Mary T. Pasko

Persistence of anti-HBs among health care personnel immunized with hepatitis B vaccine.

Health care personnel who received the hepatitis B vaccine (Heptavax-BR, MSD) were followed for persistence of hepatitis B surface antibody (anti-HBs). Response occurred in 135/146 (92.5 percent) vaccinees. Loss of anti-HBs (less than 72 RIA units; 10 S/N) occurred in 35.9 percent during the 36-month surveillance. Stepwise discriminant analysis found age and magnitude of initial antibody level, but not weight-height index, to be predictive of antibody loss over the 36 months. Twenty-four of 27 employees (88.9 percent) who lost anti-HBs responded to a fourth vaccine dose. In contrast, three of eight initial non-responders (37.5 percent) developed antibody after a fourth vaccine dose.

Long-term Evaluation of the Hepatitis B vaccine (Heptavax-B) in Hemodialysis Patients

Hemodialysis patients were screened for hepatitis B surface antibody (anti-HBs) prior to immunization at two teaching hospitals. Thirty-one of 111 patients (28%) had baseline sera positive for anti-HBs, while anti-HBs was found in 30 of 420 (7.1%) health care employees (P less than 0.001). A total of 72 hemodialysis patients (mean age, 55.7), received the hepatitis B vaccine (Heptavax-B, Merck Sharp & Dohme, West Point, PA). The responder rates (34 of 72; 47%) and nonresponder (38 of 72; 53%) rates were similar to previous reports. Neither age (P greater than 0.05) nor injection site (P greater than 0.05) appeared to influence results. Nonresponders (16 of 17; 94%) who were given a fourth vaccine dose also failed to mount an antibody response. Of the 34 responders, 18 were followed by serial anti-HBs determinations. Seven transient responders (7 of 18; 39%) were identified, and anti-HBs fell below 10 S/N (sample/control counts per minute) within 12 to 15 months of the first vaccine dose. A fourth dose was administered to this group and it extended the presence of serum anti-HBs (S/N greater than or equal to 10) in four of six patients for another 2, 8, 10, and 15 months, respectively. Antibody persisted but declined over the study period in the remainder of responders followed serially (11 of 18; 61%). When compared with those responders who lost anti-HBs, those with persistent antibody had higher anti-HBs values at 7 (P less than 0.02) and 12 months (P less than 0.005) after the first injection, and were younger (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Daptomycin Use After Vancomycin-Induced Neutropenia in a Patient with Left-Sided Endocarditis

Objective: To report a positive outcome in a patient treated with daptomycin for left-sided endocarditis associated with methicillin-resistant Staphylococcus aureus (MRSA) subsequent to vancomycin-induced neutropenia. Case Summary: A 55-year-old African American male was diagnosed with left-sided endocarditis, brain abscesses, and septic arthritis due to community-acquired MRSA. He began treatment with intravenous vancomycin to achieve a trough concentration of 15–20 μg/mL and oral rifampin 600 mg/day. A repair and resection of the mitral valve was completed on day 15 of hospitalization. Vancomycin was discontinued on day 36 secondary to drug-induced neutropenia (absolute neutrophil count nadir 162 cells/μL). Intravenous therapy with daptomycin 6 mg/kg every 24 hours was then initiated and the neutropenia resolved. The patient was discharged from the hospital on day 56. Discussion: Upon discontinuation of vancomycin, treatment options were limited to a small number of alternatives. Documented clinical experience and relevant studies are limited regarding the use of quinupristin/dalfopristin (Q/D), linezolid, trimethoprim/sulfamethoxazole (TMP/SMX), and daptomycin for the treatment of MRSA left-sided endocarditis. Daptomycin was selected because of its bactericidal qualities and its recent approval for this indication. The prognostic outlook for use of daptomycin in this treatment was uncertain; however, Q/D, linezolid, and TMP/SMX posed greater risks of failure. Conclusions: Treatment of MRSA left-sided endocarditis in patients intolerant to vancomycin is challenging. The positive outcome in our patient is likely attributable to aggressive vancomycin dosing and extended duration of treatment prior to the initiation of daptomycin. The use of daptomycin in this case enabled successful management of left-sided endocarditis.

