Biomedical subjects

Gary E Stein

Publications and source records attributed to Gary E Stein.

12 recordsLinked to original sources

PubMed2007

Human serum activity of telithromycin, azithromycin and amoxicillin/clavulanate against common aerobic and anaerobic respiratory pathogens.

Telithromycin is a new ketolide antimicrobial with a good in vitro activity against both aerobic and anaerobic respiratory pathogens. In this study, we evaluated the antibacterial activity over time of telithromycin (800mg), azithromycin (500mg), and amoxicillin/clavulanate (875/125mg) in serum following single oral doses of these agents to 10 healthy subjects. Inhibitory and bactericidal titers were determined at 2, 6, 12, and 24h after each dose and the median titer was used to determine antibacterial activity. Against two azithromycin-resistant strains of Streptococcus pneumoniae, both telithromycin (MIC=0.25 and 0.5 microg/mL) and amoxicillin/clavulanate exhibited inhibitory and cidal activity for at least 6h. All three antibiotics provided prolonged (>or=12h) inhibitory activity against strains of Hemophilus influenzae (telithromycin MIC=4.0 microg/ml). Both telithromycin and amoxicillin/clavulanate exhibited rapid and prolonged inhibitory activity (>or=12h) against each of the anaerobes studied (Finegoldia [Peptostreptococcus] magna Peptostreptococcus micros, Prevotella bivia, and Prevotella melaninogenica). Moreover, both agents provided bactericidal activity against both Prevotella species. In this ex vivo pharmacodynamic study, we found that telithromycin provided rapid and prolonged antibacterial activity in serum against macrolide-resistant strains of S. pneumoniae, beta-lactamase-positive and -negative strains of H. influenzae, and common respiratory anaerobic pathogens. These findings suggest that telithromycin could have clinical utility in the treatment of community-acquired mixed aerobic-anaerobic respiratory tract infections, including chronic sinusitis and aspiration pneumonia.

Administration, Oral↗

PubMed2006

Tigecycline: a critical analysis.

Tigecycline (GAR-936) is the first glycylcycline antibiotic to be approved by the US Food and Drug Administration (FDA). The drug overcomes the 2 major resistance mechansisms of tetracycline: drug-specific efflux pump acquisition and ribosomal protection. Tigecycline is active against many gram-positive and -negative organisms, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate and -resistant enterococci, and extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. It is also active against many anaerobic bacteria, as well as atypical pathogens, including rapidly growing, nontuberculous mycobacteria. Tigecycline is concentrated in cells and is eliminated primarily via biliary excretion. Diminished renal function does not significantly alter its systemic clearance. Furthermore, tigecycline does not interfere with common cytochrome P450 enzymes, making pharmacokinetic drug interactions uncommon. It provides parenteral therapy for complicated skin/skin-structure and intra-abdominal infections. The only prominent adverse effects are associated with tolerability, most notably nausea and vomiting. Tigecycline will be most useful as empirical therapy for polymicrobial infections, especially in cases in which deep tissue penetration is needed or in which multidrug-resistant pathogens are suspected.

Anti-Bacterial Agents↗

PubMed2006

Fluoroquinolones and anaerobes.

The usefulness of fluoroquinolones for the treatment of mixed aerobic and anaerobic infections has been investigated since these agents started being used in clinical practice. Newer compounds have increased in vitro activity against anaerobes, but clinically relevant susceptibility breakpoints for these bacteria have not been established. Pharmacodynamic analyses and corroboration by new data from clinical trials have enhanced our knowledge concerning the use of fluoroquinolones to treat selective anaerobic pathogens. These studies suggest that newer agents could be useful in the treatment of several types of mixed aerobic and anaerobic infections, including skin and soft-tissue, intra-abdominal, and respiratory infections. The major concerns with expanding the use of fluoroquinolones to treat anaerobic infections have been reports of increasing resistance in Bacteroides group isolates and the impact of these antibiotics on the incidence of Clostridium difficile-associated disease.

Anti-Bacterial Agents↗

PubMed2005

Safety of newer parenteral antibiotics.

