A retrospective evaluation of imipenem use in bone marrow transplant patients.

A retrospective, open, 3-year trend analysis of imipenem use in bone marrow transplant (BMT) patients was conducted at a 1000-bed tertiary care hospital. Broad-spectrum antibacterial drugs are routinely used to treat infections in the febrile neutropenic host. The antibacterial activity and acceptable tolerance profile of imipenem makes this agent a potentially useful addition to the traditional armamentarium which includes aminoglycosides, cephalosporins, and glycopeptides. Some authorities recommend imipenem as monotherapy in the treatment of fever of unknown origin in this select patient population. Eighty-three treatment courses (one treatment course per patient) were evaluated. The major indications for initiating therapy were fever of neutropenia (28%), suspected infection in the absence of fever (55%), and documented infection (17%). Imipenem was used as a first-line agent in 42% of patients, although imipenem monotherapy was not common. Concurrent antibacterials were usually vancomycin and tobramycin. Seventeen patients required modification of the initial regimen with vancomycin and/or tobramycin for additional coverage after an average of 8 days of imipenem therapy. Forty-eight bacterial isolates were obtained in cultures from 35 patients during the study, with gram-positive organisms predominating (in particular, staphylococci and streptococci). Pretherapy and superinfecting organisms were primarily gram-positive. Overall clinical success or improvement occurred in 42% of patients. Microbiologic outcome was indeterminate in 89% of patients, microbiologic eradication occurred in 1%, and superinfection occurred in 6%. Imipenem was relatively well tolerated. Rash and nausea/vomiting were reported most often; 29% of those patients who had adverse reactions discontinued therapy.

Amphotericin B use in a major acute care hospital.

A retrospective study was undertaken to assess the use of the antifungal agent amphotericin B in a major acute care hospital. Data were reviewed from 82 patients who were prescribed amphotericin B at Vancouver General Hospital between March 1 and September 1, 1990. Sixty-one percent of the patients treated with amphotericin B were from the hematology service, 22% were from the intensive care unit (ICU) service, and the remainder were from other hospital services. Fever of unknown origin was the most common reason for amphotericin B use in the hematology patients, while candidemia was most prevalent in the ICU patients. Renal dysfunction during treatment was common and related to the dose received. Test doses were used in the majority of courses, and premedications were also common. Cumulative doses administered were typically lower than intended. Amphotericin B treatment was considered successful in 46% of the cases reviewed. This review provides insight into how amphotericin B is used at one hospital and how this use may be improved. Potential applications for fluconazole are also discussed.

A new ciprofloxacin stepdown program in the treatment of high-risk febrile neutropenia: a clinical and economic analysis.

STUDY OBJECTIVE: To determine treatment outcomes and economic impact of a ciprofloxacin stepdown program for high-risk febrile neutropenic adults from the hospital's perspective. DESIGN: Unblinded, two-phase, single-center study. SETTING: Adult leukemia and stem cell transplant unit. PATIENTS: High-risk adults with febrile neutropenia. INTERVENTION: Two conditions were analyzed: a multidisciplinary ciprofloxacin stepdown program involving a reduction in parenteral ciprofloxacin dose from 400 to 200 mg (i.v.-i.v.) and conversion to oral ciprofloxacin (i.v.-p.o.) when criteria were met; and no i.v.-i.v. stepdown program. MEASUREMENTS AND MAIN RESULTS: Forty-six sequential treatment courses were compared with 42 treatment course from 6-month periods in preintervention (P1) and postintervention (P2) phases. Assessed parameters were clinical and microbiologic outcomes, adverse drug reactions (ADRs), and direct medical resource use and costs (1998 $Canadian) for the episode of febrile neutropenia. A decision analytic model was used to map probabilities and costs and to conduct sensitivity analyses. To supplement standard statistical testing, 1,000 bootstrap samples were created, and the mean cost difference was calculated between phases for each sample. Patient demographics, percentage i.v.-p.o. stepdown, and duration of therapy were similar between phases. Clinical success (83% P1, 81% P2), microbiologic eradication (15% P1, 24% P2), and possible ADRs (6% P1, 9% P2) did not differ. Intravenous-to-intravenous dose stepdown occurred in 33% of P2 and no P1 treatment courses (p<0.001). Resource use and costs were similar between phases, although a reduction was seen in the drug's mean total cost/day ($58 P1, $52 P2, p=0.04). There was also a trend toward a decrease in mean total treatment costs ($4,843 P1, $3,493 P2, p=0.08). In 1,000 bootstrap samples, 99.8% showed a cost advantage for P2. The model was robust to sensitivity analyses. CONCLUSION: This intervention influenced administration of ciprofloxacin without apparent compromise of patient outcomes and resulted in a reduction in total costs of treating febrile neutropenia.

