomycin is a lipopeptide antimicrobial that is primarily excreted by the kidney. We examined daptomycin bactericidal activity in an in vitro pharmacodynamic model (IVPM) under normal and simulated impaired renal function against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). METHODS: Two clinical strains MSSA-1199 and MRSA-494 were used in an IVPM. MICs and MBCs were determined according to CLSI. Daptomycin free concentrations were simulated that corresponded to dose regimens of 4, 6 and 8 mg/kg every 24 h at 8 h t(1/2) (Scheme I) and every 48 h at 30 h t(1/2) (Scheme II). In addition, we simulated daptomycin free concentrations corresponding to fractional dose regimens of 2, 3 and 4 mg/kg every 24 h at 30 h t(1/2) (Scheme III). The targeted C(max free)/MIC for 2, 3, 4, 6 and 8 mg/kg against MSSA-1199 ranged from 5.2 to 21.2. The targeted C(max free)/MIC for 2, 3, 4, 6 and 8 mg/kg against MRSA-494 ranged from 10.4 to 42.2. The targeted AUC(free)/MIC for Schemes I, II and III against MSSA-1199 ranged from 94 to 392. The targeted AUC(free)/MIC for Schemes I, II and III against MRSA-494 ranged from 188 to 581. Bactericidal activity and the potential for resistance were determined over 96 h. All models were completed in triplicate. RESULTS: Daptomycin MICs (MBCs) for MSSA-1199 and MRSA-494 were 0.5 (1.0) mg/L and 0.25 (0.25) mg/L, respectively. Daptomycin 6 and 8 mg/kg at both 8 and 30 h t(1/2) achieved 99.9% kill as early as 1 h. Daptomycin 4 mg/kg achieved 99.9% kill as early as 1 h when given at 8 and 30 h t(1/2) but was not maintained to an endpoint of 96 h (P > 0.05). CONCLUSIONS: Overall, there was no difference in kill noted for daptomycin regimens at 4, 6 and 8 mg/kg every 24 h at 8 h t(1/2) versus every 48 h at 30 h t(1/2). Fractional doses of daptomycin at 30 h t(1/2) were inferior to daptomycin regimens of 4, 6 and 8 mg/kg administered every 48 h (P = 0.03).

Anti-Bacterial Agents↗

PubMed2005

Clinical isolates of Staphylococcus aureus from 1987 and 1989 demonstrating heterogeneous resistance to vancomycin and teicoplanin.

Fifty isolates of Staphylococcus aureus, obtained during a multicenter clinical trial evaluating the efficacy of teicoplanin that was performed between 1987 and 1992, underwent glycopeptide susceptibility testing, and 2 isolates were found to be capable of growth on agar containing 4 or 8 mg/L of vancomycin. Both of these isolates were from patients that had received prolonged teicoplanin therapy and were deemed clinical failures. Extended susceptibility testing combined with mecA gene probing revealed that one isolate was susceptible to oxacillin, the other was resistant, and both were susceptible to a variety of nonglycopeptide agents. Population analyses revealed heterogeneous vancomycin- and teicoplanin-susceptibility profiles. Both strains were differentiated from recent glycopeptide intermediately resistant Staphylococcus aureus isolates by pulse-field analysis and by the fact that the resistance phenotype was stable to multiple serial passages. To our knowledge, this is the earliest report of S. aureus clinical isolates having reduced vancomycin and teicoplanin susceptibility.

Analysis of Variance↗

PubMed2005

Pharmacodynamics of cefepime alone and in combination with various antimicrobials against methicillin-resistant Staphylococcus aureus in an in vitro pharmacodynamic infection model.

Treatment options for gram-positive resistant bacteria are limited; therefore, efforts to evaluate therapy options in the critical care population are warranted. Cefepime has broad-spectrum activity against gram-negative and gram-positive organisms. We have previously demonstrated that the combination of cefepime with vancomycin, linezolid, or quinupristin-dalfopristin had an improved or enhanced effect against methicillin-resistant Staphylococcus aureus (MRSA). We investigated various regimens of cefepime alone and in combination against two clinical MRSA isolates (R2481 and R2484) in an established in vitro pharmacodynamic model. Human pharmacokinetic regimen simulations were as follows: cefepime, 2 g every 8 h (q8h) (C8) and 12 h (C12), continuous-infusion 2-g loading dose followed by 4 g alone or in combination with gentamicin and tobramycin (1.0 or 2.0 [G1 and G2 or TB1 and TB2] mg/kg of body weight q12h and 5.0 [G5 or TB5] mg/kg q24h), arbekacin (ARB) (100 mg q12h), linezolid (LIN) (600 mg q12h), tigecycline (TIG) (100 mg q24h), or daptomycin (DAP) (6 mg/kg q24h) for 48 h. The MICs for cefepime, gentamicin, tobramycin, ARB, LIN, TIG, and DAP for the two clinical MRSA isolates (R2481 and R2484) were 4 and 4, 0.25 and 0.5, 128 and 0.5, 0.5 and 0.125, 2 and 4, 0.25 and 0.25, and 0.0625 and 0.125 microg/ml, respectively. At 48 h, combinations of C12 and C8 plus ARB, G1, or G5 (range, -2.05- to -4.32-log(10) decrease) demonstrated enhanced lethality against R2481 (resistant to tobramycin) (P < 0.05). A similar relationship was demonstrated against R2484 with cefepime plus ARB, gentamicin, or tobramycin (range, -2.05- to -3.63-log(10) decrease) (P < 0.05). A 99.9% kill was achieved with cefepime plus aminoglycoside combinations as early as 2 h and maintained throughout the 48-h period. TIG was antagonistic when combined with C12 against both isolates. DAP alone achieved 99.9% kill for up to 48 h for both isolates and was the most active agent against R2481 and R2484 (-2.89- and -3.61-log(10) decrease at 48 h); therefore, combination therapy did not enhance lethality. Overall, the most potent combinations noted were cefepime in combination with low- and high-dose aminoglycosides. Further investigations with combination therapies are warranted.

