Antibiotic resistance: a self-inflicted problem.
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Drug Industry↗
Biomedical subjects
S R Norrby
Publications and source records attributed to S R Norrby.
Carbapenems.
Carbapenems are broad-spectrum beta-lactam antibiotics that cover an absolute majority of all bacterial pathogens that possess a cell wall. The only clinically important exceptions are X. maltophilia, E. faecium, and some strains of methicillin-resistant staphylococci and penicillin-resistant pneumococci. So far, after several years of clinical use of imipenemcilastatin, emergence of resistance has been a problem mainly restricted to P. aeruginosa. The pharmacokinetics of carbapenems, especially imipenem, are complicated by the renal metabolism, necessitating the imipenem-cilastatin combination. This is not required for meropenem. The safety profile of carbapenems is favorable. With imipenem-cilastatin, nausea constitutes a practical problem in that administration times may have to be prolonged. The risk for neurologic reactions with imipenem-cilastatin has become a factor reducing the possibilities to use high doses. For all indications except bacterial meningitis, the now approved maximal dose of 4 g per day should suffice. In this respect, meropenem has an advantage over imipenem-cilastatin in that it can be used in the treatment of bacterial meningitis without apparent increased risk of seizures. Carbapenems are indicated mainly as empiric monotherapy in serious infections, such as intra-abdominal infections and infections in neutropenic patients. Combinations of carbapenems and other antibiotics should not be used routinely.
Animals↗
Fluoroquinolones and bacterial enteritis, when and for whom?
During the last decade quinolones such as norfloxacin, ciprofloxacin, ofloxacin and fleroxacin have emerged as drugs of choice for treatment of various bacterial enteric infections. Controlled studies have shown that quinolones, administered in varying regimens ranging from a single dose to 5 days treatment, significantly reduce the intensity and severity of travellers' diarrhoea as well as shigellosis. They have also been found to be highly effective in the treatment of invasive non-typhoid salmonellosis as well as typhoid fever. Results from trials evaluating quinolone treatment of uncomplicated salmonella and campylobacter enteritis have generally been disappointing. We studied norfloxacin for the empirical treatment of suspected bacterial enteritis of less than 6 days duration in a large placebo controlled trial. Although statistical differences in clinical outcome favouring norfloxacin were found among 259 culture positive patients, the differences were not striking and of doubtful clinical importance. However, a clear beneficial effect of norfloxacin, resembling that observed in early treatment of travellers' diarrhoae was found among the severely ill patients who initiated treatment within 48 h of onset of symptoms to start of treatment seemed to be of major importance in relation to therapeutic efficacy. Quinolone treatment of bacterial enteritis is furthermore limited by the rapid development of resistance seen in Campylobacter spp. and the failure of these compounds to eradicate Salmonella spp. Presently quinolones can be recommended in treatment of travellers' diarrhoea and shigellosis as well as enteric fever. They have limited usefulness for the routine empirical treatment of bacterial enteritis caused by Salmonella spp and Campylobacter spp. Treatment should be restricted to early empirical treatment of the severely ill and vulnerable patients with an underlying health problem.
Anti-Infective Agents↗
Safety profile of meropenem: international clinical experience based on the first 3125 patients treated with meropenem.
