S. Ragnar Norrby

Urinary tract infections : Disease panorama and challenges

The major goal of this conference was to review new advances in our undertaking of the pathogenesis of urinary tract infections (UTIs) from the perspective of both the pathogen and the host. This initial presentation provided an appropriate context for subsequent discussion by providing an overview of the etiology and epidemiology of UTI, diagnostic and therapeutic approaches, current management strategies, evolution of antimicrobial resistance, and current approaches to prevention.

Safety and Tolerability of Fluoroquinolones

SummarySince their introduction in the mid-1980s, the fluoroquinolones have been administered to more than 100 million patients. Generally, adverse effects reported in association with the fluoroquinolones have been those that could have been predicted by previous experience with non-fluorinated derivatives and by animal toxicity studies. Examples of such adverse events are CNS-related toxicity, upper gastrointestinal tract reactions and phototoxicity. Some adverse experiences in animals, notably cartilage toxicity, have been of minimal clinical importance. This should lead to a re-evaluation of the possible paediatric indications for the fluoroquinolones.With temafloxacin, which was withdrawn from clinical use in June 1992, new and serious adverse events were reported at a frequency of about 1 per 3500 patients treated. This frequency of adverse events is too low to be detected even in very careful analyses of phase III registration studies. Anaphylaxis, haemolytic anaemia and renal failure were the most striking adverse events reported with temafloxacin, and, in addition, hypoglycaemia and hepatic failure were reported. These reactions may be attributable to an immunological reaction in some patients. Because of the rarity of these reactions, they can be detected only by studies encompassing thousands of patients, usually during postmarketing surveillance. Safety monitoring of each new fluoroquinolone during its early clinical use is therefore recommended.

Interference of Antibody Production to Hepatitis B Surface Antigen in a Combination Hepatitis A/Hepatitis B Vaccine

A randomized trial comparing 3 manufacturing consistency lots of a combination hepatitis A/hepatitis B vaccine to each other and to hepatitis A vaccine and hepatitis B vaccine given separately and concurrently was done to evaluate safety, tolerability, and immunogenicity. Healthy volunteers >/=11 years of age were divided into 4 groups. Each of 3 groups received a separate consistency lot of the combination vaccine, and 1 group received separate but concurrent injections of hepatitis A and hepatitis B vaccines. Injections were given at weeks 0 and 24. The combination vaccine was generally well tolerated. The hepatitis A portion of the combination vaccine produced clinically acceptable high seropositivity rates 4 and 52 weeks after the first injection. The hepatitis B portion of the vaccine did not produce clinically acceptable seropositivity rates 4 weeks after the second injection. Lack of antibody production may be attributed, at least in part, to immunologic interference.

Carbapenems in serious infections : A risk-benefit assessment

The tolerability of the 2 most frequently used carbapenems, imipenem/cilastatin and meropenem, is reviewed. Both of these drugs, but especially imipenem, are potentially neurotoxic and may cause seizures if overdosed relative to renal function and/or bodyweight. The therapeutic margin is considerably narrower with imipenem/cilastatin which cannot be given at doses required for treatment of bacterial meningitis. Meropenem on the other hand, is considerably less prone to cause seizures and its tolerability and efficacy are well documented in 3 relatively large, controlled studies in adults and children with meningitis. They showed that meropenem was as effective and well tolerated as cefotaxime or ceftriaxone. Another potential advantage of meropenem over imipenem/cilastatin is that it can be given intravenously at a high rate without increased risk of nausea or vomiting. An obvious reason for using a carbapenem instead of a cefalosporin for empirical treatment of life-threatening infections is that both imipenem/cilastatin and meropenem have a broader spectrum of activity. They are also more resistant to hydrolysis by the most common β-lactamases, including the class I cephalosporinase frequently produced by Enterobacter spp. and Pseudomonas spp. and the extended spectrum enzymes, now commonly found in Escherichia coli and Klebsiella spp.

