Sharon Schooley

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 μg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 μg/mL), Bacteroides fragilis (MIC 2.0 μg/mL), and Peptostreptococcus magnus (MIC 1.0 μg/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 μg/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 μg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (⩾6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 μg/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 ⩾4.0 μg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.

Development of a standardized susceptibility test for Campylobacter with quality-control ranges for ciprofloxacin, doxycycline, erythromycin, gentamicin, and meropenem

A standardized agar dilution susceptibility testing method was developed for Campylobacter that consisted of testing on Mueller-Hinton medium supplemented with 5% defibrinated sheep blood in an atmosphere of 10% CO2, 5% O2, and 85% N2. Campylobacter jejuni ATCC 33560 was identified as a quality-control (QC) strain. Minimal inhibitory concentration (MIC) QC ranges were determined for two incubation time/temperature combinations: 36 degrees C for 48 hr and 42 degrees C for 24 hr. Quality-control ranges were determined for ciprofloxacin, doxycycline, erythromycin, gentamicin, and meropenem. For all antimicrobial agents tested at both temperatures, 95-100% of the QC MIC results fell within recommended QC ranges. Twenty-one Campylobacter clinical isolates, encompassing five species of Campylobacter (C. jejuni, C. coli, C. jejuni, subsp. doylei, C. fetus, and C. lari) were tested in conjunction with the C. jejuni QC strain. While C. jejuni and C. coli could be reliably tested under both test conditions, growth of C. jejuni subsp. doylei, C. fetus, and C. lari isolates was inconsistent when incubated at 42 degrees C. Therefore, it is recommended that these species only be tested at 36 degrees C.

Urinary bactericidal activity of single doses (250, 500, 750 and 1000 mg) of levofloxacin against fluoroquinolone-resistant strains of Escherichia coli.

Increasing resistance to fluoroquinolones in uropathogens has become a clinical concern. The purpose of this study was to analyse the urinary bactericidal activity (UBA) of levofloxacin against fluoroquinolone-resistant strains of Escherichia coli. Ten healthy adult subjects (aged 23-60 years) received single doses of levofloxacin (250, 500, 750 and 1000 mg) and then blood and urine samples were collected in intervals (0-1.5, 1.5-4, 4-8, 8-12 and 12-24h) over 24h. Both serum and urine concentrations were measured by a validated high-performance liquid chromatography assay. Bactericidal titres in urine were determined against E. coli isolates with minimum inhibitory concentrations of 0.125, 4, 8, 16, 32 and 64microg/mL for levofloxacin. The mean serum pharmacokinetic parameters for these doses of levofloxacin were similar to previously published values. The mean peak urinary concentrations (0-1.5h) were 210, 347, 620 and 536microg/mL for the 250, 500, 750 and 1000 mg dose, respectively. Each dose of levofloxacin exhibited early (0-1.5h time period) bactericidal activity in urine in virtually all subjects against E. coli strains with MICs<or=32microg/mL. Moreover, high-dose (750 mg and 1000 mg) levofloxacin provided prolonged (8-12h time period) bactericidal activity in 9/10 subjects against E. coli isolates with MICs up to 32microg/mL. In summary, this ex vivo investigation found that high-dose levofloxacin can produce early and prolonged UBA against fluoroquinolone-resistant strains of E. coli. Patient outcome studies are needed to determine whether these findings translate into clinical cures.

Bactericidal Activities of Methoxyfluoroquinolones Gatifloxacin and Moxifloxacin against Aerobic and Anaerobic Respiratory Pathogens in Serum

ABSTRACT 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 μg/ml), Peptostreptococcus micros (MIC = 0.25 μg/ml), and F. nucleatum (MIC = 0.5 μg/ml) and 24 h against H. influenzae (MIC = 0.03 μg/ml), Staphylococcus aureus (MIC = 0.125 μg/ml), Peptostreptococcus magnus (MIC = 0.125 μg/ml), and Prevotella melaninogenica (MIC = 0.5 μg/ml). Moxifloxacin exhibited bactericidal activity for a median of 24 h against Streptococcus pneumoniae (MIC = 0.125 μg/ml), H. influenzae (MIC = 0.015 μg/ml), Staphylococcus aureus (MIC = 0.06 μg/ml), F. nucleatum (MIC = 0.5 μg/ml), Prevotella melaninogenica (MIC =0.5 μg/ml), Peptostreptococcus magnus (MIC = 0.125 μg/ml), and Peptostreptococcus micros (MIC = 0.25 μg/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.

