Every 36-h gentamicin dosing in neonates with hypoxic-ischemic encephalopathy receiving hypothermia.

OBJECTIVE: To examine the impact of a change in the empiric gentamicin dose from 5 mg kg(-1) every 24 h (Q24 h period) to 5 mg kg every 36 h (Q36 h period) on target drug concentration achievement in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia. STUDY DESIGN: Gentamicin drug concentrations in neonates with HIE receiving therapeutic hypothermia were examined during two time periods in a retrospective chart review. During the initial treatment period (November 2007 to March 2010; n=29), neonates received Q24 h period. During the second treatment period (January 2011 to May 2012; n=23), the dose was changed to Q36 h period. Cooling criteria and protocol remained the same between treatment periods. Gentamicin drug concentrations including achievement of target trough concentrations (<2 mg l(-1)) were compared between treatment periods. Individual Bayesian estimates of gentamicin clearance were also compared. RESULT: Neonates with an elevated trough concentration >2 mg l(-1) decreased from 38 to 4% with implementation of a Q36-h dosing interval (P<0.007). The mean gentamicin trough concentration was 2.0 ± 0.8 mg l(-1) during the Q24 h period and 0.9 ± 0.4 mg l(-1) during the Q36 h period (P<0.001). Peak concentrations were minimally impacted (Q24 h 11.4 ± 2.3 mg l(-1) vs Q36 h 10.0 ± 1.9 mg l(-1); P=0.05). The change in gentamicin trough concentration could not be accounted for by differences in gentamicin clearance between treatment periods (P=0.9). CONCLUSION: A 5 mg kg(-1) every 36-h gentamicin dosing strategy in neonates with HIE receiving therapeutic hypothermia improved achievement of target trough concentration <2 mg l(-1), while still providing high peak concentration exposure.

Voriconazole is safe and effective as prophylaxis for early and late fungal infections following allogeneic hematopoietic stem cell transplantation.

Seventy-two patients undergoing allogeneic transplantation were treated with voriconazole (VOR) as antifungal prophylaxis starting from day -2 of transplantation and continuing until withdrawal of immunosuppression. Patients were assessed for safety and the incidence of definite, probable, or possible fungal infection throughout transplantation was evaluated. VOR was well tolerated. Only 14% of patients required interruption of VOR therapy because of toxicity: liver toxicity (8%), cardiac Q-T interval prolongation (1%), or other side effects (5%). In the early post-transplant period (<120 days), only 2 patients developed invasive fungal infection: 1 mucormycosis infection and 1 disseminated Aspergillus infection. In the late post-transplant period (>120 days), no patients developed probable or definite fungal infection while receiving VOR. No Candida infections were seen in either period. These data suggest that fungal prophylaxis with VOR following allogeneic transplantation is safe and effective.

Impact of an intravenous fluconazole restriction policy on patient outcomes.

OBJECTIVE: To evaluate both the economic and clinical impact of an intravenous fluconazole restriction policy in a university teaching hospital. METHODS: Intravenous fluconazole was restricted to patients unable to take oral medications due to significant nausea or to patients whose oral intake was restricted. A retrospective chart review and computerized record review was conducted in patients receiving intravenous or oral fluconazole from January 1 to June 30, 1997, and again from January 1 to June 30, 1998, after implementation of the policy. RESULTS: Six-month institutional expenditures for intravenous fluconazole decreased following policy implementation, from $81,900 to $45,400, an estimated annual institutional savings of $73,000. A 47% reduction in the number of patients treated with intravenous fluconazole was observed over the six-month period after policy implementation. During this time, the rate of successful clinical outcomes for documented or suspected disseminated Candida albicans infection or febrile neutropenia remained the same (66.6% prepolicy and 65.9% postpolicy; p = 0.95). Similarly, the number of deaths in patients receiving fluconazole remained unchanged (p = 0.31). CONCLUSIONS: A restriction policy for intravenous fluconazole results in significant cost savings, with no significant decrease in successful outcomes or change in mortality.

Antimicrobial selection for hospitalized patients with presumed community-acquired pneumonia: a survey of nonteaching US community hospitals.