Anti-Bacterial Agents↗

PubMed2005

Short-course gentamicin in combination with daptomycin or vancomycin against Staphylococcus aureus in an in vitro pharmacodynamic model with simulated endocardial vegetations.

The ability to maximize bactericidal activity while minimizing toxicity is a therapeutic goal in the treatment of infective endocarditis. We evaluated the impact of administering short-course regimens of gentamicin in combination with daptomycin or vancomycin against one methicillin-susceptible (MSSA 1199) and one methicillin-resistant (MRSA 494) Staphylococcus aureus isolate using an in vitro pharmacodynamic model with simulated endocardial vegetations over 96 h. Human therapeutic dosing regimens for daptomycin (6 and 8 mg/kg of body weight), vancomycin, and gentamicin were simulated. Short-course combination regimens involving gentamicin were administered either as a single 5-mg/kg dose or three 1-mg/kg doses for only the first 24 h and compared to the regimens administered for the full 96-h duration. For all experiments, physiologic conditions of albumin, calcium, and pH were simulated. Both regimens of daptomycin achieved 99.9% kill by 32 h and maintained bactericidal activity against both isolates, which was significantly different from vancomycin, which displayed bacteriostatic activity (P < 0.05). The effects of all short-course regimens of gentamicin were equal to those of the full-duration regimens in combination with daptomycin. Adding three doses of gentamicin (1 mg/kg) to daptomycin resulted in enhancement and bactericidal activity at 24 h against both MRSA and MSSA. The addition of a single dose of gentamicin (5 mg/kg) enhanced or improved the activity of daptomycin and resulted in early bactericidal activity at 4 h against both isolates. The addition of three doses of gentamicin (1 mg/kg) did not improve the activity of vancomycin. However, the addition of a single 5-mg/kg dose of gentamicin to vancomycin resulted in early enhancement at 4 h and 99.9% kill at 32 h for MRSA. These results suggest that a single high dose of gentamicin in combination with daptomycin or vancomycin may be of utility to maximize synergistic and bactericidal activity and minimize toxicity. Further investigation is warranted.

Anti-Bacterial Agents↗

PubMed2005

Epidemiology, treatment, and outcomes of nosocomial bacteremic Staphylococcus aureus pneumonia.

OBJECTIVE: To describe outcomes associated with nosocomial bacteremic Staphylococcus aureus pneumonia (NBSAP) and to determine whether delay in adequate antimicrobial treatment is a risk factor for negative clinical and microbiological outcomes. DESIGN: Retrospective cohort analysis. SETTING: This study was conducted at Detroit Receiving Hospital and University Health Center, which is a 279-bed, level 1 trauma center in Detroit, MI. PATIENTS: All episodes of NBSAP identified from January 1, 1999, to April 30, 2004. RESULTS: Of 206 patients identified over a 5-year period with positive blood and respiratory cultures for S aureus, 60 patients met strict clinical, radiographic, and microbiological criteria for NBSAP. The overall mean (+/- SD) characteristics include the following: age, 55.5 +/- 15.0 years; acute physiology and chronic health evaluation II score, 20 (range, 3 to 41); ICU at onset, 93.3%; mechanical ventilation, 83.3%; length of stay (LOS) prior to NBSAP, 9 days (range, 2 to 81 days); methicillin-resistant S aureus (MRSA) rate, 70%; and all-cause hospital and infection-related mortality (IRM), 55.5% and 40.0%, respectively. Overall, S aureus pneumonia developed late in the patient's hospital stay in ICU patients previously receiving mechanical ventilation and was associated with high crude mortality and IRM rates. No significant difference existed with respect to mortality or infection-related LOS between patients who had received early appropriate antibiotic therapy vs those who had received delayed appropriate antibiotic therapy at the onset of pneumonia or in patients with methicillin-sensitive S aureus pneumonia vs those with MRSA pneumonia. CONCLUSION: IRM from NBSAP is high, and standard therapies evaluated at the time of this study resulted in poor clinical outcomes. Delayed therapy was not found to be a predictor of adverse outcomes; however, this lack of ability to detect a difference may be a product of small sample size. These findings suggest that newer agents with enhanced clinical activity in NBSAP are needed and that these should be evaluated in a real-world setting, where outcomes of the most ill patients can be assessed.

Adult↗