Prevention of Recurrent Vaginal Candidiasis with Weekly Terconazole Cream

OBJECTIVE: To investigate the prophylactic use of weekly terconazole 0.8% cream to prevent recurrent episodes of candidal vaginitis. DESIGN: Women with a documented history of recurrent candidal vaginitis (≥4 recurrences/y) were enrolled into a secondary prevention trial. None of these women were HIV positive, pregnant, diabetic, or immunosuppressed. Patients were initially treated for a symptomatic episode of candidal vaginitis and then started on weekly applications of terconazole 0.8% cream for 26 weeks. These women were then followed for an additional 26 weeks after therapy. SETTING: A university-affiliated medical school. PARTICIPANTS: The study population consisted of 22 healthy women aged 19–41 years. MAIN OUTCOME MEASURES: Patients were interviewed by phone each week concerning symptoms and compliance. They were also reminded to notify the study investigators any time vaginal symptoms of candidiasis occurred. Patients were examined whenever they developed vaginal symptoms and were treated on the basis of microscopic and culture results. RESULTS: Ten patients had 14 symptomatic cases of vaginitis during the prophylactic phase of the study, but Candida spp. were isolated during only 4 of these episodes. One episode was due to bacterial vaginosis and no pathogenic organisms were found in 9 of these cases. Eighteen of the 20 patients who completed the prophylactic phase were followed after therapy and 14 (78%) of these patients had a current case of candidal vaginitis. This incidence of infection was statistically higher than that observed during the treatment period (p < 0.001). CONCLUSIONS: Weekly applications of terconazole 0.8% cream were effective in preventing recurrent episodes of candidal vaginitis and were well tolerated.

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.

Outpatient intravenous antibiotic therapy compared with oral linezolid in patients with skin and soft tissue infections: A pharmacoeconomic analysis

Background: In patients with skin or soft tissue infections that do not require hospitalization, the choice between oral therapy and outpatient parenteral antimicrobial therapy (OPAT) depends on several factors. Oral linezolid is an effective antibiotic for skin or soft tissue infections and may be a suitable alternative to OPAT in this patient population. Objective: The aim of the study was to analyze the potential cost-effectiveness of oral linezolid compared with OPAT in adult patients with moderately severe skin or soft tissue infections referred to a hospital-based infusion center. Methods: Twenty patients with skin or soft tissue infections referred to an infusion center for OPAT were enrolled into a prospective, randomized, pilot clinical trial comparing OPAT to oral linezolid. Patients received their prescribed intravenous antibiotic (normal care group) or oral linezolid (600 mg every 12 hours) for a duration decided by their primary or emergency department physician and followed up for 4 weeks. Outcome measures recorded for the economic analysis included all clinic, emergency department, wound care, and infusion center visits as well as hospitalizations. Any additional medical care, including the number of doses of all antibiotics, was documented for each subject. The costs of care were standardized using Medicare reimbursement payments. Results: Most infections in each group involved cellulitis of the abdomen or the lower extremities. In the 10 patients who received OPAT, 2 received no additional antibiotics, 4 received additional oral therapy, and 4 were subsequently hospitalized due to lack of improvement. In the 10 patients who received linezolid, 9 were cured and 1 patient received additional oral antibiotics. None of these patients were hospitalized, but 3 received outpatient wound care. The costs for care in this pilot study, based on Medicare reimbursement payments, would average

Comparative serum bactericidal activity of clarithromycin and azithromycin against macrolide-sensitive and resistant strains of Streptococcus pneumoniae.

1855 in the OPAT group compared with

Pharmacodynamic Activity of Five Oral Cephalosporins Against Haemophilus influenzae

1038 in patients who received oral linezolid. Conclusions: Oral linezolid can be a cost-effective alternative to OPAT in patients with skin or soft tissue infections, but its use could shift a significant amount of cost for care to the patient.

Serum Bactericidal Activity of Extended-Release Clarithromycin Against Macrolide-Resistant Strains of Streptococcus pneumoniae

The serum pharmacodynamics of clarithromycin and azithromycin were studied against isolates of S. pneumoniae, including efflux resistant (M. phenotype) strains, by analyzing their serum bactericidal activity (SBA) over time. Normal healthy subjects were given a single 500 mg oral dose of these macrolides and serum samples were collected over 12 hrs. Paired isolates with MICs ranging from 0.25 ug/ml to 8.0 ug/ml were analyzed. Prolonged (at least 6 hrs) SBA was observed with clarithromycin for strains with MICs < or = 2.0 ug/ml. No SBA was observed in strains with MICs >or = 4.0 ug/ml. Azithromycin exhibited SBA for at least 6 hrs for strains up to a MIC = 0.5 ug/ml. No SBA was observed for isolates with MICs > or = 1.0 ug/ml. In contrast to azithromycin, clarithromycin exhibited SBA for at least one-half of its normal dosing interval against S. pneumoniae strains well above its current susceptibility breakpoint concentration of 0.25 microg/ml. These findings may have relevance to the ongoing debate as to the appropriate susceptibility breakpoints for the newer macrolides.