Continuous intrathecal pump infusion of baclofen with antibiotic drugs for treatment of pump-associated meningitis. Case report.

Intrathecal baclofen administered by means of an implantable pump is being increasingly used for successful treatment of spasticity. Meningitis following intrathecally administered baclofen is a rare but serious complication that is difficult to treat without removal of the pump. Because success rates with intravenously administered antibiotic drugs for the treatment of meningitis have been low, intrathecal administration of antibiotic agents is often required to eradicate the pathogen. The authors report the case of a patient in whom Staphylococcus epidermidis meningitis developed after insertion of an intrathecal baclofen pump. The patient was successfully treated by intrathecal coadministration of vancomycin and baclofen.

Aprotinin reduces the need for blood products during liver transplantation.

BACKGROUND: Bleeding complications and blood product consumption have been a major concern during liver transplantation. Prevention of plasminogen activation and fibrinolysis by aprotinin administration has been shown to reduce perioperative bleeding during operations associated with high blood-product consumption. PATIENTS AND METHODS: Use of blood-products (packed red cells, frozen plasma, platelets, and cryoprecipitate) was analyzed both during the three stages of orthotopic liver transplantation and during total hospitalization of the 26 patients transplanted without aprotinin and the subsequent 40 patients with aprotinin. A similar analysis was performed for 15 patients immediately before and after the introduction of aprotinin to eliminate the "learning curve" effect for liver transplantation. The effect of epsilon-amino-caproic acid was analyzed as 13 patients received neither epsilon-aminocaproic acid nor aprotinin and 13 patients received epsilon-aminocaproic acid but not aprotinin. RESULTS: There was a significant reduction in total hospital use of cryoprecipitate, frozen plasma, platelets, and red cells in the aprotinin-treated patients. This reduction was seen during the anhepatic and reperfusion stages of liver transplantation. There was no difference in blood product consumption between the groups who were or were not treated with epsilon-aminocaproic acid. CONCLUSION: Aprotinin significantly reduces the need for red cell, frozen plasma, platelet, and cryoprecipitate transfusion use during orthotopic liver transplantation, and appears to be more efficacious than epsilon-aminocaproic acid.

Cost analysis of an adult outpatient parenteral antibiotic therapy (OPAT) programme. A Canadian teaching hospital and Ministry of Health perspective.

BACKGROUND: Outpatient parenteral antibiotic therapy (OPAT) programmes have become prevalent over the past 2 decades. From the US perspective, these programmes have been shown to reduce healthcare costs. No comprehensive analysis has been published from the Canadian perspective. OBJECTIVE: To describe a Canadian OPAT programme for the 3-year period since its inception and to conduct a treatment cost analysis. DESIGN AND METHODS: Demographics and resource utilisation data (health professional labour, laboratory and diagnostic tests, antimicrobials, delivery, home nursing care, catheters and catheter placement) were prospectively collected for enrollees in the OPAT programme over the evaluation period. Avoided hospital resource utilisation was estimated via retrospective chart review by the investigators. Costs were retrospectively assigned to each resource and total cost avoidance by the OPAT programme was determined from each perspective. PERSPECTIVE: A teaching hospital and a provincial Ministry of Health (MOH). MAIN OUTCOME MEASURES AND RESULTS: 140 treatment courses were initiated for 117 adult patients (mean age 54 years) who were enrolled into the programme. Mean pre-OPAT length of hospital stay was 12 days, and mean OPAT duration was 22.5 days. Bone/joint (39%), skin and soft tissue (16%), cardiac (13%) and respiratory tract (12%) infections were the most common infections managed. The most commonly used antimicrobials were vancomycin (29%), cloxacillin +/- gentamicin (22%) and ceftriaxone +/- gentamicin (11%) 85% of enrollees successfully completed their planned antimicrobial treatment regimens. Premature discontinuation of antimicrobial therapy for various reasons occurred in the remaining 15% of courses. The mean cost per treatment course of OPAT was 1910 Canadian dollars ($Can) from the hospital perspective and $Can6326 from the MOH perspective. Assuming that patients would have otherwise completed their antimicrobial therapy in hospital, the mean cost per treatment course was estimated to be $Can14,271. The overall cost avoidance of the OPAT programme was $Can1,730,520 (hospital perspective) and $Can1,009,450 (MOH perspective) over the 3-year assessment period. Sensitivity analyses revealed the results to be robust to plausible changes. CONCLUSIONS: This analysis supports the premise that an adult OPAT programme can substantially reduce healthcare costs in the Canadian healthcare setting.

