Daniel H. Havlichek

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.

Cardiovascular Manifestations in Human Immunodeficiency Virus-Infected Patients

Human immunodeficiency virus (HIV) is now a pandemic. It afflicts multiple organs, including the cardiovascular system. This occurs by direct invasion as well as opportunistic infections complicating acquired immunodeficiency syndrome. The presence of newer highly active antiretroviral therapy has led to longer survival of patients infected with HIV, but the cardiac abnormalities related to HIV have remained less well characterized. It is now evident that cardiac involvement in patients with acquired immunodeficiency syndrome is relatively common. This includes coronary artery disease, dilated cardiomyopathy, pericardial effusion, pulmonary hypertension, and ill effects of highly active antiretroviral therapy in the form of lipodystrophy, lipoatrophy, and dyslipidemia. In fact, HIV can now be viewed as a potential risk factor for coronary artery disease, and the dilemma facing clinicians is how to quantify this risk. Awareness of accelerated coronary artery disease and dilated cardiomyopathy is critical to implement preventive measures early in the course of HIV. However, better guidelines are still needed on the basis of prospective randomized controlled studies involving large populations. In conclusion, this review describes cardiac abnormalities associated with HIV, including possible molecular mechanisms. The co-morbid sequelae, their presentation, and pharmacologic management are also discussed.

Age-related hepatitis B seroconversion rates in health care workers

BACKGROUND Protective hepatitis titers are reported for more than 90% of healthy adults who received three intradeltoid injections of vaccine. Some factors that influence seroconversion rates include age, sex, and presence of chronic diseases. METHODS Because of work-related factors that placed them at risk of acquiring hepatitis B, 112 employees, who ranged in age from 20 to 70 years with a mean age of 39.2 years, completed the hepatitis B vaccination series between 1986 and 1993. All participants received three vaccinations. RESULTS Hepatitis B surface antibody did not develop in 16 of 112 recipients (14.2%, 95% CI, 7.6% to 20.8%). Race, sex, and duration to antibody titer did not affect rates of seroconversion. Age greater than 50 years was associated with significantly decreased seroconversion rates (64.7%, 95% CI, 42.0% to 87.4%) compared with seroconversion rates of those younger than 50 years of age (89.5%, 95% CI 83.3% to 95.7%, p = 0.02). CONCLUSIONS Our results indicate that when a hepatitis B immunization program is implemented, seroconversion rates are lower than published rates for healthy adults and adolescents. We recommend that seroconversion data from immunization programs for employees at risk for hepatitis B be reviewed and that postimmunization testing be considered to ensure adequate protection for those employees at highest risk for nonconversion.

The new macrolide antibiotics: Azithromycin and clarithromycin

Azithromycin (Zithromax) and clarithromycin (Biaxin Filmtabs) are new macrolide antibiotics with several advantages over erythromycin. Azithromycin has an expanded spectrum against gram-negative bacilli. Clarithromycin is more active than erythromycin against gram-positive cocci; combination with its 14-hydroxy metabolite enhances its antimicrobial activity. These new agents penetrate well into tissues and concentrate in macrophages and polymorphonuclear leukocytes. They offer improved bioavailability and an extended half-life. The high tissue-to-serum level and extended elimination half-life of azithromycin allow for once-daily dosing and short-course therapy. Clarithromycin and 14-hydroxyclarithromycin maintain high serum levels and tissue-to-serum concentrations. Both of these new agents have been effective in streptococcal pharyngitis, acute sinusitis, acute lower respiratory tract infections, skin and soft-tissue infections, and sexually transmitted diseases. A single dose of azithromycin is effective for genital chlamydial infections. Adverse reactions to these agents have usually been mild and have not included serious organ toxicity. In clinical trials, the rate of premature discontinuation of therapy has been less than observed with erythromycin. Azithromycin and clarithromycin should be used according to the current guidelines of the Food and Drug Administration; their future role will be determined by ongoing laboratory and clinical evaluations.

Infectious Diseases Subspecialty: Declining Demand Challenges and Opportunities

A significant decline in the number of applicants for infectious diseases fellowship positions has been noted in recent years. Most reduction is seen among international medical graduates. Reasons for the decline are speculated upon and possible solutions are offered.