Data from 3125 patients (3220 patient exposures) treated with meropenem were compared with those from 2886 patients (2960 patient exposures) treated with a variety of comparator agents including cephalosporins (alone or in combination with aminoglycosides or an anti-anaerobe agent) and imipenem/cilastatin. Patients treated included those with bacterial infections of the lower respiratory tract, urinary tract and skin and soft tissues, abdominal, obstetric and gynaecological infections, meningitis, febrile episodes in neutropenic patients and paediatric patients with infections. In three studies, meropenem was administered intramuscularly; in the remainder, meropenem was given by 15-30 min iv infusion or by bolus injection over approximately 5 min. The usual dosages were 500 mg or 1 g 8 hourly in adults and 10 or 20 mg/kg 8 hourly in children. In bacterial meningitis, the meropenem dosage in adults was 2 g 8 hourly and 40 mg/kg 8 hourly in children. The overall pattern and frequency of adverse events with meropenem were similar to those of the other beta-lactam antibiotics with which it was compared. The most frequently reported adverse events were diarrhoea, rash, nausea and vomiting, thrombocytosis, eosinophilia and changes in hepatic biochemistry. Abnormal laboratory tests occurred with similar frequencies between meropenem and the comparator agents. The safety profile of meropenem was similar in adults and children, and the presence of renal impairment did not alter the safety profile of meropenem. Experience in clinical studies in 3220 patient exposures has revealed no unusual or unexpected toxicity. The possibility of administration by either iv infusion or bolus injection with a low incidence of nausea and vomiting also provides flexibility in the clinical management of patients. Moreover, the low incidence of reported seizures and good tolerability at high doses, make meropenem particularly useful for the treatment of meningitis and other indications which carry a risk of seizures, or in the treatment of serious infections where high doses of antibiotics are frequently indicated.
Bacterial Infections↗
Comparative antibacterial activity of L-695,256, a carbapenem active against methicillin-resistant staphylococci.
The activity of a new prototype carbapenem, L-695,256, against clinical isolates of gram-positive and gram-negative aerobes was studied in vitro by agar dilution. L-695,256 was highly active against methicillin-resistant and -susceptible isolates of staphylococci (MICs, 0.016 to 2 micrograms/ml) and against penicillin-resistant pneumococci (MICs, 0.016 to 0.064 micrograms/ml), irrespective of penicillin susceptibility. Activity against members of the family Enterobacteriaceae was less than that of imipenem, while Proteus mirabilis and Morganella morganii were more susceptible to L-695,256.
Anti-Bacterial Agents↗
Evaluation of antibiotics for treatment of urinary tract infections.
The evaluation of new regimens for treatment of urinary tract infections (UTIs) has often been unsatisfactory. A major reason has been the lack of internationally accepted guidelines for design and conduct of UTI trials. The introduction of new guidelines has largely overcome this problem. However, some problems remain, and this review especially addresses the problem of defining outcomes of treatment of UTI. New, somewhat controversial definitions of bacteriuria are well documented for various types of UTI, but have not been properly evaluated as end-points for defining bacteriological responses to treatment.
Anti-Bacterial Agents↗
The use of fluoroquinolones in neutropenic patients--analysis of adverse effects.
The fluoroquinolones have been extensively used in the neutropenic patient. When fluoroquinolone monotherapy was used as prophylaxis, frequently for extended periods, the rate of adverse effect of ciprofloxacin (6.9%) ofloxacin (11.6%) and norfloxacin (5.5%) were significantly lower than those of the comparator agents--co-trimoxazole, vancomycin and polymycin. Rash and gastrointestinal upset were the commonest adverse effects associated with the fluoroquinolones. When used as monotherapy for bacterial infections, often intravenously and in high dosages, the cumulative rate of adverse effects caused by the fluoroquinolones (12.6%) was similar to that caused by the comparator agents (10.3%), but significantly higher than reported for non-neutropenic patients (6.4%) and for prophylactic use. The main adverse events were also rashes (15.4%) and gastrointestinal upset (6.1%). When fluoroquinolones were used as therapy of bacterial infections in combination with other agents, the incidence of adverse events was 14.9%, which was similar to the comparator agents (13.5%). Adverse events were also similar except that nephrotoxicity was commonest with comparator combinations (4.0%). The data suggest that fluoroquinolone prophylaxis in neutropenic patients, even for prolonged periods, is safer than the comparator agents, but is associated with more frequent adverse events than in non-neutropenic patients. Fluoroquinolone therapy, frequently with high dosages, is associated with similar rate of adverse events as the comparator agents. When used in combination with the other antibiotics, fluoroquinolones are as safe as the comparator agents.
Animals↗
Evaluation of new anti-infective drugs for the treatment of infection with human immunodeficiency virus. The European Working Party of the European Society of Clinical Microbiology and Infectious Diseases.