The influence of a hospital pharmacy residency program on career advancement and satisfaction.

A mail survey of practicing hospital pharmacists in British Columbia who graduated since the introduction of hospital residency programs was conducted to determine the influence of a hospital pharmacy residency program on career advancement and satisfaction. Respondents included 33 past residents and 38 non residents. Career advancement was measured by union grade level. Professional and employment satisfaction were assessed using a five-level satisfaction scale. Percentage time allocated to each of administrative, clinical, distributional and research activities was determined for each group. Past residents were also requested to estimate residency program time allocation devoted to these activities which would best prepare them for their present employment. The results of this study indicate that in the ten years the program has been in operation, no difference can be demonstrated between past residents and non residents with respect to career advancement, professional satisfaction or employment satisfaction. Past residents recommend that a hospital residency should consist of approximately 40% clinical activities, 30% distributional activities and the remainder time allocated equally to administrative and research activities. Further research is recommended to evaluate the impact of a hospital pharmacy residency program in a location independent of union grade restrictions and later in the career of past residents to determine the influence of these factors on career advancement and satisfaction.

Ciprofloxacin use under a reserved drug and stepdown promotion program.

This study retrospectively evaluated the use of parenteral ciprofloxacin (PC) under the influence of a reserved antimicrobial drug program and an intravenous-oral stepdown program. During the first three months following its formulary introduction, 92 PC treatment courses were initiated. Fifty of these treatment courses in 49 adults were randomly selected for study. The hematology service accounted for 50% of the courses reviewed. The balance were initiated in the intensive care unit (16%), and six other services (34%). PC was used for the treatment of febrile neutropenia (50%), respiratory tract infections (20%), gram-negative sepsis (10%), and five other indications. Initial use of the intravenous formulation was considered appropriate in 92% of courses. Stepdown therapy occurred in 17 (34%) of treatment courses. Of the 26 patients considered candidates for oral therapy, seven patients (27%) were eligible for earlier stepdown and nine patients (35%) did not receive oral drug. According to our criteria, unnecessary use of the intravenous route occurred in 20% of PC treatment days. Mean total cost (acquisition plus delivery) of therapy per course was $668. This cost was higher in the hematology service (mean $990) than any other service (p = 0.0015). When stepdown therapy was employed the mean daily cost of therapy was $43.63 vs. $55.61 when the oral dosage form was not used (p = 0.04). Parenteral drug costs totalling $6245 were avoided by subsequent use of the oral dosage form. If full compliance with stepdown criteria had occurred, an estimated total savings of $10,769 could have been realized.

Drug usage review of cefamandole at a teaching hospital.

A drug usage audit of cefamandole was conducted at a 900-bed teaching hospital. Health records of all in-patients receiving cefamandole during a three-month period (November 1, 1985 to January 31, 1986) were retrospectively reviewed. Treatment of lower respiratory tract infections accounted for 35 (44%) of the 79 treatment courses examined. Surgical antimicrobial prophylaxis for cardiovascular procedures involved 26 (33%) courses of therapy and 15 (19%) courses were associated with biliary tract procedures. The three remaining treatment courses (4%) included therapy for septicemia, orthopedic surgery prophylaxis, and a leg ulcer. Twenty-eight percent of all treatment courses were deemed to be appropriate. Thirty-two percent were considered controversial, and 40 percent inappropriate. The majority of the suboptimal use identified involved prescribing cefamandole for cardiovascular surgery prophylaxis. The role of cefamandole in the acute hospital setting is reviewed with reference to other available first, second and third-generation cephalosporins. General recommendations for its use are outlined.

Sequential antibiotic therapy: Effective cost management and patient care.

The escalating costs associated with antimicrobial chemotherapy have become of increasing concern to physicians, pharmacists and patients alike. A number of strategies have been developed to address this problem. This article focuses specifically on sequential antibiotic therapy (sat), which is the strategy of converting patients from intravenous to oral medication regardless of whether the same or a different class of drug is used. Advantages of sat include economic benefits, patient benefits and benefits to the health care provider. Potential disadvantages are cost to the consumer and the risk of therapeutic failure. A critical review of the published literature shows that evidence from randomized controlled trials supports the role of sat. However, it is also clear that further studies are necessary to determine the optimal time for intravenous to oral changeover and to identify the variables that may interfere with the use of oral drugs. Procedures necessary for the implementation of a sat program in the hospital setting are also discussed.

A critical reevaluation of the "therapeutic range" of aminoglycosides.

