Development of resistance and cross-resistance in Pseudomonas aeruginosa exposed to subinhibitory antibiotic concentrations.

The purpose of this study was to compare resistance and cross-resistance development in Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients to commonly used antipseudomonal antibiotics. Isolates were repeatedly exposed to subinhibitory concentrations of either azlocillin, tobramycin, ceftazidime or ciprofloxacin. On 10 consecutive occasions, samples were removed from the half-MIC well of a microtitre plate and regrown in drug-free medium to provide the next inoculum for MIC determination. The increase in MIC at the end of the treatment period was significant (p<0.05) for all selecting antibiotics. Cross-resistance to unrelated antibiotics was not observed, but was significant (p<0.05) in all beta-lactams (ticarcillin, piperacillin, ceftazidime and cefsulodin) studied where azlocillin was the selecting antibiotic. The addition of clavulanic acid to ticarcillin and of tazobactam to piperacillin had no effect on cross-resistance. The development of resistance to azlocillin was associated with increased beta-lactamase activity and a change in isoelectric point of the beta-lactamases. The result of this study supports a rotational policy for antipseudomonal antibiotics in CF patients.

Causality assessment of adverse effects: when is re-challenge ethically acceptable?

One of the most difficult tasks in the evaluation of a medicine is whether it causes a particular rare and unusual (idiosyncratic) adverse effect. Such causality assessments are sometimes done by drug de-challenge and re-challenge. When the adverse effect is potentially serious, there is clearly an important decision to be made as to whether the re-challenge is justifiable and hence ethical. The recent controversy about the potential cardiotoxicity of fexofenadine, the fatalities associated with penicillin re-challenge and the fatalities associated with abacavir re-challenge highlight some of the potential serious risks of drug re-challenge. The associated important ethical issues are discussed. In particular, there is the need to ensure respect for the patient and to consider the scientific and social value of the re-challenge. A framework for evaluating and assessing the appropriateness of a particular drug re-challenge is proposed in the light of recent as well as long-standing discussions of drug re-challenge, patient informed consent and the ethics of human experimentation, in general. It is suggested that a drug re-challenge should be approached with the same rigour and standards of documentation as are currently required of clinical trials. Given the potential conflicts of interest inherent with any drug study, it is argued that the safeguards, as may be provided by scrutiny by an ethics committee, are necessary for a drug re-challenge. For the investigator contemplating the conduct of a drug re-challenge we would recommend the following: (i) a careful risk-benefit assessment as part of the decision-making process; (ii) careful scientific preparation, including appropriate expert support and emergency back-up facilities, if re-challenge is deemed necessary; (iii) the writing of a detailed protocol for independent approval and for safeguarding all concerned; and (iv) meticulous record keeping.

The Cochrane Skin Group. Preparing, maintaining, and disseminating systematic reviews of clinical interventions in dermatology.

In 1979, Prof Archie Cochrane challenged the medical profession to produce a critical summary of randomized controlled clinical trials according to specialty, which should be updated periodically. The Cochrane Collaboration, an international voluntary group of reviewers and researchers from a range of professional backgrounds dedicated to producing systematic reviews, was established in 1992 in response to Cochrane's challenge. Systematic reviews produced by the Cochrane Collaboration start with individuals who formulate questions that are important to the care of patients. Every effort is then made to locate published and unpublished evidence to answer the question, and explicit criteria are used to select studies for inclusion in the review and to assess their quality. If appropriate, meta-analysis is used to combine results from several smaller studies to produce an overall result. Reviews are published in the Cochrane Library, an electronic publication (CD-ROM or diskette form), and the reviews are updated quarterly. In December 1997, a Cochrane Skin Group was registered with the Cochrane Collaboration to prepare, maintain, and disseminate reviews on the effects of health care for people with dermatological conditions. Currently, 25 titles and 9 review protocols have been registered with the Cochrane Skin Group, and the first set of dermatological reviews will be available before the end of 1999. The Cochrane Skin Group aims to become the best source of unbiased external evidence for summarizing the effects of dermatological care.

Meta-analysis of randomised controlled trials comparing latanoprost with timolol in the treatment of patients with open angle glaucoma or ocular hypertension.