OBJECTIVE: To describe and evaluate empiric antimicrobial regimens chosen for hospitalized patients with presumed community-acquired pneumonia (CAP) in US hospitals, including compliance with the American Thoracic Society (ATS) guidelines. Secondary outcomes included length of stay (LOS) and mortality associated with the choice of therapy. METHODS: A nonrandomized, prospective, observational study was performed in 72 nonteaching hospitals affiliated with a national group purchasing organization. Patients with an admission diagnosis of physician-presumed CAP and an X-ray taken within 72 hours of admission were eligible for the study. Demographic, antibiotic selection, and outcomes data were collected prospectively from patient charts. RESULTS: 3035 patients were enrolled; 2963 were eligible for analysis. Compliance with the ATS guidelines was 81% in patients with nonsevere CAP. The most common antibiotic regimen used for empiric treatment was ceftriaxone alone or in combination with a macrolide (42%). The overall mortality rate was 5.5%. The addition of a macrolide to either a second- or third-generation cephalosporin or a beta-lactam/beta-lactamase inhibitor was associated with decreased mortality and reduced LOS. CONCLUSIONS: Most hospitalized patients with CAP receive antimicrobial therapy consistent with the ATS guidelines. The addition of a macrolide may be associated with improved patient outcomes.

Ceftriaxone therapy for staphylococcal osteomyelitis: a review.

Ceftriaxone, although less active than standard antistaphylococcal agents, is potentially useful in the treatment of osteomyelitis. Thirty-one patients with osteomyelitis due to Staphylococcus aureus were identified, 22 of whom were treated with ceftriaxone and 9 with other agents. Of those patients treated with ceftriaxone, 17 were cured; all treatment failures were associated with chronic osteomyelitis and continued presence of necrotic bone or infected hardware. It is concluded that ceftriaxone is effective in the ambulatory treatment of S. aureus osteomyelitis.

Prevention of adverse events in hospitalized patients using an antimicrobial review program.

OBJECTIVE: To evaluate whether an antimicrobial review system is associated with a reduction in antimicrobial-associated adverse events. DESIGN: All antimicrobial medication orders for patients hospitalized over a two-year period were evaluated. High-level interventions intended to prevent adverse antimicrobial events were collated. Based on literature estimates of adverse antimicrobial events, potential reduction of high-level adverse antimicrobial events was estimated. SETTING: Department of Clinical Pharmacy and Division of Infectious Diseases at a tertiary care teaching hospital. RESULTS: A total of 452 interventions were classified as "high-level." The incidence of preventable adverse antimicrobial events requiring intervention was 16 per 1000 antimicrobial orders. The incidence of high-level errors necessitating intervention was 4.4 per 1000 antimicrobial orders. An estimated 125 to 198 high-level adverse events were avoided. CONCLUSION: An antimicrobial review program has the potential to reduce significant adverse events in hospitalized patients.

Use of antimicrobial agents in patients with cardiovascular disease.

Antimicrobial agents are widely utilized in the prevention and treatment of infection in patients with cardiovascular diseases. Knowledge of spectrum of activity, pharmacology, adverse effect and toxicity profile, and emergence of resistant pathogens is critical to the appropriate use of these agents. The following review will emphasize the safe, effective use of antimicrobial drugs in the cardiovascular patient.

Risk factors for amphotericin B-induced nephrotoxicity.

The association of amphotericin B with nephrotoxicity is well known, but risk factors for this complication are not well characterized. One hundred and seventy-eight patients who received > 3 days of intravenous amphotericin B and a minimal total cumulative dose > 100 mg were reviewed retrospectively. The mean age, average cumulative dose of amphotericin B and duration of therapy were 46 +/- 22 years, 536 +/- 547 mg and 16.6 +/- 8.2 days, respectively. Eighty-six percent of patients received amphotericin B for empirical therapy of febrile neutropenia. Various definitions of nephrotoxicity were used; these were as follows (the incidence of nephrotoxicity as determined by the given definition is given in parentheses): definition 1, a change in creatinine of > 46 mumol/L over baseline (50%); definition 2, a doubling of creatinine over baseline (49%); definition 3, a change in creatinine of > 92 mumol/L (29%); definition 4, a doubling and/or a change in creatinine of > 92 mumol/L (49%); definition 5, an increase in creatinine to > 230 mumol/L (8%). Multivariate analysis showed that nephrotoxicity was associated with a greater cumulative dose of amphotericin B and receipt of concomitant nephrotoxic drugs for all definitions (P < 0.05). In those patients who experienced severe nephrotoxicity (creatinine increased to > 230 mumol/L), cyclosporin therapy was the most significant risk factor (odds ratio 18.8, P = 0.022). Haemodialysis was necessary in one patient, but multiple concomitant risk factors for renal dysfunction were present. No patient experienced irreversible nephrotoxicity. These findings allow for stratification of patients at risk for amphotericin B-induced nephrotoxicity and rational use of alternative agents.

