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Enoxacin decreases the metabolic clearance of the bronchodilator theophylline not only in severely ill patients, but also in patients with stable chronic obstructive airways disease. In this comparative study, significantly increased plasma theophylline concentrations were measured during co-administration of enoxacin (110.9%) and, to a lesser degree, also during co-administration of pefloxacin (19.6%) and ciprofloxacin (22.8%). Total body clearance of theophylline was significantly decreased by enoxacin (63.6%), ciprofloxacin (30.4%) and pefloxacin (29.4%). The pharmacokinetic parameters of theophylline did not change during co-administration of ofloxacin and nalidixic acid. There is growing evidence that the observed interaction is caused not by the parent drugs, but by the 4-oxo metabolite of enoxacin, pefloxacin and ciprofloxacin. [ABSTRACT FROM AUTHOR]

In patients treated concurrently with theophylline and enoxacin, a new broad-spectrum antibacterial agent of the quinolone class, unexpectedly high plasma theophylline concentrations were measured. In part I of this study, daily plasma theophylline concentrations were measured in 14 patients. The mean +/- s.d. theophylline concentrations increased from 8.5 +/- 2.8 micrograms ml-1 prior to enoxacin to a maximum of 21.7 +/- 7.8 micrograms ml-1 during coadministration. In part II, six of these patients received aminophylline intravenously at a constant infusion rate and under controlled conditions. Plasma theophylline concentrations rose from 8.4 +/- 2.4 micrograms ml-1 prior to enoxacin treatment to 15.0 +/- 5.1 micrograms ml-1 at day 3 of coadministration (P less than 0.005). Plasma protein-binding and renal clearance of theophylline remained unchanged, whereas total body clearance of theophylline significantly decreased (P less than 0.005). From these observations it is concluded that the rise of plasma theophylline concentrations is caused by a reduced metabolic clearance of theophylline. If concomitant use of both drugs is necessary, monitoring of plasma theophylline concentration and adjustment of the theophylline dose is recommended. [ABSTRACT FROM AUTHOR]

The Dutch Working Party on Antibiotic Policy (SWAB) develops evidence-based guidelines, aimed at optimalisation of antibiotic use and limitation of the spread of antimicrobial resistance. A revision of the SWAB guideline for the treatment of community-acquired pneumonia (CAP), published in 1998, was considered necessary because of changes in resistance patterns and new insights into the epidemiology, diagnostics and treatment of CAP. In contrast to the former version, this guideline is transmural and has been drawn up according to the recommendations for evidence-based guideline development by a multidisciplinary committee consisting of experts from all relevant professional societies. The 'severity of disease' exhibited by the patient with pneumonia on admission is considered important for the choice of the optimum empirical treatment strategy. Severely ill patients are treated empirically with a drug directed against multiple potential pathogens, including Legionella spp. Classification according to 'severity of disease' can be accomplished with a validated scoring system (Pneumonia Severity Index or CURB-65 score) or pragmatically, based on the site of treatment: an outpatient setting, a clinical ward or an intensive care unit. The Legionella urine antigen test plays an important role in decisions on the choice of initial antibiotic treatment.

The Stichting Werkgroep Antibioticabeleid (SWAB, Foundation Antibiotic Policy Team) issued guidelines for empirical antimicrobial therapy in the hospital of sepsis in adults. A distinction is made between sepsis in patients with and patients without neutropenia. Patients without neutropenia are subdivided according to the setting where they contracted sepsis: at home, in the hospital or in the intensive-care unit. Because of the diversity in antibiotic spectrum of the different classes of cephalosporins, they can be used in all the categories of sepsis. The use of antibiotics with a very broad spectrum, like carbapenems and piperacillin-tazobactam, or antibiotics which can be applied in infections with microorganisms difficult to treat, like quinolones and glycopeptides, is limited in the empirical treatment of sepsis in order to combat development of resistance. It is crucial to streamline antibiotic therapy as soon as the causative agent of the sepsis is known; this includes choosing an antibiotic with the narrowest possible spectrum.

The Stichting Werkgroep Antibioticabeleid (SWAB, Foundation Antibiotics Policy Team) has issued guidelines for empirical antimicrobial therapy of adult patients with bronchitis in hospital. Acute bronchitis is rarely caused by bacteria: therefore antibiotic treatment is not indicated in most cases. In an exacerbation of asthma or chronic obstructive pulmonary disease (COPD), the primary treatment aims at combating the inflammatory reaction and the bronchospasm. In case of increasing dyspnoea, (increase of) sputum production and (increase of) purulence of the sputum, antibiotic treatment may lead to shortening of the symptoms and sickness duration. Doxycycline is to be preferred because of its spectrum, easy dosage and favourable price. If the patient has not had antibiotics earlier, amoxicillin also is a good choice. Macrolide antibiotics are no preparations of first choice because large-scale use readily leads to resistance.