AIM: To evaluate the comparative efficacy and tolerance of latanoprost versus timolol through a meta-analysis of randomised controlled trials (RCTs). METHODS: Systematic retrieval of RCTs of latanoprost versus timolol to allow pooling of results from head to head comparison studies. Quality of trials was assessed based on randomisation, masking, and withdrawal. Sensitivity analyses were used to estimate the effects of quality of study on outcomes. The data sources were Medline, Embase, Scientific Citation Index, Merck Glaucoma, and Pharmacia and Upjohn ophthalmology databases. There were 1256 patients with open angle glaucoma or ocular hypertension reported in 11 trials of latanoprost versus timolol. The main outcome measures were (i) percentage intraocular pressure (IOP) reduction for efficacy; (ii) relative risk, risk difference, and number needed to harm for side effects such as hyperaemia, conjunctivitis, increased pigmentation, hypotension, and bradycardia expressed as dichotomous outcomes; and (iii) reduction in systemic blood pressure and heart rate as side effects. RESULTS: Both 0.005% latanoprost once daily and 0.5% timolol twice daily reduced IOP. The percentage reductions in IOP from baseline (mean (SE)) produced by latanoprost and timolol were 30.2 (2.3) and 26.9 (3.4) at 3 months. The difference in IOP reduction between the two treatments were 5.0 (95% confidence intervals 2.8, 7.3). However, latanoprost caused iris pigmentation in more patients than timolol (relative risk = 8.01, 95% confidence intervals 1.87, 34.30). The 2 year risk with latanoprost reached 18% (51/277). Hyperaemia was also more often observed with latanoprost (relative risk =2.20, 95% confidence intervals 1.33, 3.64). Timolol caused a significant reduction in heart rate of 4 beats/minute (95% confidence interval 2, 6). CONCLUSION: This meta-analysis suggests that latanoprost is more effective than timolol in lowering IOP. However, it often causes iris pigmentation. While current evidence suggests that this pigmentation is benign, careful lifetime evaluation of patients is still justified.

Mega-mergers in the pharmaceutical industry. In whose interests?

Companies merge to achieve economies of scale. In an industry such as the pharmaceutical industry which relies on a high level of investment in research and development, such mergers appear rational. However, it is not at all obvious that a higher level of investment by a smaller number of firms will necessarily lead to an increased rate of genuine innovations. There is a risk that conflicts of interest and the pursuit of short term gains may encourage more mergers than is optimal for the industry. The impact of mega-mergers in the pharmaceutical industry on research output, employees, shareholders, financial advisers, managers and patients is discussed. A healthy pharmaceutical industry, able to invest the necessary resources in the development of innovative medicines is in the interest of patients and shareholders alike. Over-concentration may interfere with innovative activity and lead to monopolistic power. Close scrutiny of merger activity is important but in a deregulated world, governments may have little power to act. In any case, a drug-specific monopolistic industry may be beneficial to some countries which may therefore be reluctant to act in the interest of the world as a single community in search of more effective medicines.

Herbal remedies: issues in licensing and economic evaluation.

In recent years, the use of alternative therapies has become widespread. In particular, there has been a resurgence in the public's demand for herbal remedies, despite a lack of high-quality evidence to support the use of many of them. Given the increasing pressures to control healthcare spending in most countries, it is not surprising that attention is being focused on the cost effectiveness of herbal remedies. We address the question of whether there is sufficient information to enable the assessment of the cost effectiveness of herbal remedies. In so doing, we discuss the current state of play with several of the more high-profile alternative herbal remedies [Chinese medicinal herbs for atopic eczema, evening primrose oil, ginkgo biloba, hypericum (St John's wort)] and some which have made the transition from being alternative to being orthodox remedies. We use historical context to discuss, on the one hand, the increasing commodification of herbal remedies and on the other, the trend towards greater regulatory control and licensing of alternative herbal remedies. We argue that unless great care is exercised, these changes are not necessarily in the best interests of patients. In order to identify cost-effective care, we need reliable information about the costs as well as the efficacy and safety of the treatments being assessed. For most alternative therapies, such data are not available. We believe that studies to gather such data are long overdue. Whilst we argue strongly in favour of control of some herbal remedies, we urge caution with the trend towards licensing of all herbal remedies. We argue that the licensing of those herbal remedies with equivocal benefits and few risks, as evidenced by a long history of safe use, increases barriers to entry and increases societal healthcare costs.