Lipid formulations of amphotericin B: clinical efficacy and toxicities.

Commercially available lipid formulations of amphotericin B (Abelcet, Amphotec, and AmBisome) represent a significant advance in drug delivery technology. Differences in biochemical, pharmacokinetic, and pharmacodynamic properties among the lipid products have been shown in in vitro and in vivo models. Clinical experience with these products has been primarily in patients either refractory to or intolerant of conventional amphotericin B deoxycholate (AmBd). None of the lipid-based products demonstrates superior efficacy when prospectively compared with AmBd in the treatment of documented infections. When used for the empirical treatment of febrile neutropenia, AmBisome significantly reduced the incidence of proven emergent fungal infections but did not improve short-term survival rates, in comparison with AmBd. Acute infusion-related adverse events vary, whereas nephrotoxicity is reduced with all three lipid formulations. Until superior efficacy is clearly shown (for documented infections) or pharmacoeconomic analyses document the value of these drugs, use of such expensive agents should be highly restricted to those who are intolerant of or refractory to AmBd.

Aerosolized amphotericin B in prophylaxis of pulmonary aspergillosis.

Although many prophylactic measures have been attempted, Aspergillus continues to be a significant cause of morbidity and mortality in neutropenic BMT patients. The data describing the efficacy of AAB in patients with neutropenia is ambiguous and inconclusive. All of the available studies lack adequate study design, making a definitive conclusion difficult. Additionally, the role of concomitant oral antifungal prophylaxis has not been addressed and needs to be examined. Regardless, the studies suggest AAB may be effective during periods of environmental exposure to Aspergillus, as seen during periods of construction, when used in combination with HEPA filtration. Further investigation is required to assess the effectiveness of AAB in BMT patients who are not housed in sterile environments. Until more information is available, the role of AAB in preventing IPA in neutropenic BMT patients remains unclear, particularly in the absence of HEPA filtration.

Practical strategies for the appropriate use of antimicrobials.

The use and misuse of antimicrobial agents is well documented in the literature. A variety of mechanisms has been used to enhance the appropriate use of these agents. A widely used initial strategy is the formation of multidisciplinary groups, such as Pharmacy and Therapeutics Committees or antimicrobial subcommittees, which are responsible for all antimicrobial policies for the health-care facility. Other techniques include the use of antimicrobial order sheets, automatic stop orders, therapeutic substitution, antibiotic restriction systems, and the use of selective antimicrobial susceptibility reporting systems. Many of these strategies have been reported to be effective in the management of antimicrobial usage; however, they also result in increased administrative and monitoring costs. Antimicrobial control systems must be individualized to the health-care facility.

Influence of timing of antibiotic administration on tissue concentrations during surgery.

BACKGROUND: Prophylactic antibiotics must be administered so as to achieve adequate tissue levels before the initial surgical incision. We characterized antimicrobial tissue concentrations following intravenous administration at various times prior to surgical incision. PATIENTS AND METHODS: Twelve patients scheduled for elective colorectal surgery were randomized to receive cefmetazole 2 g by intravenous push either immediately prior to incision or 15 to 60 minutes prior. Blood and wound-muscle samples were obtained at predetermined intervals and assayed by high-performance liquid chromatography. RESULTS: Tissue distribution of the study drug was extremely rapid. All patients had theoretically adequate tissue levels at the time of incision. Levels above MIC90 of the common pathogens were sustained throughout the surgical procedure regardless of the timing of administration. CONCLUSIONS: Administration of cefmetazole immediately prior to surgical incision should be effective prophylaxis for surgical wound infections.