Several parenteral antimicrobials have been introduced into clinical practice over the course of the last decade. Some of these agents (e.g., linezolid, daptomycin, and tigecycline) are prototypes of new classes of compounds. In comparative clinical trials, these newer anti-infectives have been shown to be safe and to have low rates of discontinuation by patients. However, long-term use has revealed unique toxicities associated with the use of some of these drugs. The adverse events and potential drug interactions associated with the use of these antibiotics are variable and require familiarity with the safety profile of each drug. It is especially important that clinicians be able to recognize serious adverse events associated with the use of specific drugs, because most of the adverse events can be readily reversed by cessation of therapy.

Anti-Bacterial Agents↗

PubMed2005

Pharmacokinetics and pharmacodynamics of linezolid in obese patients with cellulitis.

BACKGROUND: Linezolid is an oxazolidinone antimicrobial with excellent oral bioavailability and tissue penetration and is active against multidrug-resistant skin/soft tissue pathogens. OBJECTIVE: To study the pharmacokinetics and antibacterial activity of linezolid against selective skin/soft tissue pathogens in obese patients. METHODS: We obtained multiple serum samples from 7 obese patients (>50% over their calculated ideal body weight) receiving oral linezolid 600 mg every 12 hours for treatment of cellulitis. Following a minimum of 3 doses, serum concentrations of linezolid were measured in each subject prior to (trough) and 1 and 6 hours after a dose. These samples were then tested against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (linezolid minimum inhibitory concentrations [MICs] 1.0, 2.0, 4.0 microg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 microg/mL), Bacteroides fragilis (MIC 2.0 microg/mL), and Peptostreptococcus magnus (MIC 1.0 microg/mL). Serum inhibitory titers (SITs) and bactericidal titers (SBTs) were measured at each time point, and the median activity for these 7 patients was calculated. RESULTS: Mean linezolid serum concentrations were 4.2, 12.3, and 7.2 microg/mL at these respective time points. Median SITs for 12 hours (100% of the dosing interval) were observed against each organism with the exception of the least susceptible strain of MRSA (MIC 4.0 microg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (> or =6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 microg/mL) as well as the strain of VRE and P. magnus. CONCLUSIONS: Serum concentrations of oral linezolid in this patient population were diminished compared with those of healthy volunteers, but still provided prolonged serum inhibitory activity against common pathogens associated with skin/soft tissue infections. One treatment concern would be an obese patient receiving oral linezolid who was infected with a less susceptible (MIC > or =4.0 microg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.

Acetamides↗

PubMed2005

Antimicrobial resistance in the hospital setting: impact, trends, and infection control measures.

The growing threat posed by antibiotic-resistant pathogens is a major challenge for infectious disease practitioners and public health officials. In recent years, the prevalence of resistance among key bacterial pathogens, including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae, and Enterococcus sp, has increased at an alarming rate. The impact of antimicrobial resistance is manifold and can ultimately lead to treatment failure and increased morbidity and mortality. To control the spread of resistance and subsequent impact, a multifaceted approach is warranted. Awareness and surveillance of antimicrobial resistance, prudent use of antibiotics, and compliance with infection control techniques may help contain the emergence and spread of resistant organisms.

Anti-Infective Agents↗

PubMed2004

Urinary concentrations and bactericidal activities of newer fluoroquinolones in healthy volunteers.

Eleven healthy male subjects participated in a crossover study to compare the urine concentrations and bactericidal activities of newer fluoroquinolones against common uropathogens. Each volunteer received a single oral dose of gatifloxacin (400 mg), levofloxacin (250 mg), moxifloxacin (400 mg) and trovafloxacin (200 mg), and a urine sample was obtained at 2, 6, 12 and 24 h after the dose. Urine concentrations were highest with gatifloxacin and levofloxacin and lowest with trovafloxacin. Each drug concentration was studied against a levofloxacin susceptible and moderately-susceptible strain of Escherichia coli (minimal inhibitory concentration, MICs: 0.125 and 4 mg/l), K. pneumoniae (MICs: 0.125 and 4 mg/l), Pseudomonas aeruginosa (MICs: 0.5 and 4 mg/l) and Enterococcus faecalis (MICs: 0.25 and 4 mg/l). The duration of urine bactericidal activity (UBA) was based upon the median bactericidal titre at each time period. Both gatifloxacin and levofloxacin exhibited prolonged (> or = 6 h) UBA against all of the study isolates. Moxifloxacin exhibited prolonged UBA against both isolates of E. coli, K. pneumoniae and E. faecalis but not against either strain of P. aeruginosa. Prolonged UBA was not observed for trovafloxacin against the moderately-susceptible strains with the exception of E. faecalis. Furthermore, UBA was not observed for trovafloxacin against the susceptible strain of P. aeruginosa. Although these newer fluoroquinolones exhibited similar in vitro activity against these uropathogens, only those compounds with the highest urinary concentrations (gatifloxacin and levofloxacin) produced prolonged UBA against both strains of P. aeruginosa. The findings from this study suggest that both microbiological activity and urinary concentrations are important parameters to consider when choosing a fluoroquinolone for empirical treatment of urinary tract infections (UTIs).