Tissue penetration and antimicrobial activity of standard- and high-dose trimethoprim/sulfamethoxazole and linezolid in patients with diabetic foot infection

OBJECTIVES The purpose of this study was to conduct a pharmacokinetic and pharmacodynamic evaluation of high (320/1600 mg) and standard (160/800 mg) doses of trimethoprim/sulfamethoxazole and linezolid in outpatients with mild diabetic foot infections (DFIs). METHODS Both viable skin/soft tissue from the infection site and serum were obtained at various times after antibiotic administration from 18 patients (6 per study group) being treated with linezolid, standard doses of trimethoprim/sulfamethoxazole or high doses of trimethoprim/sulfamethoxazole during a follow-up clinic visit. These samples were assayed for drug concentrations by liquid chromatography in tandem with mass spectrometry. Patient sera were also utilized in time-kill assays against two strains of Staphylococcus aureus and three strains of β-haemolytic streptococci. RESULTS The mean tissue/serum ratio for linezolid was 0.46 (range, 0.18-0.71). The mean tissue/serum ratio for trimethoprim was 1.2 (range, 0.3-4.5) for both standard and high doses, and 0.23 (range, 0.1-0.46) and 0.36 (range, 0.14-1.28) for standard and high doses of sulfamethoxazole, respectively. Linezolid exhibited inhibitory activity in time-kill assays against strains of S. aureus (0.45 ± 0.5 log10 cfu/mL) and β-haemolytic streptococci (2.2 ± 0.6 log10 cfu/mL), while trimethoprim/sulfamethoxazole exhibited bactericidal (>3 log kill) activity against all of these isolates. These findings were consistent for each sampling time and for high as well as standard doses of trimethoprim/sulfamethoxazole. CONCLUSIONS This pharmacokinetic/pharmacodynamic study found that trimethoprim/sulfamethoxazole exhibits good skin/soft tissue penetration in patients with DFIs as well as bactericidal activity in serum against strains of S. aureus and β-haemolytic streptococci.

Pharmacokinetics and Monte Carlo Simulations of Doripenem in Patients with Febrile Neutropenia

Background: Doripenem is a group 2 carbapenem with enhanced in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. There is a paucity of pharmacokinetic/pharmacodynamic data on doripenem in patients with febrile neutropenia. Objective: To conduct a pharmacokinetic evaluation of 2 doses of doripenem in patients with febrile neutropenia and provide probability estimates of attaining effective drug exposure against common gram-negative pathogens. Methods: We obtained multiple blood samples from 12 adults with febrile neutropenia who were receiving either 500 mg or 1000 mg of intravenous doripenem over 4 hours every B hours. Following at least 2 doses, serum concentrations were measured in each subject at 1, 4, 6, and 8 hours after initiation of a dose by a validated high-performance liquid chromatography assay. The derived pharmacokinetic parameters from these serum levels were used to perform a 5000-patient Monte Carlo simulation against bacteria with minimal inhibitory concentrations (MICs) of 0.008-64 mg/L to determine probability estimates of the time in which unbound drug concentrations remain above the MIC (fT>MIC). Results: The mean pharmacokinetic parameters in these patients were a volume of distribution of 43.9 L, an elimination rate constant of 0.37 h-1, a total clearance of 14.4 L/h, and an area under the concentration-time curve of 57.6 mg·h/L. An optimal probability of target attainment (40% fT>MIC) of 90% was obtained against bacteria with MICs ≤2 mg/L and ≤4 mg/L with 500-mg and 1000-mg doses, respectively. Adverse events associated with doripenem were not observed. Conclusions: The findings from this analysis of doripenem suggest that higher doses, as well as prolonged infusions, may be necessary to optimally treat selected gram-negative bacteria (eg, P. aeruginosa) in patients with febrile neutropenia.

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

Sparfloxacin: Potential Clinical and Economic Impact in the Treatment of Respiratory Infections

1855 in the OPAT group compared with

Profile of oritavancin and its potential in the treatment of acute bacterial skin structure infections.

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.