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.

Antibiotic resistance: a view from the pharmaceutical industry.

The development of new antibiotics has been successful in significantly reducing morbidity and mortality. With increasing use there has occurred an increase in antibiotic resistance but not a parallel increase in new agents with significantly improved spectrum of activity. Without concerted action from the pharmaceutical industry, physicians, academia, health care providers, and governments, the prospects look gloomy.

Antibiotic treatment and associated prolonged prothrombin time.

The incidence and type of pathology causing a prolonged prothrombin time and clinical bleeding episodes were assessed in a multicentre study of 1109 patients receiving cefotetan, a N-methyl-thiotetrazole (NMTT), or equivalent antibiotics. There was no significant difference in the incidence of a prolonged prothrombin time (9.9% with cefotetan, 8.0% with comparable antibiotics) of clinical bleeding episodes. However, prothrombin time increases of greater than 12 seconds were significantly (p = 0.002) greater with cefotetan (3.8%) than with comparators (0.8%). In both antibiotic groups increases in prothrombin time were more likely following surgery and in patients who were older, with a high platelet count, low albumin, or higher urea and creatinine concentrations. All antibiotic treatment can be associated with prolonged prothrombin times and new agents should always be assessed in a large multicentre study before the practical, clinical importance of haemostatic defects can be defined.

The pharmacokinetics of meropenem in volunteers.

Two human volunteer studies were performed with meropenem: a dose proportionality study of 0.25, 0.5 and 1.0 g and a probenecid interaction study. Six volunteers took part in each study. Meropenem was generally well tolerated: One volunteer was withdrawn from the dose proportionality study because of looseness of stool and abdominal pain after a dose of 1.0 g. The plasma concentrations of meropenem were linearly related to dose. The half-life of meropenem was approximately 1 h and the urinary recovery of unchanged drug was 79%. In the presence of probenecid the plasma half-life of meropenem was increased by 33% but the urinary recovery was unaffected.

The human pharmacokinetics of cefotaxime and its metabolites and the role of renal tubular secretion on their elimination.

The pharmacokinetics of cefotaxime were investigated in human volunteers given constant intravenous infusions, intravenous bolus, and intramuscular doses of the drug. After intravenous dosing, the plasma levels of cefotaxime declined in a biphasic manner with a terminal half-life varying between 0.92 and 1.65 hr. Moreover, the pharmacokinetics were linear up to at least a 2.0 g dose for volume of distribution based on area (23.3-31.3 l), plasma clearance (249-2.88 ml/min), and renal clearance (151-177 ml/min). Renal tubular secretion of intact cefotaxime and each of its metabolites was demonstrated by its interaction with probenecid, although the ratio of drug to metabolites ultimately excreted in urine after probenecid was similar to that seen normally (54 +/- 6, 19 +/- 4, 6.5 +/- 0.7 and 5.5 +/- 0.7% for cefotaxime, DACM, M2, and M3, respectively, when calculated as a percentage of the dose). The observed half-lives of DACM, M2, and M3 were 2.3 +/- 0.4, 2.2 +/- 0.1 and 2.2 hr, respectively. However, when the true half-life of DACM was calculated (0.83 +/- 0.23 hr) it was not only significantly shorter than that observed but also shorter than that for intact cefotaxime. The plasma clearance of DACM (744 +/- 226 ml/min) was much higher than that of cefotaxime while the volume of distribution was of a similar order (56 +/- 24 l). When administered intramuscularly, there was good absorption of cefotaxime from the site of injection (92-94%) giving maximum plasma levels of the drug of between 30 and 35 mg/l at approximately 40 min after dosing. Thereafter, the plasma levels of cefotaxime declined in a monophasic manner with a half-life (1.0-1.2 hr) similar to that of the terminal half-life seen after intravenous administration. Lidocaine had no significant effect on either its absorption or elimination kinetics.

Cefotaxime: United Kingdom clinical trial results in the treatment of severe infections.

A multicentre study was carried out to assess the efficacy and tolerance of the wide-spectrum cephalosporin, cefotaxime, in the treatment of 411 hospitalized patients, most of whom were seriously ill with severe infections, including septicaemia, lower respiratory tract infection, urinary tract infections and soft tissue infection. Almost half the patients had failed to respond to previous antibacterial therapy and, in general, prognoses were poor. Patients received cefotaxime by intramusclar or/and intravenous injection in unit doses ranging from 0.5 to 2.0 g, 6 to 12 hourly, for periods up to 10 days or more. The results of clinical response in those who could be assessed showed a cure rate of 75% in 103 patients with septicaemia and over 80% in all other conditions.The bacteriological findings after treatment showed a similarly high eradication rate in a wide range of pathogens, particularly so in infections caused by E. coli, Klebsiella, H. influenzae, Proteus, Staph, aureus, staph. epidermis and Strep. pneumoniae. Useful clinical activity was also demonstrated in infections caused by moderately sensitive pathogens such a Pseudomonas and Strep. faecalis. Cefotaxime was well tolerated by the majority of patients, the commonest side-effects reported being moderate pain of short duration or phlebitis on injection, rash and diarrhoea, as with other cephalosporins. It is concluded that cefotaxime should be considered as a first line antibiotic for patients with severe infections caused by susceptible pathogens.