Antipseudomonal activity of simulated infusions of gentamicin alone or with piperacillin assessed by serum bactericidal rate and area under the killing curve.

The objectives of this study were to (i) determine which of three simulated dosing regimens (gentamicin alone, simultaneous infusions of gentamicin and piperacillin, or staggered infusions of gentamicin and piperacillin) produced the fastest killing rate of Pseudomonas aeruginosa in serum, using the serum bactericidal rate (SBR) assay; and (ii) describe an alternative method of analysis of killing curves, the area under the killing curve (AUKC). Gentamicin alone or combined with piperacillin was added to heat-inactivated human serum to approximate drug concentrations achieved after the above-mentioned types of infusion. By a microdilution technique, seven strains of P. aeruginosa were exposed to no drug (control) and gentamicin alone or with piperacillin; colony counts were determined at hourly intervals for 5 h, and log10 CFU per milliliter was plotted versus time. Linear regression was used to calculate the slope (SBR) of each timed killing curve for each drug concentration tested alone or in combination. In addition, the AUKC for each curve was calculated. To compare simulated infusion regimens further, the cumulative AUKC (the sum of AUKCs for specific time points along the serum concentration-time curve for each simulated regimen) was calculated. With the SBR assay or AUKC determination, there was a significant increase in the rate of killing of all test strains by the combination compared with gentamicin alone only at gentamicin concentrations which exceeded the MIC (8, 5, and 2.5 micrograms/ml). Mean cumulative AUKC of the simultaneous-infusion regimen was significantly less (indicating faster killing) than either the staggered-infusion regimen or the gentamicin infusion alone. Both the SBR and AUKC have the potential for integration of in vitro microbiologic effects and in vivo pharmacokinetics of antimicrobial agents.

Serum bactericidal rate as measure of antibiotic interactions.

The serum bactericidal rate (SBR) assay was used to assess the antipseudomonal activity of gentamicin with or without piperacillin. Heat-inactivated donor serum was spiked with gentamicin, piperacillin, or a combination at concentrations representative of levels in serum and tested against five P. aeruginosa strains isolated from blood. The SBR assay was performed as follows: colony counts in test samples (control, gentamicin, piperacillin, and combination) were determined at 0, 2, 4, 6, and 8 h after inoculation of a test strain. Log10 CFU per milliliter was plotted versus time, and linear regression analysis was performed; the slope of the regression line was defined as the SBR. The SBRs of agents alone and in combination were compared statistically. The SBR of gentamicin was dependent on the serum concentration. The combination of gentamicin and piperacillin always resulted in a higher SBR than did either drug alone. However, this difference was not statistically significant for highly gentamicin-susceptible strains (MIC, less than or equal to 2 micrograms/ml) until the gentamicin concentration was reduced below the MIC. For a gentamicin-resistant strain (MIC, 8 micrograms/ml), the combination of gentamicin and piperacillin produced mean SBRs similar to that found with gentamicin-susceptible strains. These results provide evidence that the SBR assay may be a useful method of evaluating antibiotic interactions, since it can be done by using serum and since it compares the antibacterial activity of drugs statistically rather than requiring arbitrary criteria to define interactions.

Ceftriaxone disposition in open-heart surgery patients.

