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PubMed1992

Recombinant granulocyte colony-stimulating factor (rG-CSF): pharmacoeconomic considerations in chemotherapy-induced neutropenia.

Recombinant granulocyte colony-stimulating factor (rG-CSF) therapy is associated with a dose-proportional reduction in the frequency, duration and severity of neutropenia associated with cytotoxic chemotherapy. This is associated with a decrease in the incidence of infection, with subsequent reductions in the number of hospitalisations, days of hospitalisation and antibiotic requirements. These effects produce marked reductions in costs, and could contribute substantially towards offsetting the costs of rG-CSF, although the magnitude of the savings will vary between institutions and with the chemotherapy regimen used. Other benefits include a reduction in the frequency and severity of mucositis, and an improved patient quality of life. However, further research is required to evaluate other potentially important considerations including the targeting of specific patient populations (e.g. those receiving regimens with a curative intent), and additional improvements in patient quality of life and, perhaps, mortality. Thus, although specific pharmacoeconomic analyses are limited, preliminary evidence indicates that rG-CSF, administered prior to the onset of neutropenia in patients receiving cytotoxic chemotherapy, can provide cost reductions both from an institutional and a payor perspective, with even greater potential savings from a societal viewpoint.

Cost-Benefit Analysis↗
PubMed1992

Drug cost containment at a large teaching hospital.

Faced with a reduction in the 1990-91 pharmaceutical budget despite escalating prices, decisive cost-saving measures had to be implemented in our 1500-bed state-funded teaching hospital. 15 drug categories were reviewed by the Medicines Control Committee in conjunction with specialist work groups based on a detailed audit of the previous year's pharmaceutical expenditure. The usage of medicines was rationalised by paying particular attention to expensive agents, substitution of less expensive alternatives, deletion of nonessential drugs from the formulary, restriction of certain medicines and by imposing fixed budgets. 65 items were deleted from the hospital formulary. The previous trend of an increase in annual expenditure was reversed during the 1990 to 1991 financial year; for the first time, it was less than the allocated budget. The 20 pharmaceuticals making the greatest contribution to the drug bill comprised 31% of total expenditure in the 1989 to 1990 financial year and 26% in 1990-91 and declined from R7.4 million to R5.7 million during this period, a decrease of 23%. A decrease in expenditure was realised in 14 of the 15 categories reviewed. Overall a 20% saving, or R3.3 million, was achieved for these categories.

Budgets↗
PubMed1993

The formulary decision-making process in a US academic medical centre.

This article reviews and describes the formulary decision-making process in an academic medical centre. The pharmacy and therapeutics (P & T) committee is the organisational nucleus of the drug use control process in the institutional environment. Thomas Jefferson University Hospital (TJUH), a 720-bed academic medical centre in an urban locality in the US, is used as a model representative of how most of these committees function. Survey responses collected from 29 peer academic medical centres are presented to compare and contrast the structure and function of the P & T committee at TJUH with corresponding procedures in other university hospitals in the US. TJUH is typical of the institutions which comprise the University Hospital Consortium (UHC). The P & T committee of TJUH is composed of 29 members, meets once per month for 10 months of the year, and has a network of 13 subcommittees. TJUH has an intermediately controlled (mixed) formulary, and uses both restricted drugs and treatment guidelines. Of the 29 UHC member institutions responding to the survey, the average P & T membership is 18, the average meeting frequency is 11 times per year, and 83% of these committees have a network of subcommittees. None describe their formulary system as open, 86% have a closed formulary and 14% have a mixed formulary system. There is a restricted drug programme in 76% of the institutions, 79% utilise treatment guidelines, 76% practice therapeutic interchange and all employ generic substitution. Specific areas addressed in this review include the history of the formulary system, the structure and function of the P & T committee, types of formularies, cost containment and the formulary decision-making process, the impact of organisational culture on physician decision making, the role of the pharmacy department, the role of pharmaceutical sales representatives and their impact on prescribing habits, the impact of the Joint Commission on Accreditation of Healthcare Organisations (JCAHO) Agenda for Change on the formulary process, and future challenges.

Academic Medical Centers↗
PubMed1993

Decision analysis in formulary decision making.

