Controversies in antimicrobial therapy: formulary decisions on third-generation cephalosporins

Factors affecting the admission of antimicrobial agents to hospital formularies are discussed, using third-generation cephalosporins as examples. Inappropriate antimicrobial therapy is costly in terms of wasted drugs, ineffective therapy, and drug toxicity. In 1984, 10 of the top 15 drug products (in sales to hospitals) were antimicrobial agents; these accounted for $1 billion in sales. Since third-generation cephalosporins are very similar in terms of spectra, clinical efficacy, and safety, they are useful in illustrating the process a hospital might use in deciding which individual agent to admit to a formulary. Five factors should be considered in formulary evaluations of antimicrobial agents: in vitro activity, pharmacokinetic disposition, adverse effects, clinical efficacy, and total economic impact. As applied to third-generation cephalosporins, this decision analysis leads to the conclusion that these agents should be considered therapeutic alternates. The decision would then rest solely on the institution-specific factors of microbial susceptibility patterns, patient case-mix, and acquisition costs. Antimicrobial agents account for the largest financial expenditure among hospital drug products; a set of these agents should be selected carefully to meet the needs of the individual institution.     

Review of the new second-generation cephalosporins: cefonicid, ceforanide, and cefuroxime

The new second-generation cephalosporins, cefonicid, ceforanide, and cefuroxime, have recently become available. These agents are generally less active against gram-positive cocci than first-generation cephalosporins and, at best, equal to cefoxitin and cefamandole against many gram-negative bacteria. Cefuroxime, however, is the most active cephalosporin for beta-lactamase-producing Haemophilus influenzae. These newer agents have superior pharmacokinetic characteristics over cefoxitin and cefamandole. Smaller doses, longer dosing intervals and, potentially, a reduction in total drug cost may be the real advantage of these agents. Open trials and a limited number of comparative studies have documented the effectiveness of cefonicid, ceforanide, and cefuroxime in the treatment of most mild-to-serious infectious diseases, although failures with cefonicid in the treatment of staphylococcal infections have been reported. Notably, cefuroxime has received approval for the treatment of common pediatric bacterial meningitis infections. Replacement of cefamandole or cefoxitin with one of these "longer-acting" agents may be cost-beneficial; however, clinicians must be on alert for the development of bacterial resistance or decreased efficacy.     

The impact of formulary reservations on drug utilization: a controlled trial

A controlled trial was conducted in two teaching hospitals (A and B), with similar case mixes to determine the impact of reservations, which were educational in nature, on the utilization of oral ciprofloxacin. Over a two-month period the health records of all the patients who received the drug were reviewed, and information on utilization and demographics of patients receiving the drug was recorded. As well, the number of admissions to the two hospitals over this period were compared. If culture and sensitivity (C & S) results were available, appropriateness was assessed in accordance with criteria for use established at site A; in the absence of C & S information, consensus by two microbiologists was used. Over the two-month period a total of 136 patients received ciprofloxacin at the two institutions. At site A, which had reservations, the number of patients who continued to receive ciprofloxacin upon admission was significantly decreased relative to site B, which did not have reservations (14% vs. 36% respectively, p = .029). As well, when assessed by total number of admissions to the institutions, the number of patients receiving ciprofloxacin at site A was less than site B (1.5% vs. 2.6% respectively, p = .003)). While the utilization was decreased at site A vs. site B, the proportion of patients with therapy deemed to be appropriate was not different between the two sites. Educationally based reservations are an effective formulary tool for optimizing drug utilization.     

Financial impact of an aminoglycoside substitution program.

In recent years, efforts toward cost containment have been emphasized in order to reduce health care costs. One area to be examined for cost containment is the field of antibiotics because of their escalating costs and the degree of inappropriate use. In June of 1985, an aminoglycoside substitution program was initiated wherein gentamicin was automatically substituted for tobramycin unless the physician specifically stated otherwise. Specific guidelines for tobramycin use were not established. The purpose of the study was to develop guidelines for the appropriate use of tobramycin and to determine the cost savings of the substitution program. A list was prepared of all patients who had received either gentamicin or tobramycin between July 1, 1985 and December 31, 1985. The health records of every fourth patient receiving gentamicin and all patients receiving tobramycin were retrospectively reviewed in depth. The remainder of the gentamicin cases were given a cursory review for substitutions from written tobramycin orders. Costs for both drugs were calculated from pharmacy drug acquisition records. Nine courses of tobramycin and 390 courses of gentamicin were found. Thirty-two gentamicin courses were substituted for tobramycin. Cost savings for the substituted gentamicin was approximately $1200 (45%). Additional savings would have been realized had four tobramycin courses been changed to gentamicin when culture and sensitivity results were reported. The cost of instituting the substitution was negligible. Guidelines for appropriate tobramycin use are presented.     

Building a better online formulary.

The history of and improvements made to the University of Michigan Health System (UMHS) inpatient online formulary are described. The current formulary at UMHS is the third version of the Web-based formulary. The original effort in 1997 consisted of converting word-processing documents to HTML format and exporting this information to the university's intranet. There was no mechanism to search for formulary items, no therapeutic class cross-referencing, and no cost information. Documents and their conversion had to be manually maintained. The second version incorporated a series of automatic daily computer downloads from the inpatient pharmacy computer system. Web pages were built to dynamically display the formulary information from the database based on users' requests. The formulary enabled searching by brand or generic names, provided therapeutic category cross-references, listed the location of products within automated dispensing cabinets, provided accurate cost information, and was always up-to-date. Maintenance efforts drastically decreased. The current version has incorporated additional logic to meet users' needs. If no matches are found, the system expands its search by automatically linking to UMHS's inpatient pharmacy system repository of all drugs, finding matches to what the user entered, and then returning the names of therapeutically similar formulary agents to the user. A cross-index feature allows the system to return all the drugs that fall under the searched therapeutic category. Dramatic improvements have been made to UMHS's inpatient online formulary in the past two years. The current formulary provides a very low-cost, easily maintainable, and effective means to access the formulary and clinically relevant and timely information specific to each medication.     