The effects of cardiopulmonary bypass (CPB) with hypothermia and systemic heparinization on ceftriaxone disposition were evaluated in seven male patients. A bolus dose of drug (14 mg/kg of body weight) was given, and blood and urine specimens were collected before, during, and after CPB for 96 h. Creatinine, albumin, and total and free ceftriaxone concentrations in plasma were measured. The ceftriaxone free fraction (ff) in vitro was estimated by equilibrium dialysis, and the in vivo ff was obtained by the ratio of renal clearance due to filtration to creatinine clearance. Pharmacokinetic parameters were based on concentrations of total drug and free drug. Albumin decreased from 3.10 +/- 0.29 g/dl presurgery to 1.42 +/- 0.17 g/dl and recovered to 2.46 +/- 0.26 g/dl on postoperative day 4. CPB markedly increased the in vitro ff, which was reversed by protamine post-CPB (ff pre-CPB, 0.15 +/- 0.01; during CPB, 0.53 +/- 0.20; post-CPB, 0.16 +/- 0.02). The in vitro ff exceeded the in vivo ff (0.53 +/- 0.20 versus 0.24 +/- 0.07), probably due to continued free fatty acid release caused by heparin during dialysis. Clearances based on free drug decreased, and the renal clearance due to filtration increased (7.6 +/- 2.8 versus 15.0 +/- 4.5 ml/min) while the creatinine clearance decreased (114 +/- 29 versus 72 +/- 28 ml/min) during CPB. Diminished binding owing to low albumin and free fatty acids explain this behavior. Lower binding also increased the volume of distribution (154 +/- 41 ml/kg) and extended the half-life (15 +/- 6 h). In summary, ceftriaxone disposition was significantly altered by CPB, resulting in marked increases in free drug concentrations, half-life, and volume of distribution and in decreased intrinsic clearance.

Update on Pressure Ulcer Management and Deep Tissue Injury

Objective: To review recent literature regarding therapeutic management of pressure ulcers and to discuss the potential implications of the newly recognized entity, deep tissue injury (DTI). Data Sources: A MEDLINE search was conducted of pressure ulcer therapy published between January 2001 and October 2009. Key search terms included pressure ulcers, deep tissue injury, nutrition, antibiotics, and therapy. Study Selection and Data Extraction: Comparative clinical trials involving pharmacologic agents in the treatment of pressure ulcers and DTI were evaluated. Included trials were those with defined interventions and outcome parameters for wound healing. Data Synthesis: Pressure ulcers remain an important issue in the care of elderly and immobilized patients. DTI has been recently added by the National Pressure Ulcer Advisory Panel as a separate category in the staging of pressure ulcers. There is currently a lack of consensus on how to identify and treat DTI. but preventive measures typically employed in the management of all pressure ulcers have been recommended. Recent studies on topical phenytoin, silver preparations, and growth factors report benefit in the management of pressure ulcers. However, studies evaluating these treatment approaches often lack the sample size necessary to adequately support recommendations. Conclusions: Determining the extent of tissue damage in DTI is currently not possible. Therefore, management recommendations focus on limiting extension of the ulcer stage through preventive strategies. Routine use of topical phenytoin, silver preparations, or growth factors in therapy of pressure ulcers cannot be recommended until more data from rigorously designed studies are available.

Multi-Institutional Study of Women and Underrepresented Minority Faculty Members in Academic Pharmacy

Objectives. To examine trends in the numbers of women and underrepresented minority (URM) pharmacy faculty members over the last 20 years, and determine factors influencing women faculty members’ pursuit and retention of an academic pharmacy career. Methods. Twenty-year trends in women and URM pharmacy faculty representation were examined. Women faculty members from 9 public colleges and schools of pharmacy were surveyed regarding demographics, job satisfaction, and their academic pharmacy career, and relationships between demographics and satisfaction were analyzed. Results. The number of women faculty members more than doubled between 1989 and 2009 (from 20.7% to 45.5%), while the number of URM pharmacy faculty members increased only slightly over the same time period. One hundred fifteen women faculty members completed the survey instrument and indicated they were generally satisfied with their jobs. The academic rank of professor, being a nonpharmacy practice faculty member, being tenured/tenure track, and having children were associated with significantly lower satisfaction with fringe benefits. Women faculty members who were tempted to leave academia for other pharmacy sectors had significantly lower salary satisfaction and overall job satisfaction, and were more likely to indicate their expectations of academia did not match their experiences (p<0.05). Conclusions. The significant increase in the number of women pharmacy faculty members over the last 20 years may be due to the increased number of female pharmacy graduates and to women faculty members’ satisfaction with their careers. Lessons learned through this multi-institutional study and review may be applicable to initiatives to improve recruitment and retention of URM pharmacy faculty members.