Although decision making about what drugs to include in an institutional formulary appears to lend itself readily to quantitative techniques such as decision analysis and cost-benefit analysis, a review of the literature reveals that very little has been published in this area. Several of the published decision analyses use non-standard techniques that are, at best, of unproved validity, and may seriously distort the underlying issues through covert under-counting or double-counting of various drug attributes. Well executed decision analyses have contributed to establishing that drug acquisition costs are not an adequate measure of the total economic impact of formulary decisions and that costs of labour and materials associated with drug administration must be calculated on an institution-specific basis to reflect unique staffing patterns, bulk purchasing practices, and the availability of surplus capacity within the institution which might be mobilised at little marginal cost. Clinical studies of newly introduced drugs frequently fail to answer the questions that weigh most heavily on the structuring of a formal assessment of a proposed formulary acquisition. Studies comparing a full spectrum of therapeutically equivalent drugs are rarely done, and individual studies of particular pairs of drugs can rarely be used together because of differences in methodology or patient populations studied. Gathering of institution-specific economic and clinical data is a daunting, labour-intensive task. In many institutions, incentive and reward structures discourage behaviour that takes the broad institutional perspective that is intrinsic to a good decision analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost-Benefit Analysis↗
PubMed1993

Tamoxifen: a review of pharmacoeconomic and quality-of-life considerations for its use as adjuvant therapy in women with breast cancer.

Extensive clinical experience, summarised in the recent overview of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), have confirmed that tamoxifen reduces the rate of both disease recurrence and mortality when administered as adjuvant therapy in women with early breast cancer. Tamoxifen is now established as the preferred adjuvant agent in postmenopausal women; in particular, patients with node-positive, estrogen receptor-positive breast cancer have the most to gain from tamoxifen therapy. Data from a decision-analysis model indicated that tamoxifen monotherapy had a cost-utility ration {$US6000 per additional quality-adjusted life-year (QALY), in 1989 dollars} 5 to 6 times lower than that cited as the cost-acceptability cut-off point in the US. While tamoxifen monotherapy is effective in postmenopausal women, the EBCTCG overview findings indicate that a combined regimen of tamoxifen and antineoplastic chemotherapy has superior efficacy in the same patient group. An issue of current interest is whether the added benefit offered by such a regimen can be justified in terms of added toxicity and cost. Data from a decision-analysis model indicate that combined therapy has a high incremental cost-utility ratio ($US58 000 per additional QALY, in 1989 dollars) compared with no therapy in postmenopausal women. However, the quality-of-life measures TWiST (Time Without Symptoms and Toxicity) and Q-TWiST (quality-adjusted TWiST) indicate that the early toxicity associated with a combined regimen appears to be justified given the superior long term benefits. Patient preference data from 1 study further indicate that the degree of benefit offered by a combined regimen would be acceptable to the majority (73%) of patients. Other areas where pharmacoeconomic analyses may help define more closely the optimal use of adjuvant tamoxifen is in patients at low risk of developing metastatic disease and in determining the optimal duration of therapy. Both areas require further clinical data. In conclusion, tamoxifen adjuvant monotherapy has a low cost-utility ratio in postmenopausal women with node-positive, estrogen receptor-positive breast cancer. Combined therapy in the same patient group has a high cost-utility ratio compared with no therapy but quality-of-life and patient preference data suggest that the costs may be justified. Firm conclusions relating to the use of the drug in other patient subgroups and the optimal duration of therapy await further research.

Age Factors↗
PubMed1993

Formulary considerations in selection of beta-blockers.