Adult↗

PubMed2003

Serum bactericidal activity of the methoxyfluoroquinolones gatifloxacin and moxifloxacin against clinical isolates of Staphylococcus species: are the susceptibility breakpoints too high?

Healthy volunteers received a single dose of gatifloxacin and moxifloxacin (400 mg each), and serum samples were obtained from these volunteers over a 24-h period. Prolonged (> or =12 h) serum bactericidal activity (SBA) was observed for both agents against staphylococcal isolates with minimum inhibitory concentrations (MICs) of gatifloxacin of < or =0.5 mug/mL. In strains with gatifloxacin MICs of 1.0 mug/mL, SBA was observed for < or =6 h, and, for isolates with gatifloxacin MICs of 2.0 mug/mL, little or no SBA was observed for either drug. The relative lack of SBA against less susceptible strains of staphylococci suggests that the current susceptibility breakpoint concentration (MIC, 2.0 mug/mL) for these methoxyfluoroquinolones against Staphylococcus is too high.

Adult↗

PubMed2003

Review of the in vitro activity and potential clinical efficacy of levofloxacin in the treatment of anaerobic infections.

The activity of levofloxacin against aerobic bacteria has been well documented both in vitro and clinically, but its anaerobic activity has been infrequently studied. This new fluoroquinolone exhibits good in vitro activity (MIC(S) < or =2.0 microg/mL) against many anaerobic pathogens associated with acute sinusitis, bite wounds, and other soft-tissue infections. It is less active against Bacteroides fragilis (MIC (90)=2-4 microg/mL ) and has poor inhibitory activity against non-fragilis B. fragilis group species that are associated with gastrointestinal and genitourinary tract infections. Levofloxacin does not antagonize the in vitro activity of clindamycin and metronidazole and often provides additive or synergistic activity against anaerobic bacteria with these agents. In pharmacodynamic models, levofloxacin exhibits rapid bactericidal activity at 2-4 times the MIC of anaerobic bacteria. Prolonged killing is observed when the area-under-the concentration-time-curve to MIC ratio is greater than 40. In clinical efficacy trials, levofloxacin has been effective in the treatment of patients with gynecologic, skin and skin-structure, and bone infections involving anaerobic pathogens. Both micro-biologic and pharmacodynamic studies support further evaluations of levofloxacin in the treatment of selective mixed aerobic/anaerobic infections.

Journal Article↗

PubMed2003

Bactericidal activities of methoxyfluoroquinolones gatifloxacin and moxifloxacin against aerobic and anaerobic respiratory pathogens in serum.