Long-term Study of Lyme Borreliosis in a Highly Endemic Area in Sweden

From May 1991 to May 1994, Lyme borreliosis was studied prospectively in 301 residents living on Aspö, a highly endemic area for the disease. The study included annual questionnaires and blood samples for serology. Immunoglobulin G (IgG) antibodies to Borrelia burgdorferi sensu lato were detected by enzyme-linked immunosorbent assay in 63/301 (21%) of the residents at the start of the study. Seropositivity rates increased with time, and 3 years later 101/301 (34%) were positive. A total of 34 individuals developed physician-verified manifestations of Lyme borreliosis during the study period. Nine individuals developed an erythema migrans, despite a previously treated Lyme borreliosis or pre-existing high levels of IgG antibodies to B. burgdorferi s.l.

Comparative immunogenicity and tolerance of Vaqta and Havrix

In an open-label, randomised trial, 520 adults of both sexes aged 18-30 years were allocated to receive one of two inactivated hepatitis A vaccines; Vaqta or Havrix, at 0 and 24 weeks. Doses used were 50 or 100 antigen units (U) of Vaqta and 1440 enzyme linked immunosorbent assay U of Havrix given as 1 ml intramuscular injections. For each trial group safety data were available for all subjects and full serological data for more than 80% of randomised volunteers. Local side effects which were mild in most cases were significantly (p < 0.0001) more common with Havrix than with Vaqta, irrespective of dose given. Systemic tolerance was similar for the 3 regimens. From 4 weeks after the first dose, > or =94% of the subjects had seroconverted. The mean antibody titres 4 weeks after the second vaccine dose were 2978, 4346 and 1589 mIU/ml in subjects who were randomised to Vaqta 50 U/dose, Vaqta 100 U/dose and Havrix 1440 U/dose, respectively. The 2 vaccines had similar immunogenicity but local tolerance was better with Vaqta.

Cost-effective prophylaxis of surgical infections.

There are few formal pharmacoeconomic studies of antibacterial prophylaxis in surgery. An important reason for this is that such prophylaxis is difficult to study, because extremely large patient samples are needed to demonstrate differences or equalities with reasonable statistical power. When the cost effectiveness of various regimens is evaluated, indirect methods must often be used. Clearly, the ideal prophylactic regimen, both clinically and economically, is one that is easy to administer, has a low acquisition cost, can be given as a single dose and provides maximal protection against postoperative infections. However, if and when such a regimen is identified, its universal acceptance and use might have negative ecological consequences (e.g. the selection of resistant organisms in the hospital environment). Thus, the search for the ideal prophylactic regimen must be a continuous process.SummaryThere are few formal pharmacoeconomic studies of antibacterial prophylaxis in surgery. An important reason for this is that such prophylaxis is difficult to study, because extremely large patient samples are needed to demonstrate differences or equalities with reasonable statistical power. When the cost effectiveness of various regimens is evaluated, indirect methods must often be used. Clearly, the ideal prophylactic regimen, both clinically and economically, is one that is easy to administer, has a low acquisition cost, can be given as a single dose and provides maximal protection against postoperative infections.However, if and when such a regimen is identified, its universal acceptance and use might have negative ecological consequences (e.g. the selection of resistant organisms in the hospital environment). Thus, the search for the ideal prophylactic regimen must be a continuous process.

Pharmacoeconomic Studies on Antibiotics

It has become more and more evidem that not only heahhcare administrators but also physicians and nurses must take an active part in trying to reduce costs for healthcare. One field which has received much attention. probably because cost reductions normally do not result in hospital staff reductions. is the cost of drugs. Pharmacoeconomics has become a special field of interest and scientific efforts, In assessments of economic consequences of drug utilisation, it is importantto realise that neither expertise in the field of pharmacology, nor in economic sciences alone suffice; bothJields must be combined. If that is not the case, the risk of fal se conclusions is obvious. In the area of antibiotics, few high quality studies on pharmacoeconomics have been published . and there are reasons to suspect thai quite a few of the publications which have appeared were supported by the pharmaceutical industry. In this article, by an author who has some knowledge in the development and use of antibiotics bUi who lacks formal training in economic sciences. some problems in evaluations of pharmacoeconomic studies on antibiotics are discussed. For a more extensive overview of the field. the reader should consult a review by Davies and colleagues (1992).