Selection of beta-adrenergic blockers for formulary addition can be a difficult task, especially with the increasing availability of new beta-blockers, as well as the numerous differences in pharmacodynamic and pharmacokinetic properties of currently available agents. Nevertheless, appropriate evaluation of the important characteristics of beta-blockers should allow selection of the most cost-effective agents for formulary addition. Most importantly, differences in efficacy, product formulation and cost should be carefully considered when making formulary decisions. Notably, evidence from clinical trials indicates differences in efficacy among beta-blockers for post-myocardial infarction prophylaxis, situational anxiety, essential tremor, thyrotoxicosis, migraine prophylaxis and prevention of bleeding associated with oesophageal varices. For many clinical situations, it is also important to select an effective agent that is available in both an oral and intravenous formulation, especially for cardioprotection after acute myocardial infarction and for use in supraventricular arrhythmias. In addition, availability of sustained release products and generic formulations should be considered for their potential to increase compliance and decrease cost, respectively. Comparative drug costs, as well as costs associated with decreased compliance, should also be carefully evaluated. Differences in beta-receptor selectivity, duration of action and presence of intrinsic sympathomimetic activity (ISA) are also important considerations in the selection of beta-blockers for formulary consideration. Although degree of selectivity is relative, beta 1-selective agents may be less likely to induce bronchospasm in patients with chronic obstructive pulmonary disease (COPD) and may be less likely to affect glucose homeostasis in patients with diabetes mellitus. Duration of action of a beta-blocker is an important consideration for evaluation of efficacy throughout the recommended dosage interval. In addition, beta-blockers with a long duration of action can often be administered once or twice daily, potentially leading to increased compliance and thereby improved effectiveness and economic efficiency. The presence of ISA is an important consideration because certain beta-blockers with ISA may be less effective than those without ISA for certain indications. Factors considered to be less important when making formulary decisions of choice of beta-blockers include the route of elimination, lipophilicity and presence of membrane stabilising activity.

Adrenergic beta-Antagonists↗
PubMed1993

Clozapine: an appraisal of its pharmacoeconomic benefits in the treatment of schizophrenia.

Clozapine, an antipsychotic agent with relatively weak central antidopaminergic activity, displays atypical pharmacological and clinical properties vis-a-vis the classic antipsychotics. Thus, clozapine is effective against both the positive and negative symptoms of schizophrenia and has a low propensity to cause extrapyramidal effects. Furthermore, clozapine is effective in a substantial proportion (up to 60%) of patients who are refractory to or intolerant of standard antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (approximately 1% of patients) and the associated need for regular haematological monitoring currently restricts the drug's use to the treatment of chronic and severe schizophrenia refractory to standard antipsychotic therapy, and to those patients unable to tolerate such therapy. In the US, the current wholesale price of clozapine (exclusive of monitoring) is $US2.85 per 100mg tablet, amounting to $US4160 annually (1992 dollars) at the most commonly prescribed dose of 400 mg/day ($US2.40 per tablet and $US3510 annually to state programmes through Medicaid reimbursement legislation). In the UK, the annual cost of clozapine (at the average dose of 300 mg/day), inclusive of blood monitoring, is 1806 British pounds sterling (1992 pounds). Although the acquisition cost of clozapine is high in comparison with that of standard antipsychotics, preliminary cost-effectiveness estimates in patients with treatment-resistant schizophrenia suggest that the clinical benefits of the drug (viz. improved psychopathology, social functioning and quality of life) may confer medium to long term economic benefits, primarily by reducing the need for psychiatric hospital services. This effect is most likely to be seen on long term ( greater than or equal to 2 years) maintenance therapy with clozapine. Savings in hospital costs are, however, likely to be offset, at least initially, by increased reliance on outpatient services, and clozapine may therefore confer additional economic costs during the first year or so of treatment. In the longer term, however, the initial cost investment may be recouped in the form of savings to psychiatric institutions and insurers.

Clozapine↗
PubMed1994

Formulary management of antiulcer drugs: economic considerations.