This guideline describes the preclinical documentation required for a new drug active against human immunodeficiency virus (HIV) and offers suggestions regarding the design and implementation of phase 1, 2, and 3 clinical trials. Drugs with a low level of potential toxicity, especially those that are not nucleoside analogues, should be evaluated in healthy individuals who are not infected with HIV before trials in HIV-infected patients commence. The guideline also discusses possible clinical and laboratory end points for efficacy and emphasizes the need for careful validation of all laboratory end points used. The approach of the guideline is deliberately general: more specific recommendations would soon become outdated in this field, which is characterized by extremely rapid developments.
Anti-Infective Agents↗
Monotherapy in serious hospital-acquired infections: a clinical trial of ceftazidime versus imipenem/cilastatin. European Study Group.
The clinical and bacteriological efficacy and safety of the antibiotics ceftazidime or imipenem/cilastatin in seriously ill patients with nosocomial infections were compared in a prospective, open, evaluator-blind, multicentre comparative trial. The study was performed in 26 European centres, the majority being intensive care units. Subjects were randomized to receive either ceftazidime 2 g bid or imipenem cilastatin 0.5 g qid given for at least five days after stratification for pneumonia, septicaemia or urinary tract infection (UTI). Three hundred and ninety-three patients with serious nosocomial infections (254 with pneumonia; 91 with septicaemia and 48 UTI were treated between February 1988 and January 1990 and their clinical and bacteriological response to antibiotic treatment assessed. There were no significant differences between ceftazidime and imipenem/cilastatin in clinical efficacy. The failure rates in evaluable patients were 22 and 26% in pneumonia, 23 and 19% in septicaemia and 0 and 5% respectively in those with UTI. Overall there was no significant difference between the two antibiotics for bacteriological response in the three infection strata. However, in patients with pneumonia ceftazidime was significantly more effective than imipenem/cilastatin in clearing patients of Pseudomonas spp.: 3/17 and 11/19 patients respectively had persistent growth of Pseudomonas spp. post-treatment (P = 0.004), and in one ceftazidime failure resistance emerged compared to six imipenem/cilastatin failures in which resistance emerged. Few drug-related adverse events were recorded in either treatment group. Monotherapy with either ceftazidime (2 g bid) or imipenem/cilastatin (0.5 g qid) is safe and effective and could be considered as an alternative to combination therapy for the treatment of serious hospital-acquired infections.
Adolescent↗
Efficacy of antimicrobial agent treatment in relation to treatment regimen: experimental models and clinical evaluation.
The effect of the duration of treatment on clinical and bacteriological efficacy is generally poorly evaluated for antimicrobial agents. Infection model studies have to a large extent concentrated on endocarditis. In clinical trials systematic and well controlled studies are abundant in the field of urinary tract infections and streptococcal tonsillopharyngitis, but almost non-existent in other types of infections. Paradoxically, most of the infections studied by experimental models are uncommon in man and evaluation of optimal treatment periods for these by clinical trial is therefore difficult. In the evaluation of new antimicrobial agents, closer collaboration of experimental model and clinical trial investigators is required to design models of infections and clinical trials to evaluate optimal duration of treatment.
Animals↗
Safety and tolerability of fluoroquinolones.
Since 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.
Adverse Drug Reaction Reporting Systems↗
Cefpirome: efficacy in the treatment of urinary and respiratory tract infections and safety profile.