Gatifloxacin (Bristol-Myers Squibb) and moxifloxacin (Bayer) are new methoxyfluoroquinolones with broad-spectrum activity against aerobic and anaerobic pathogens of the respiratory tract. In this investigation, we analyzed the bactericidal activity in serum over time of these antimicrobials against three aerobic (Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus) and four anaerobic (Peptostreptococcus micros, Peptostreptococcus magnus, Fusobacterium nucleatum, and Prevotella melaninogenica) bacteria associated with respiratory tract infections. Serum samples were obtained from 11 healthy male subjects following a single 400-mg oral dose of gatifloxacin and moxifloxacin. These samples were collected prior to and at 2, 6, 12, and 24 h after the dose of each drug. Gatifloxacin exhibited bactericidal activity for a median of 12 h against Streptococcus pneumoniae (MIC = 0.5 micro g/ml), Peptostreptococcus micros (MIC = 0.25 micro g/ml), and F. nucleatum (MIC = 0.5 micro g/ml) and 24 h against H. influenzae (MIC = 0.03 micro g/ml), Staphylococcus aureus (MIC = 0.125 micro g/ml), Peptostreptococcus magnus (MIC = 0.125 micro g/ml), and Prevotella melaninogenica (MIC = 0.5 micro g/ml). Moxifloxacin exhibited bactericidal activity for a median of 24 h against Streptococcus pneumoniae (MIC = 0.125 micro g/ml), H. influenzae (MIC = 0.015 micro g/ml), Staphylococcus aureus (MIC = 0.06 micro g/ml), F. nucleatum (MIC = 0.5 micro g/ml), Prevotella melaninogenica (MIC =0.5 micro g/ml), Peptostreptococcus magnus (MIC = 0.125 micro g/ml), and Peptostreptococcus micros (MIC = 0.25 micro g/ml). The results from this pharmacodynamic study suggest that these fluoroquinolones would have prolonged killing activity against these organisms in vivo and may have clinical utility in the treatment of mixed aerobic-anaerobic respiratory tract infections.

Adult↗

PubMed2002

Viral load as a surrogate end point in HIV disease.

OBJECTIVE: To examine the role of viral load as a surrogate end point for HIV disease progression and death. DATA SOURCES: A MEDLINE search was conducted for the years 1990-March 2001. In addition, relevant articles were cross-referenced to screen for additional information. STUDY SELECTION AND DATA EXTRACTION: Data regarding the validity of viral load as a surrogate end point for disease progression or death are cited. Emphasis was placed on randomized, controlled trials, but descriptive studies are also included. DATA SYNTHESIS: Recently, viral load has emerged as an important biomarker for monitoring HIV disease and antiretroviral therapy. Both baseline viral load and changes in viral load with time predict HIV disease progression and death. In fact, disease progression increases consistently once viral load exceeds 10,000 copies/mL, and AIDS and death primarily occur in patients with viral loads > 100,000 copies/mL. Changes that occur in viral load after initiation of antiretroviral therapy, however, do not fully explain the entire treatment effect. Also, separate comparisons of antiretroviral regimens may demonstrate similar differences in viral load changes but not similar differences in disease progression. CONCLUSIONS: Viral load is an important monitoring parameter for HIV disease and antiretroviral therapy. However, changes in viral load do not explain the entire clinical improvement that occurs after initiation of therapy. Although viral load is a clinically important surrogate end point for HIV disease, it cannot fully account for all associated treatment effects.

Antiretroviral Therapy, Highly Active↗

PubMed2002

Serum bactericidal activity of extended-release clarithromycin against macrolide-resistant strains of Streptococcus pneumoniae.

STUDY OBJECTIVE: To investigate the serum bactericidal activity (SBA) over time of extended-release clarithromycin against moderately resistant strains of Streptococcus pneumoniae. DESIGN: Prospective, single-dose pharmacodynamic study. SETTING: University-affiliated research center. SUBJECTS: Eleven healthy male volunteers. INTERVENTION: All volunteers received a single dose of extended-release clarithromycin as two 500-mg tablets, and blood samples were obtained at 0, 2, 6, 12, and 24 hours after administration of the dose. MEASUREMENTS AND MAIN RESULTS: For each blood sample, a serum bactericidal titer (SBT) was determined against S. pneumoniae strains with minimum inhibitory concentrations (MICs) of 0.5, 1.0, 2.0, 4.0, and 8.0 microg/ml to clarithromycin. The median SBT was determined for each time period. The extended-release formulation of clarithromycin exhibited SBA for 24 hours against pneumococcal strains with MICs of 0.5, 1.0, and 2.0 microg/ml. No SBA was observed against isolates with MICs of 4.0 or 8.0 microg/ml. CONCLUSION: The extended-release formulation of clarithromycin, taken once/day, will provide SBA for 24 hours against strains of S. pneumoniae with MICs of 2.0 microg/ml or less.

Adult↗