Peptic ulcer disease (PUD) is a common medical problem costing billions of dollars annually around the world. Since the availability of the first histamine H2-receptor antagonist, cimetidine, many economic analyses have been conducted to compare the impact of this drug class on resource consumption. H2-Antagonists have been shown to reduce mortality, hospitalisations, ambulatory care visits and endoscopy use caused by PUD. Because of changing risk factors and variations in diagnosis, it remains controversial whether these drugs have had a long term impact on PUD incidence and prevalence. Three studies conducted after the introduction of cimetidine showed it to reduce total direct medical healthcare expenditures, despite increases in drug costs. Studies investigating the short term treatment of PUD show mixed results because of diverse study designs and different comparator drugs. No specific therapy appears consistently superior economically because of variations in population studies, ulcer relapse rates and drug acquisition costs. However, maintenance therapy for PUD has been shown to be cost-effective. When compared with surgery--an extremely efficacious option--maintenance therapy (both daily and intermittent) is cost-effective over at least a 10-year period. Within the maintenance therapy options, daily ranitidine has been shown to be more cost-effective than intermittent therapy for up to 2 years. Omeprazole is the least costly and most efficacious treatment for gastroesophageal reflux disease (GORD or GERD) compared with ranitidine and/or lifestyle modification alone. It has also been shown that the costs for empirical treatment of GORD are offset by the costs of additional investigation of those who do not have the disease. Thus the decision of whether to treat empirically should be based on physician and patient preferences, and not on costs. The use of misoprostol for ulcers caused by nonsteroidal anti-inflammatory drugs is somewhat controversial. Three studies examining the short term (3-month) costs of misoprostol generally show it to be cost saving or cost neutral. Misoprostol is consistently more cost beneficial in elderly or other high risk patients. Results are highly sensitive, however, to several parameters, such as patient type, ulcer severity and rate, drug costs and patient compliance. One study examining prophylaxis using misoprostol over 1 year showed it to be a generally expensive therapy for primary prevention, but was more cost effective for those with a proven GI bleed in the previous year.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1994

Fluoroquinolones: use of clinical data to aid formulary choice by the system of objective judgement analysis (SOJA) method.

Fluoroquinolones are used in many hospitals for the treatment of complicated urinary tract infections, gastrointestinal infections, hospital acquired pneumonia and osteomyelitis. A review of the fluoroquinolones by the System of Objective Judgement Analysis (SOJA) method is presented. The following selection criteria were involved in the study: the number of registered indications, the number of dosage forms, the ratio between the area under the plasma concentration-time curve (AUC) and the minimum inhibitory concentration for 90% of strains (MIC 90), variability of the oral bioavailability, drug interactions, dosage frequency, equal dosage for oral and parenteral use, development of resistance, clinical efficacy, adverse events, cost and documentation. Both the oral and the parenteral formulation were included in the study. Ofloxacin shows the highest score, mostly because of the lower incidence of drug interactions, dosage frequency, cost and (relative to ciprofloxacin) a similar dosage for oral and parenteral use. Ciprofloxacin is the best documented drug. Pefloxacin shows the lowest SOJA score. Users of this method are free to determine the relative weight of the various selection criteria that they consider to be correct, although some of the criteria are internationally valid.

Administration, Oral↗
PubMed1994

Expert systems. Assisting formulary decision making in the ambulatory setting.

In this article, the author reviews the application of a computer-assisted decision support system to their formulary decision-making process. Basic information is presented describing expert systems, which are a type of computer-assisted decision support system, and their advantages and disadvantages. A specific example of an expert system, 'RXPERT', is described. 'RXPERT' is a prototype expert system that models the decision-making process for an ambulatory (nonhospital) formulary. This formulary is the underpinning of the prescription drug benefit programme for the nearly 1 million residents of Saskatchewan, Canada. In the current formulary decision process, each drug product is evaluated by 2 separate committees, with the third and final decision resting with the Ministry of Health. The first committee, the Drug Quality Assessment Committee (DQAC), comprises members with expertise in medicine, pharmacology, clinical pharmacy, pharmaceutics, statistics, and regulatory processes. The DQAC evaluates information from the drug manufacturer and other independent sources, and makes an initial assessment with respect to clinical aspects of alternative therapies and generic interchangeability. The committee then makes its recommendation to the Saskatchewan Formulary Committee (SFC). The SFC reviews the recommendation of the DQAC and considers the administrative and economic implications of accepting the product for the patient, the programme, and healthcare professionals' practice. The SFC either reaffirms the recommendation of the DQAC or modifies it based on further review, and forwards its recommendation to the Ministry of Health. Finally, the Ministry of Health reviews the evaluation and determines the drug's formulary status.(ABSTRACT TRUNCATED AT 250 WORDS)

Decision Making, Computer-Assisted↗
PubMed1995

Formulary management of macrolide antibiotics.