Systematic review of comparative efficacy and tolerability of calcipotriol in treating chronic plaque psoriasis.

OBJECTIVES: To evaluate the comparative efficacy and tolerability of topical calcipotriol in the treatment of mild to moderate chronic plaque psoriasis. DESIGN: Quantitative systematic review of randomised controlled trials. SUBJECTS: 6038 patients with plaque psoriasis reported in 37 trials. MAIN OUTCOME MEASURES: Mean difference in percentage change in scores on psoriasis area and severity index, and response rate ratios for both patients' and investigators' overall assessments of marked improvement or better. Adverse effects were estimated with the rate ratio, rate difference, and number needed to treat. RESULTS: Calcipotriol was at least as effective as potent topical corticosteroids, calcitriol, short contact dithranol, tacalcitol, coal tar, and combined coal tar 5%, allantoin 2%, and hydrocortisone 0.5%. Calcipotriol caused significantly more skin irritation than potent topical corticosteroids (number needed to treat to harm for irritation 10, 95% confidence interval 6 to 34). Calcipotriol monotherapy also caused more irritation than calcipotriol combined with a potent topical corticosteroid (6, 4 to 8). However, the number needed to treat for dithranol to produce lesional or perilesional irritation was 4 (3 to 5). On average, treating 23 patients with short contact dithranol led to one more patient dropping out of treatment owing to adverse effects than if they were treated with calcipotriol. CONCLUSIONS: Calcipotriol is an effective treatment for mild to moderate chronic plaque psoriasis, more so than calcitriol, tacalcitol, coal tar, and short contact dithranol. Only potent topical corticosteroids seem to have comparable efficacy at eight weeks. Although calcipotriol caused more skin irritation than topical corticosteroids this has to be balanced against the potential long term effects of corticosteroids. Skin irritation rarely led to withdrawal of calcipotriol treatment. Longer term comparative trials of calcipotriol versus dithranol and topical corticosteroids are needed to see whether these short term benefits are mirrored by long term outcomes such as duration of remission and improvement in quality of life.

Do codeine and caffeine enhance the analgesic effect of aspirin?--A systematic overview.

OBJECTIVE: To assess whether codeine and caffeine enhance the analgesic effect of aspirin in post-operative pain. METHOD: Systematic overview of the literature and meta-analysis of published randomized controlled trials (RCTs). RESULTS: Codeine 60 mg leads to a small increase in the analgesic effect of 650 mg of aspirin when total pain relief score (TOTPAR%) is used as a efficacy end-point. This increased effect was not seen when sum of pain intensity (SPID%) and proportions of patients responding with moderate to excellent pain relief were used as outcome measures. Caffeine did not enhance the analgesic effect of aspirin. CONCLUSION: Codeine 60 mg may produce a small increase in the analgesic effect of aspirin 650 mg. However, this effect is not clinically meaningful. Caffeine has no adjuvant analgesic effect. At over-the-counter (OTC) doses, caffeine and codeine are not useful in aspirin formulations.

Analgesic efficacy of ibuprofen alone and in combination with codeine or caffeine in post-surgical pain: a meta-analysis.

OBJECTIVE: To estimate the analgesic effect of ibuprofen and to test whether codeine and caffeine enhance its effect on post-surgical pain. METHOD: Systematic overview of the literature and meta-analysis of published randomised, controlled trials. RESULTS: Ibuprofen is effective in dental pain, episiotomy pain and other post-operative pain. There is a dose response relationship over the range 50-400 mg. The difference in total pain-relief score relative to placebo was 19-31%. On average, patients were over three times more likely to obtain moderate to excellent pain relief with ibuprofen than with placebo (response-rate ratio = 3.45) and the number needed to treat was 2.44. Codeine 60 mg enhanced the analgesic effect of ibuprofen 400 mg by about 8% in the total pain-relief scale, but it also increased its adverse effects. The additive effect of caffeine was inconsistent. CONCLUSION: Ibuprofen is an effective analgesic in post-operative pain. Codeine 60 mg adds to the analgesic effect of ibuprofen 400 mg. Any additive caffeine effect requires validation.