Routine pharmacokinetic drug monitoring has become an inherent component of aminoglycoside therapy over the last 10-15 years. The intent of this monitoring is to improve the outcome of treatment and to decrease the incidence of toxicity through the attainment and maintenance of serum aminoglycoside concentrations within a normal therapeutic range. The primary objective of this review was to critically analyze the scientific support for the following premises: (1) there is a causal relation between peak serum aminoglycoside concentrations in serum and the outcome of treatment; (2) there is a causal relation between trough serum aminoglycoside concentrations in serum and the outcome of treatment; (3) outcome is improved by monitoring and maintenance of serum aminoglycoside concentrations in the normal therapeutic range; (4) there is a causal relation between serum aminoglycoside concentrations and toxicity; and (5) monitoring and maintenance of serum aminoglycoside concentrations within a normal therapeutic range decrease the risk of toxicity. After a critical review of the literature, it was concluded that the evidence was insufficient to support the presently accepted normal therapeutic range. Recommendations for the monitoring of aminoglycoside therapy were drawn up.

Pharmacokinetics and safety of antimicrobial agents during pregnancy.

The use of antimicrobial agents during pregnancy poses unique concerns because of both potential toxicity and special pharmacokinetic considerations that have important therapeutic implications for both mother and fetus. Various physiologic adaptations occur with advancing gestation, including marked increases in maternal intravascular volume, glomerular filtration, and hepatic and metabolic activities; thinning and maturation of the fetomaternal membrane; and increases in transplacental diffusion capacity. The net result is that maternal antimicrobial concentrations tend to be 10%-50% lower in late pregnancy and the immediate postpartum period than in the nonpregnant state. Placental transfer of antimicrobial agents and their excretion in amniotic fluid or breast milk are similarly affected by hemodynamic changes, membrane transport characteristics, and maturation or metabolic activity of the specific organs involved. Review of the literature suggests that, although the need for caution in the use of antimicrobial agents during pregnancy has been well emphasized, firm data on the pharmacokinetics, efficacy, and optimal use of these drugs in this situation are extremely sparse and urgently needed. However, recommendations regarding the use of specific antibacterial, antifungal, antiviral, and antiparasitic agents against selected infections during pregnancy can be made.

Influence of body fat on the volume of distribution of theophylline.

Twenty-six acutely bronchospastic patients admitted to the emergency room of an acute care hospital were studied to determine the influence of body fat on the volume of distribution (Vd) of theophylline. Total body weight (TBW), height, skinfold thickness (at three sites), and theophylline levels around an intravenous aminophylline dose were measured. Ideal body weight (IBW), percentage of body fat, and absolute and relative Vd of theophylline were calculated. Vd of theophylline correlated better with IBW than TBW. No relationship was identified between Vd normalized to IBW and either percentage of body fat or the ratio of TBW to IBW. This indicates that in our sample (0.8 IBW less than TBW less than 1.4 IBW), distribution of theophylline into adipose tissue was not an important determinant of Vd. Theophylline's Vd was best estimated by the formula Vd (L) = 0.419(L/kg) X IBW(kg).

Adverse reactions in a dose-ranging study with a new long-acting fluoroquinolone, fleroxacin.

New fluoroquinolones have generally been well tolerated. In a double-blind evaluation of oral fleroxacin, using 400, 600, or 800 mg once daily for 7 days in an ambulatory setting for treatment of uncomplicated genital infections, we encountered unexpectedly high rates of adverse reactions. The objective of this analysis was to determine whether any factors in addition to dose could be found to account for our observations. Adverse reactions developed in 66 (84%) of 79 individuals, and severe reactions arose in 38 (48%). Most frequent were central nervous system reactions (70%), with insomnia being especially frequent (49%); gastrointestinal reactions (39%) and photosensitivity reactions (10%) were also common. Development of any reaction (central nervous system reactions, insomnia, and severe intestinal reactions) was dose related. Development of photosensitivity reactions correlated with an outdoor occupation. No other factors, including usual daily caffeine use, correlated with the development of adverse reactions. In our study, fleroxacin taken as a single daily 600- or 800-mg dose was associated with an unacceptably high rate of adverse reactions. Other studies are required to determine whether this problem is unique to fleroxacin or will occur with higher doses of other fluoroquinolones possessing similar chemical modifications and/or good tissue penetration and very long half-lives.

Impact of a two-stage intervention program on cefazolin usage at a major teaching hospital.