Selection of macrolide antibiotics for formulary addition can be a difficult task, with the increasing availability of new agents as well as the numerous differences in pharmacokinetic and pharmacodynamic properties of available agents. Nonetheless, appropriate evaluation of the important characteristics of macrolide antibiotics should allow selection of the most cost-effective agents for formulary addition. Most importantly, differences in antimicrobial activity and efficacy, product formulation, tolerability and cost should be carefully considered when making formulary decisions. Notably, evidence from in vitro studies and clinical trials indicate differences between the macrolide antibiotics, especially in the management of a variety of opportunistic infections in immunocompromised patients. For selected clinical situations, it may be important to select an effective agent available in both oral and intravenous formulations, especially in severe pneumonia caused by Legionella spp. In addition, the availability of generic formulations should be considered for its potential to reduce cost. Comparative drug costs, as well as costs associated with noncompliance, should also be evaluated carefully. Dosage regimens should also be considered, as shorter durations of therapy and less frequent dose administration may lead to increased compliance and thereby improved effectiveness and economic efficiency.

Anti-Bacterial Agents↗
PubMed1996

Pharmacoeconomics and formulary decision making.

Pharmacoeconomic assessment of formulary actions has become increasingly common in local, national, and international formulary decision making. Tactics for managing medication use include formulary management and drug policies. Pharmacoeconomic data can provide support for these formulary decisions. For example, pharmacoeconomic data can support the inclusion or exclusion of a drug on or from the formulary and support practice guidelines that promote the most cost-effective or appropriate utilisation of pharmaceutical products. Various strategies can be used to incorporate pharmacoeconomics into formulary decision making. These include using published pharmacoeconomic studies and economic modelling techniques, and conducting local pharmacoeconomic research. Criteria for evaluating the pharmacoeconomic literature, suggestions for employing economic models, and suggested guidelines for conducting pharmacoeconomic projects are discussed. Although most formularies are viewed as cost-containment tools, formularies should not be a list of the 'cheapest' alternatives. Today's formulary should contain agents that optimise therapeutic outcomes while controlling cost. Pharmacoeconomic assessments of formulary decisions help to ensure that the agents promoted by our formularies yield the highest outcome per dollar spent. A discussion of the process for formulary action in a US hospital, the influence of pharmacoeconomics on US formularies, and strategies for incorporating pharmacoeconomics into formulary decision making are presented in this paper.

Decision Making, Organizational↗
PubMed1996

Formulary management of drugs for cancer-associated hypercalcaemia.

Hypercalcaemia associated with cancer is seen not infrequently in hospital practice and can be a source of considerable morbidity. Over the past decade, our understanding of the pathogenesis of this syndrome has advanced, allowing improved treatment protocols. Because one of the principal abnormalities relates to an increase in bone resorption, antiresorptive agents such as calcitonin and the bisphosphonates have been shown to be of value. In the medium to longer term, the bisphosphonates -particularly pamidronic acid[pamidronate;aminohydroxypropylidene bisphosphonate (APD)] and clodronic acid [clodronate; dichloromethyl bisphosphonate (Cl2MDP)]¿ appear to be more efficacious in terms of their calcium-lowering effect than calcitonin, and also appear to be associated with fewer adverse effects than most other agents. However, the importance of energetic re-expansion of the extracellular space with 0.9% sodium chloride before bisphosphonate therapy is extremely important. Cancer-associated hypercalcaemia, especially with squamous cancer, is often associated with the production of parathyroid hormone-related protein (PTHrP). Where this is the case, it usually reflects the presence of more advanced disease with shortened life expectancy, and poorer response to calcium-lowering therapy. Multiple treatments with larger doses of bisphosphonate may be required for these patients.

Cost-Benefit Analysis↗
PubMed1996

Formulary management of ACE inhibitors.