The efficacy and safety of cefpirome was reviewed from the documentation of comparative pivotal trials in patients with urinary tract or lower respiratory tract infections UTIs and LRTIs, respectively). A majority of patients with UTIs had pyelonephritis and/or complicated UTIs. Most patients with LRTIs had community acquired pneumonia. Studies of UTI included 865 patients treated with cefpirome 1 g bid and 443 patients allocated to ceftazidime 1 g bid. Satisfactory clinical outcome was reported in 87% and 83%, respectively. Eradication of organisms causing bacteriuria was achieved in 87% and 86%, respectively. In the LRTI trials 199 patients received cefpirome 1 g bid and in 653 patients it was dosed 2 g bid. Comparators were ceftazidime 2 g bid (N = 197) or 2 g tid (N = 296) or ceftriaxone 1 g bid (N = 77). With all treatments unsatisfactory clinical or bacteriological outcome was recorded in < 15% of the patients. The safety of cefpirome and comparators was evaluated in pivotal phase II and III studies and deaths were analysed in all clinical trials for which data were available by June 30th 1991. Cefpirome did not differ from comparators in terms of frequencies or distribution within body systems of adverse events. Death rates were 3.9% in 9189 patients receiving cefpirome and 5.1% in 3162 receiving a comparator. The deaths were in an absolute majority of cases not considered related to study drug given. The most common cause of death was infection, indicating that the trial samples were selected from populations of patients with serious infections. Cefpirome was as safe and efficaceous as its comparators and is a new injectable cephalosporin with broader spectrum than ceftazidime. It should be a suitable alternative for empiric treatment of serious infections in hospitalised patients.
Adolescent↗
Efficacy of cefpirome in the treatment of septicaemia.
From a total of 4180 patients entered in 15 phase II-III clinical trials involving cefpirome, an analysis was carried out on 378 patients with bacteriologically confirmed or suspected septicaemia who were treated with cefpirome (n = 282) or comparator drugs (ceftazidime, n = 80; ceftriaxone, n = 15; imipenem/cilastatin, n = 1). Gram-negative organisms were the causative pathogens in over half of the patients, with Escherichia coli being the most common species found. The most frequently isolated Gram-positive bacterium was Streptococcus pneumoniae. Causative organisms were eradicated in over 90% of patients receiving cefpirome or comparators. Only 4/230 pathogens tested were resistant to cefpirome in vitro. Among patients with bacteriologically confirmed septicaemia, a satisfactory clinical response was documented in 131/176 (74%) cefpirome vs 34/50 (68%) ceftazidime vs 5/10 (50%) ceftriaxone recipients, improvement in 39/176 (22%) vs 11/50 (22%) vs 5/10 (50%), and failure in 6/176 (4%) vs 5/50 (10%) vs 0/10 (0%), respectively. Similar results were achieved in patients with 'suspected' septicaemia. Cefpirome 1 or 2 g twice daily offers an effective treatment option for patients with septicaemia. The higher dosage regimen produced superior bacteriological clearance rates and is therefore preferable in patients with severe septicaemia.
Anti-Bacterial Agents↗
Design of clinical trials in patients with urinary tract infections.
This overview deals with the optimization of the design of clinical trials in patients with urinary tract infections (UTIs). Despite the fact that UTI is one of the most common types of infection and that the main end-point (elimination or persistence of bacteriuria) is objective and easy to register, the quality of studies performed and published has generally been less than optimal. Problems that should always be addressed in the study protocol are definitions of terms used, for example bacteriuria, level of the infection (cystitis or pyelonephritis), and uncomplicated and complicated infections; dimension of the patient's sample to allow adequate testing of a null hypothesis; procedures before, during and after treatment; methods for analysis of the results.
Bias↗
Fluoroquinolones and bacterial enteric infections.
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Anti-Infective Agents↗
Ecological effects of short-term ciprofloxacin treatment of travellers' diarrhoea.
Forty-two subjects travelling to Mexico for 11 days were enrolled in a randomized, double-blind, placebo-controlled trial comparing ciprofloxacin 250 mg twice daily for three days or placebo for treatment of travellers' diarrhoea. Seventeen (41%) subjects were randomized to treatment. By the last treatment day, all seven evaluable subjects in the ciprofloxacin group, and three of eight evaluable subjects in the placebo group were cured (P = 0.04). The mean time to cure was 26 h for ciprofloxacin and 60 h for placebo-treated patients (P = 0.03). Faecal specimen were collected pre-travel, after four days in Mexico, 48 h post-travel and four weeks post-travel. Potentially pathogenic Escherichia coli strains carrying diarrhoeagenic virulence genes were detected by DNA hybridization tests, during or after travel, in 41% of treated and 31% of asymptomatic travellers. Travel, irrespective of diarrhoea and type of treatment, had a minor impact on the aerobic and anaerobic microflora. In travellers with ongoing diarrhoea, a suppression of the numbers of anaerobic bacteria was found, but the microflora was otherwise virtually unaffected. Significantly increased frequencies of E. coli resistant to ampicillin, doxycycline, chloramphenicol and co-trimoxazole were found during and after travel in all categories of travellers, though more frequently in subjects who experienced diarrhoea. The susceptibility of Bacteroides spp. remained unchanged. The sensitivity of E. coli to ciprofloxacin was not affected by travel, except in four ciprofloxacin-treated subjects who acquired multiresistant E. coli with ciprofloxacin MICs of > or = 0.125 mg/L post-travel. Bacteroides strains with MICs of > or = 64 mg/L were isolated post-travel from four ciprofloxacin-treated patients, and from one of the other 34 travellers not treated with ciprofloxacin.