Alkalimetric microassay of cephalosporins.

Alkalimetric pH-stat titrations of cephalosporin C, cephacetril and their deacetyl derivatives using an acetyl esterase and beta-lactamase are described. The esterase was used to assay highly purified samples of cephalosporin C and cephacetril, and also to prepare analytically defined solutions of the deacetyl cephalosporins. Lactamase-catalyzed hydrolysis of the parent compounds was then found to generate exactly 2 equivalents of acid per mole; that of the deacetyl derivatives exactly 1 equivalent.     

Effect of patient notification of formulary change on formulary adherence

OBJECTIVE: To evaluate the impact of patient notification of impending formulary changes on formulary adherence. METHODS: This pilot program in a large, Midwest-based health insurer utilized a randomized controlled trial research design. A list of 30 chronic-use medications that were to change formulary status were selected for the pilot. A review of adjudicated pharmacy claims records was performed to identify patients receiving one or more of the formulary change medications on the list. Members of 112 individual health plans of this large health insurer, all of whom were subject to the same drug formulary, were randomized to either the intervention (letter) or control arm. Patients in the intervention arm were sent a targeted communication that described the patient.s formulary change medication(s) and provided therapeutic option(s) for the formulary change medication(s). Pharmacy claims for patients in both arms were examined at 110 days after the date of the mailing to determine if there was a switch to a formulary alternative. Multivariate regression modeling was performed to adjust for baseline differences between the arms. RESULTS: A total of 7,247 unique formulary change medication regimens were identified (3,817 in the control arm and 3,430 in the letter arm) for 6,518 subjects (3,387 in the control arm and 3,131 in the letter arm). A higher proportion of formulary change medication regimens in the intervention arm were switched to a formulary alternative compared with the control arm (19.2% vs. 12.0%, P<0.001). After adjustment for baseline differences, regression modeling indicated that subjects in the intervention arm were 1.33 times more likely to switch to a formulary alternative (P<0.001). CONCLUSION: A letter-based, formulary change notification program is a pragmatic and effective strategy to increase drug formulary adherence. Such a program does not restrict access to medications but, rather, provides education and personalized information that may allow patients to participate more actively in their pharmacotherapy decision making.     

New cephalosporins and 7 alpha-methoxy cephalosporins. Chemistry and biological activities

The synthesis and the in vitro activity of a number of cephalosporins and 7 alpha-methoxy cephalosporins having 7-acyl substituents derived from 1-methyl-4 (or 5)-nitro-1H-imidazolyl-thioacetic acids are described. The microbiological profile is influenced by the position of both the nitro group and the side-chain sulfur atom on the 1-methyl imidazole, and by the nature of the 3-substituent.     

Electronic structures of cephalosporins and penicillins. 9. Departure of a leaving group in cephalosporins.

Molecular orbital calculations by the CNDO/2 method are used to study the potential energy surface for the stretching and rupturing of the CH2-OAc bond in a model cephalosporin structure, 7-amino-3-(acetoxymethyl)-3-cephem. The bond is easier to stretch and break when a nucleophilic group is in the vicinity of or attached to the beta-lactam carbonyl carbon (C8). The rate of acylation by a beta-lactam antibiotic at the receptor sites in bacterial cell-wall enzymes will be enhanced by a suitable leaving group at the 3' position. An orientational specificity is predicted for the direction of departure of the leaving group. Regardless of the direction the nucleophile approaches C8, the CH2-OAc bond is easiest to break when the acetate group departs from the alpha face of the molecule.     

Survey of formulary system policies and procedures.

A telephone survey was conducted to determine the policies and procedures of hospital formulary systems. Directors of pharmacy at a random sample of 150 community hospitals were interviewed, and letters were sent to each respondent requesting copies of the formulary and drug evaluation form. One hundred thirty hospitals completed the interview (gross response rate of 87%), and 35 evaluation forms and 49 printed formularies were received. Almost all hospitals had a formulary system and a printed formulary; the most frequently stated purposes were to decrease costs and to ensure appropriate therapy. Most formularies received were simple drug lists with no supporting information. The typical pharmacy and therapeutics committee consisted of 11 members, met every month, and reported to the executive committee. About 80% of the responding institutions had formal procedures for considering formulary additions. Less than half had standardized drug evaluation forms. Most hospitals have a formulary system and a printed version of the formulary; however, the formulary often serves primarily as a drug list, with no supporting information.     

Microionization constants of commercial cephalosporins.

The equilibrium constants of five commercial cephalosporins were determined. Two are monoacidic and possess one Ka while three are amphoteric and have four microconstants. Although several assumptions were made in the calculations, good agreement was found between the compounds and with previously reported macroionization constants. By utilizing the microionization constants, the ratios of zwitterion to unchanged species were calculated to be in the 900-50,000 range and to have a maximum concentration between pH 3.5 and 5.