An increasing number of ACE inhibitors have become available in recent years. Because these agents are all similar, careful scrutiny is required in order to determine specific advantages of particular agents when making formulary decisions. Differences between agents with regard to structure and tissue specificity have been identified, but the clinical relevance of these differences is not clear. ACE inhibitors vary greatly with regard to bioconversion, distribution and elimination. Disease states such as congestive heart failure (CHF) and hepatic or renal insufficiency may affect the disposition of specific ACE inhibitors. These agents may differ substantially in duration of action, and ACE inhibitors that are given once daily may optimise patient compliance and decrease costs. ACE inhibitors have been extensively studied in patients with hypertension, CHF or nephropathy, and following myocardial infarction (MI). Differences in efficacy between agents are often a result of variations in study design, or because nonequipotent dosages were compared. It is likely that the benefits of ACE inhibitors are class effects, and it is probably reasonable to use an agent even if large scale clinical trials have not been performed with that particular drug. Few differences have been found between ACE inhibitors with regard to adverse effects or drug interactions, and these factors are of minor importance when making formulary decisions. Cost and availability may vary among agents, and will depend on geographical location and institution-specific purchasing contracts. ACE inhibitors have shown positive effects on quality of life when compared with agents of other classes. Quality-of-life studies that have directly compared ACE inhibitors have produced conflicting results. In the setting of hypertension, cost-effectiveness evaluations typically find that the newer, longer-acting ACE inhibitors provide the greatest financial benefit. Differences in cost effectiveness in the post-MI patient population are typically the result of variations in protocol design, including duration of treatment and nondrug costs. ACE inhibitors are fairly homogeneous and selection between agents can be difficult. Clinical efficacy, time course of action, and cost are the primary concerns in selecting agents for inclusion on a formulary.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Formulary submission guidelines for Blue Cross and Blue Shield of Colorado and Nevada. Structure, application and manufacturer responsibilities.

From 1 January 1999, all requests by pharmaceutical manufacturers and others to Blue Cross and Blue Shield (BCBS) of Colorado and Nevada for the listing of new pharmaceutical products or any proposed change to the formulary status of an existing product must be accompanied by a submission which meets the informational and analytical standards set out in the BCBS Guidelines for Formulary Submissions for Pharmaceutical Product Evaluation. These submission requirements relate both to the anticipated therapeutic impact of a new product and to claims made as to its anticipated pharmacoeconomic impact. The guidelines have been developed because BCBS is concerned that decisions to admit a drug to formulary have been based in the past on incomplete information. In order to rectify this situation (and to meet quality control objectives), it has been decided that all submissions to BCBS should meet a common information standard that describes both the characteristics of the product and its expected impact in a disease or therapeutic area. Unlike guidelines that have been introduced in countries such as Australia and the Canadian Province of Ontario, these guidelines take an explicit systems approach to the case a manufacturer must make before a product is considered for formulary listing. While the notion of systems impact requirements is not new, this is the first time that a managed healthcare system in the US has adopted this explicit perspective and notified manufacturers that traditional pharmacoeconomic evaluations may not meet the information needs of drug purchasers. The purpose of this paper is to describe the BCBS formulary guidelines and to demonstrate how manufacturers are expected to meet the information needs of a systems impact perspective in submissions to the pharmacy and therapeutics committee.

Blue Cross Blue Shield Insurance Plans↗
PubMed2003

Impact of a web-based antimicrobial approval system on broad-spectrum cephalosporin use at a teaching hospital.

OBJECTIVE: To achieve sustained improvement in use of cefotaxime and ceftriaxone (CEFX) in a major teaching hospital, as measured against national antibiotic guidelines. DESIGN AND SETTING: Pre- and post-intervention survey of CEFX use in the Royal Melbourne Hospital, a tertiary hospital in Melbourne, Victoria. INTERVENTION: Web-based antimicrobial approval system linked to national antibiotic guidelines was developed by a multidisciplinary team and implemented in March 2001. MAIN OUTCOME MEASURES: Change in rate of CEFX use (defined daily doses [DDDs] per 1000 acute occupied bed days) over 8 months pre- and 15 months post-intervention; concordance of indication for CEFX with national antibiotic guidelines pre- and post-intervention. RESULTS: CEFX use decreased from a mean of 38.3 DDDs/1000 bed days pre-intervention to 15.9, 18.7 and 21.2 DDDs/1000 bed days at 1, 4 and 15 months post-intervention. Concordance with national antibiotic guidelines rose from 25% of courses pre-intervention to 51% within 5 months post-intervention (P < 0.002). Gentamicin use also increased, from a mean of 30.0 to 48.3 DDDs/1000 bed days (P = 0.0001). CONCLUSION: The web-based antimicrobial approval system achieved a sustained reduction in CEFX use over 15 months as well as increased prescribing concordance with antibiotic guidelines. It has potential for linking to electronic prescribing and for wider use for other drugs, as well as for research into the epidemiology of antibiotic use.

Anti-Bacterial Agents↗