Challenges in the design of trials to evaluate antibacterial agents in serious infections

Decisions on the introduction of a new antibiotic for treatment of serious infections should be based on its (i) comparative in-vitro activity; (ii) pharmacokinetic properties; (iii) clinical and bacteriological efficacy in comparative clinical trials; and (iv) safety profile. For most new antibiotics abundant documentation is normally available on their antibacterial activities, including, when relevant, those against nosocomial pathogens such as Pseudomonas aeruginosa, Pseudomonas spp., Enterobacter spp., Serratia spp., Acinetobacter spp. and Citrobacter spp. The documentation of the pharmacokinetic properties of a new antibiotic is also quite extensive in most cases. However, it is not unusual that information is insufficient about the kinetics of an antibiotic in special patient groups, for example elderly patients, neonates and infants. Such data should be required before an antibiotic is accepted for routine therapy in hospitalized patients (Working Party of the British Society of Antimicrobial Chemotherapy, 1989). This article will deal with the optimal conduct of comparative efficacy and safety trials of antibacterial agents in seriously ill patients. As an example, an ongoing prospective, comparative, randomized, open, evaluator-blinded multi-clinic trial of ceftazidime vs. imipenem/cilastatin in patients with serious hospital acquired pneumonia, urinary tract infections or septicaemia, will be discussed.

Antibiotic resistance: a self-inflicted problem

Since the introduction of sulphonamides and benzylpenicillin, bacteria have developed resistance to antibiotics. Until recently this was a manageable problem because new antibiotics able to overcome resistance were continuously being developed. This is no longer the case. We now see bacteria resistant to all or most marketed antibiotics. An example is multi-resistant strains of enterococci, which have caused outbreaks of untreatable and even fatal nosocomial infections [1–3]. Another example is penicillin-resistant pneumococci, which are now common all over the world [4, 5]. Such strains are still treatable when they cause respiratory tract infections, but meningitis may be therapy-resistant [6]. Also, we now frequently face problems with the lack of inexpensive oral antibiotics for treatment of infections like otitis media [7]. In most countries, nosocomial infections caused by methicillin®resistant staphylococci are common, and there are indications also that communityacquired skin and soft tissue infections may be caused by methicillin-resistant Staphylococcus aureus [8]. If this happens, we might find ourselves having access to few, if any, oral antibiotics for treatment of soft tissue infections. With Gram-negative enteric bacteria, many hospitals face a situation where a majority of organisms such as Enterobacter spp. and Pseudomonas spp. are resistant to third-generation cephalosporins. For example, of blood culture isolates in one university hospital in Hong Kong, only 14% of Enterobacter spp. and 28% or Acinetobacter spp. were susceptible to ceftazidime in 1993 and 1994 (unpublished data). Another major threat is the increasing frequency of multiply resistant strains of Mycobacterium tuberculosis [9, 10]. This problem is likely to be aggravated when the number of AIDS cases increases in countries with high endemicity of tuberculosis, like India and Thailand. What are the reasons for this development and what can be done about it? The main cause of antibiotic resistance is overuse of antibiotics. In Finland, a high proportion of strains of group A betahaemolytic streptococci became resistant to erythromycin and other macrolides when the use of these antibiotics increased [11]. In all countries, the use of antibiotics has increased dramatically during the last decade but there has been no corresponding decreases in morbidity or mortality in bacterial infections. Thus, there clearly is an overuse of antibiotics and if this main problem is not addressed, the resistance situation is unlikely to improve. The patient is sometimes blamed for the overuse of antibiotics. An overbelief in the benefits of antibiotics, especially for treatment of respiratory tract infections, is common in the public. This may lead to pressure by patients or their parents to receive antibiotic treatment. If physicians give in to such demands the result will be ineffective therapy which may cause adverse effects and which increases the ecological pressure with subsequent risk of emergence of antibiotic resistance in bacteria colonizing the oropharynx. The obvious solution is to explain to the patient why a majority of respiratory tract infections should not be treated with antibiotics. In tuberculosis, the problem is the opposite. Here the main reason for the emergence of resistance is poor compliance leading to insufficient treatment and resistance. Again, proper information is essential as is the search for regimens that are inexpensive, well tolerated and easy to take. Pharmacists are normally not trained to prescribe antibiotic treatment. However, in many countries antibiotics are (officially or unofficially) available