To reduce antimicrobial drug costs associated with the administration of cefazolin, a two-stage therapeutic intervention--employing persuasive (informational) and power (therapeutic interchange) strategies--was initiated at this 1,000-bed major Canadian teaching hospital. The target of the intervention was to extend the dosage interval of cefazolin to q8h. During a 12-week preimplementation period, 32% of orders specified 8-hour dosage intervals. This percentage increased to 58% after the 3-week, initial informational stage of the intervention. When therapeutic interchange was employed, the percentage of orders for extended intervals rose to an average of 97% over a 32-week postimplementation period. An estimated annual cost savings of $58,000 resulted from this intervention. Manpower requirements to implement and maintain this program were minimal and prescriber antagonism was not encountered.

Auditing antibiotic use in a teaching hospital: focus on cefoxitin.

The prevalence and nature of antibiotic misuse in a major teaching hospital was assessed by means of a quality-of-use audit. Cefoxitin was chosen for study. The use of cefoxitin increased rapidly during the study period, accounting for 17.7% ($15300) of the pharmacy's costs for cephalosporins during the first year of its availability but 47.7% ($60707) during the second year. Cefoxitin was inappropriately used for 43% of the patients receiving it during the first 2-month audit period and for 25% of those receiving it during the second audit period, 1 year later (p less than 0.01 by chi-square analysis).

Application of a modified bioassay for monitoring serum teicoplanin and vancomycin in febrile neutropenic patients.

Teicoplanin is a glycopeptide antibiotic with a mode of action and spectrum of activity similar to those of vancomycin. Its efficacy and tolerability as empiric therapy and its pharmacokinetic properties in neutropenic patients are being studied in a double-blinded, randomized trial in comparison with those of vancomycin. We report here a modified agar diffusion bioassay which is suitable for monitoring levels of either teicoplanin or vancomycin in serum during combination therapy with beta-lactams, aminoglycosides, and amphotericin B. Serum samples spiked with either teicoplanin or vancomycin gave reproducible results (mean coefficient of variation, 8.8%) regardless of the presence of tobramycin, amikacin, piperacillin, ceftazidime, amphotericin B, or their combinations. Among 25 patients who received teicoplanin at a dosing schedule of 6 mg/kg every 24 h intravenously, steady state was reached after 14.2 +/- 4.0 days, and 1-h peak and trough concentrations of teicoplanin in serum at steady state were 40.8 +/- 15.0 and 12.5 +/- 3.2 mg/liter, respectively. In contrast, among 25 patients who received vancomycin at a dosing schedule of 15 mg/kg every 12 h intravenously, steady state was reached by 24 h, and the 1-h peak and trough concentrations in serum were 37.5 +/- 15.6 and 8.3 +/- 3.8 mg/liter, respectively. The elimination half-lives for teicoplanin estimated by two separate approaches agreed closely with each other: 80.5 +/- 21.5 h by an accumulation model (M. Gilbaldi and D. Perrier, Pharmacokinetics, 2nd ed., p. 121, 1982) and 87.3 +/- 19.3 h as predicted from the degree of renal function (M. Rowland, Clin. Pharmacokinetic 18:184-209, 1990). These values were 14- to 15-fold higher than that for vancomycin (5.6 +/- 1.8 h). Since considerable variability was noted in the pharmacokinetic parameters for both teicoplanin and vancomycin among the individual patients, our data further emphasized the need for frequent monitoring of these drugs during empiric therapy of the febrile neutropenic patient.

Intravenous-to-oral stepdown program: four years of experience in a large teaching hospital.

OBJECTIVE: To assess the impact of an intravenous-to-oral (iv-po) stepdown program on the relative use of oral and parenteral dosage forms of select antimicrobials. DESIGN: A retrospective review of drug utilization records before and after a trial comparing metronidazole and clindamycin prescribing trends from a 12-month baseline period to a four-year follow-up period. SETTING: One thousand-bed Canadian tertiary care referral teaching center. INTERVENTION: An authorized iv-po stepdown program was developed to promote the oral route of drug administration. Reminders of iv-po stepdown were produced for metronidazole and clindamycin and these notes were sent to nursing units with the parenteral dosage form. The notes then were attached to the front of the health record to serve as a reminder to prescribers that an equally effective, well-tolerated, and less-expensive oral dosage form was available for use. RESULTS: A 44 percent relative increase in the use of oral metronidazole and a 79 percent relative increase in the use of oral clindamycin occurred. When acquisition and delivery costs were considered, cumulative cost savings from 1988 to 1991 resulted for metronidazole ($31,920) and clindamycin ($53,880). CONCLUSIONS: This intervention represents a simple yet effective method of promoting a process of stepdown from parenteral to oral antibiotic therapy.