Administration, Oral↗
Pharmacokinetics of cefepime dihydrochloride arginine in subjects with renal impairment.
In this study, the safety, tolerance, and pharmacokinetics of a single 1-g intravenous dose of cefepime (BMY-28142) were investigated. Twenty-three volunteers with various degrees of renal function were assigned to four trial groups according to glomerular filtration rates (GFR). Group IV consisted of five patients with end-stage renal disease undergoing treatment with hemodialysis. Cefepime concentrations in samples from plasma, urine, and infusion solutions were assayed with high-pressure liquid chromatography. The volume of distribution corresponded to the assumed extracellular fluid volume and did not differ significantly between the four groups. The area under the concentration-time curve increased as renal function decreased; in group II (GFR, 31 to 80 ml/[min x 1.73 m2]; n = 6), it was already three times higher than in group I (GFR, > or = 80 ml/[min x 1.73 m2]; n = 5). Mean residence time was 2.4, 6.8, 11.4, and 31.6 h for the four groups, respectively. Total clearance decreased (97.2, 34.6, 19.8, and 6.3 ml/[min x 1.73 m2]) with decreasing renal function, and a linear relationship between total plasma clearance and GFR was found with the regression equation y = 0.92x-2.0 (r = 0.991). Renal clearance was linearly correlated to GFR with the regression equation y = 0.87x-6.1 (r = 0.989), indicating that renal elimination is mainly by glomerular filtration. During hemodialysis, the extraction ratios were between 0.40 and 0.65. Dialysis clearance varied between 69.9 and 94.6 ml/(min x 1.73 m2).
Adult↗
Pharmacokinetics of meropenem in subjects with various degrees of renal impairment.
Five healthy volunteers and 18 patients with various degrees of renal impairment received 500 mg of meropenem intravenously as a 30-min infusion. Five dialysis patients were dosed 2 h prior to hemodialysis, and four of them were also dosed between hemodialysis treatments. Plasma and urine samples were collected for up to 48 h and 12 h, respectively. Concentrations of meropenem and its open ring metabolite ICI 213,689 were determined by high-performance liquid chromatography and radioimmunoassay, respectively. The subjects were divided into four groups with glomerular filtration rates (GFR) of greater than 80, 30 to 80, 5 to 29, or less than 5 ml/min. There were linear correlations between the GFR and the rates for total plasma clearance as well as renal clearance of meropenem (group mean values for total clearance of 186, 74, 53, and 19 ml/min/1.73 m2, respectively). In subjects with normal renal function, nonrenal clearance accounted for approximately 20% of total elimination, increasing to about 50% in patients with GFR between 5 and 29 ml/min/1.73 m2. The terminal half-life of meropenem increased from 0.9 h in the healthy volunteers to 6.8 h in patients with end-stage renal disease. The half-life of ICI 213,689 was 2.31 h in the healthy volunteers and increased to 23.6 h in patients with GFR of 5 to 29 ml/min. In patients with end-stage renal disease, half-lives could not be measured, as concentrations were hardly declining during the 48-h observation period. The area under the concentration-time curve for meropenem increased more than 10-fold. Both meropenem and its open ring metabolite were readily dialyzable, with dialysis clearances of 79 and 81 ml/min/1.73 m2, respectively.
Adult↗