Teicoplanin: a new glycopeptide antibiotic complex.

The chemistry, microbiology, pharmacokinetics, clinical efficacy, and adverse effect profile of teicoplanin are reviewed and, where appropriate, compared with vancomycin. Teicoplanin is a glycopeptide antibiotic with potent bactericidal activity against a wide variety of aerobic and anaerobic gram-positive bacteria. In contrast to the structurally related vancomycin, teicoplanin has a prolonged elimination half-life of approximately 60 hours and it may be safely administered by the intramuscular route. Adverse effects of teicoplanin include ototoxicity, nephrotoxicity, skin rash, eosinophilia, neutropenia, and transient elevation of serum aminotransferases. Teicoplanin may be beneficial as an alternative to vancomycin for patients with poor vascular access and in those requiring long-term outpatient therapy. The role of teicoplanin in the treatment and prophylaxis of gram-positive infections will ultimately depend on its unfolding safety and efficacy profile.

Use of Antifungal Therapy in Hospitalized Patients II. Results after the Marketing of Fluconazole

OBJECTIVE: To evaluatethe prescribing patternsof antifungal agents in the hospital setting after the introduction of fluconazole, a new broad-spectrum bis-triazole antifungal agent. Also comparedare the prescribing patterns of antifungal agents prior to (phase I) and following (phase II) fluconazole marketing. DESIGN: A prospective cohort of hospitalized patients prescribed topical or systemic antifungal agents. Data were collected from December 1990 to April 1991. SETTING: Fifty-seven hospitals ranging in size from 100 to more than 500 beds. Sixty-three percentare affiliated with medical schools. PATIENTS: Participating pharmacists consecutively identified 15 patients receiving systemic antifungal therapy and 5 patients receiving topical antifungal therapy. INTERVENTIONS: Observational data on patient antifungal therapy, risk factors for fungal infections, comorbidities, concurrent medications, and culture data were collected. MEASURES: Differences in prescribing patterns before and after the marketing of fluconazole were assessed using t-tests and chi-square tests. RESULTS: Of 818 patients studied, 615 (75.2 percent) received systemic antifungal therapy. Five hundred forty-six patients received a single antifungal agent; 348 (63.7 percent) received fluconazole, 105 (19.2 percent) received ketoconazole, 92 (16.8 percent) received amphotericin B, and 1 (0.2 percent) received flucytosine. Sixty-nine patients received two or more systemic agents either concurrently or consecutively. The use of parenteral amphotericin B, alone or in combination with flucytosine and/or an azole, declined from 56.8 percent in the phase I study to 24.2 percent in the current study. The use of parenteral therapy also declined from 56.8 to 40.2 percent. Ketoconazole was used in more than 90 percent of the oral and esophageal infections in the phase I study, but its use declined to only 33 percent in this study. Fluconazole was used most frequently across all sites of presumed or documented infections, with the exception of fungemia. Of the presumed or proven systemic or blood infections, amphotericin B was used alone or in combination in 48.4 percent of the patients and fluconazole was used exclusively in 39.0 percent of the patients. Fluconazole was used more often than amphotericin B (22 vs. 3 patients, respectively) for prophylaxis of systemic infections. The overall use of antifungal prophylaxis also increased from the phase I (9.5 percent) to phase II (13.7 percent). CONCLUSIONS: The introduction of fluconazole had a major impact on the prescribing patterns of antifungal therapy. Although amphotericin B remained the preferred agent for treatment of suspected or proven systemic, central nervous system, or blood infections, use of fluconazole for these indications approached nearly 40 percent. Further studies are needed to address the role of fluconazole in the prophylaxis and treatment of systemic mycoses.