Design and delivery of non-parenteral vaccines.

Non-parenteral delivery of vaccines is reviewed focusing on the delivery systems that have been used for various mucosal routes of administration. Systems considered include biodegradable micro- and nanoparticles, liposomes, live bacterial and viral vectors and mucosal adjuvants. New approaches to mucosal vaccine formulation using: (i) gene fusion technology to create non-toxic derivatives of mucosal adjuvants, (ii) genetically inactivated antigens with a deletion in an essential gene, (iii) coexpression of an antigen and a specific cytokine that is important in the modulation and control of a mucosal immune response, and (iv) genetic material itself that would allow DNA or RNA uptake and its endogenous expression in the host cell are described.

Clinical measures of disease severity and outcome in psoriasis: a critical appraisal of their quality.

In clinical trials, a wide range of outcome measures has been used to evaluate the severity of psoriasis and its response to treatment. Despite their widespread use, many measures have received little attention with regards to their reliability and validity. Selecting an appropriately developed measurement tool is therefore of critical importance. We conducted a literature survey to examine the status of clinical outcome measures used in psoriasis research. The measures most commonly used were individual sign scores, e.g. for erythema, plaque thickness or scaling, and pooled indices, e.g. the Psoriasis Area and Severity Index. None of these, however, systematically fulfilled all the requirements of a validated instrument for disease assessment. Ideally, a core set of reliable and validated outcome measures for use in all psoriasis clinical trials is needed. Objective instrumental methods should minimise observer variation, but unless a simple non-invasive method can be developed, the uptake of such technology will probably be limited by cost and lack of practicality. Moreover, the translation of instrumental readings into clinically relevant measures is always a major problem, and for none of the methods has there been a robust mapping of instrumental readings on to a clinically meaningful scale. Further research is needed to determine the most appropriate and sensitive parameters to use as surrogate measures for capturing the distress which psoriatic patients feel but which is not measured with sufficient sensitivity or precision with current quality of life or distress questionnaires.

Ability of azlocillin and tobramycin in combination to delay or prevent resistance development in Pseudomonas aeruginosa.

The ability of combinations of azlocillin and tobramycin to prevent or delay resistance development in eight Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients was studied using chequerboard titration and in-vitro serial subculture. No isolate had developed resistance to tobramycin after 12 treatments with the antibiotic combination. Azlocillin resistance had not developed in four isolates after 16 exposures, and was delayed in the other four isolates for at least eight exposures. Beta-lactamase production was responsible for azlocillin resistance in two isolates and occurred to a lesser extent in a third.

Self-medication of antibacterials without prescription (also called 'over-the-counter' use). A report of a Working Party of the British Society for Antimicrobial Chemotherapy.

The availability of antimicrobial agents for self-medication may increase and could include antibacterial agents for oral or topical use. Wholesale deregulation of antibacterials would be undesirable and likely to encourage misuse of classes of agents currently important in the management of serious infections. Changed regulation from Prescription-Only Medicine (POM) to Pharmacy (P) medicine of selected agents with indications for short-term use in specific minor infections and illness is likely to have advantages to the user. However, safeguards to their use would need to be included in the Patient Information Leaflet (PIL). Agents and indications for self-medication are discussed. Any alteration in licensed status from POM to P will require careful risk-benefit assessment, including the likely impact on bacterial resistance. Safety issues also include concerns relating to age of the user, pregnancy, underlying disease and the potential for drug interactions. The importance of appropriate information with the PIL is emphasized, as is the role of the pharmacist, while ways of improving adverse event notification and monitoring are discussed. The paucity of good denominator-controlled data on the prevalence of in-vitro resistance is highlighted, and recommendations for improving the situation are made. There are currently no levels of resistance accepted by regulatory bodies on which to base a licensing decision, be it for granting a product licence, renewal of a licence or a change in licensed status from POM to P. Due consideration should be given to: the validation of user-defined indications in comparison with those medically defined; the enhancement of pharmacy advice in the purchase of such agents; improved safety monitoring; the establishment of systematic surveillance of susceptibility data.