The Netherlands Antibiotic Policy Foundation issued guidelines for empirical antimicrobial therapy of adult pneumonia patients in hospitals. A distinction is made between pneumonia contracted at home or in hospital because of the differences in micro-organisms and resistance patterns. These two categories are subdivided further with an empirical antibiotic treatment being chosen on the basis of the causative agents to be expected. For instance, pneumonia contracted at home is mostly caused by Streptococcus pneumoniae, to be treated with benzylpenicillin or amoxicillin. With regard to nosocomial pneumonia, treatment varies according to whether a pneumonia has or has not been contracted in the intensive care unit. Combating development of resistance is alloted an important place. Emphasis is laid on 'streamlining' the therapy, i.e. its adjustment (including choosing an antibiotic with the narrowest possible spectrum) once the causative agent is known.

The worldwide problem of antibiotic resistance of bacteria is a point of concern in the Netherlands as well. Responsible use of existing antibiotics was the incentive to establish a foundation, with the acronym SWAB, the primary goal of which is to optimize the use of antibiotics in the Netherlands in order to diminish the development of antibiotic resistance. One of the SWAB projects is the development of national guidelines for the use of antibiotics in hospitals. These guidelines are prepared by a committee of experts and reviewed by external consultants: infectious disease specialists, medical microbiologists and pharmacists. The revised version of the guidelines is submitted for publication in this journal. The SWAB hopes that these guidelines will make the prevention of antibiotic resistance a major factor in the choice of the antibiotic. Streamlining antibiotic therapy is an important tool in this respect.

A pooled data analysis of two double-blind studies encompassing 1137 episodes of community-acquired pneumonia in hospitalised adults, of which 560 were treated with sparfloxacin and 577 were randomised to comparator antibacterial agents (amoxycillin/clavulanic acid, erythromycin or amoxycillin administered at reference dosages), was performed. The global efficacy rate at the end of treatment in evaluable patients treated with sparfloxacin was 88.3% compared with 84.1% in those who received comparator antibacterial agents. This analysis verified the efficacy of this new aminofluoroquinolone, given orally once daily, in the treatment of community acquired pneumonia. The overall outcome favoured sparfloxacin for use in the empirical treatment of community-acquired pneumonia.

The antibiotic policy in 34 Dutch formularies for the treatment of urinary tract infections (UTI) was evaluated. A great variation in antibiotic therapy for the treatment of cystitis was observed: the length of therapy ranged from 1 to 14 days, the agents recommended included older compounds such as trimethoprim-sulfamethoxazole and newer agents such as ciprofloxacin. Recommendations for the treatment of acute pyelonephritis were: a 2 week course of co-trimoxazole in 20 out of 34 formularies. Likewise for acute prostatitis less variation was observed for the length of treatment, i.e. 2 weeks co-trimoxazole, doxycycline or quinolones.

In order to assess the guidelines available in Dutch hospitals for the treatment of patients with serious infection of unknown aetiology, 39 antibiotic formularies used in 88 hospitals were analyzed. The recommendations considered were those for the treatment of sepsis for which the source was not apparent or which originated in the urinary tract, respiratory tract or abdomen. beta-Lactam antibiotics (most commonly amoxycillin and cefuroxime) were the preferred agents for empirical therapy of infections of all types; an aminoglycoside was also included in the majority of regimens, irrespective of the clinical presentation. However, there were wide variations in the choice and dosages of the drugs administered. Because of the absence of local data for the susceptibilities of blood culture isolates, the appropriateness of the recommendations could not be properly evaluated.

The guidelines for antimicrobial prophylaxis in various types of bowel surgery (colorectal, biliary and gastroduodenal) in 33 antibiotic formularies used by 89 Dutch hospitals were studied. The majority of the formularies recommended drugs with adequate efficacy against bacteria most frequently associated with surgical wound infection. Amoxicillin/clavulanic acid and first- or second-generation cephalosporins, with or without metronidazole, were recommended most frequently. Recommendations for third-generation cephalosporins and broad-spectrum penicillins were limited. A relatively high proportion (between 52 and 66%) of the formularies recommended multiple-dose regimens.

Data on the use of antimicrobial drugs was collected by means of an inquiry to 30 hospitals in Belgium (15 in Dutch sectors and 15 in the French sectors), 21 hospitals in Germany and 20 hospitals in the Netherlands. The use of these drugs was expressed as the number of defined daily doses (DDD) per 100 bed days by the anatomical therapeutical chemical classification system. The total use of antimicrobial agents was significantly (p < 0.001) higher in both parts of Belgium (55.6 and 52.0 DDD per 100 bed days) than in Germany (37.9 DDD) or the Netherlands (34.1 DDD). In particular, amoxicillin-clavulanic acid, the first- and second-generation cephalosporins, aminoglycosides and fluoroquinolones were used more in Belgium than in either of the other countries. At least part of the differences observed in antimicrobial drug use could be explained by differences in written antibiotic policy.

The pharmacokinetics of a single iv dose of 10 mg diazepam and the renal excretion of its metabolites resulting from N-demethylation and C-3-hydroxylation were investigated in 10 healthy volunteers when diazepam was administered alone and on day 3 of administration of the fluoroquinolone ciprofloxacin (500 mg twice per day). No significant changes in the diazepam half-life, its volume of distribution, the total body clearance, or the renal clearance were observed. In addition, the renal excretion of the metabolites desmethyldiazepam, 3-hydroxydiazepam (temazepam), and 3-hydroxydesmethyldiazepam (oxazepam) were not altered by ciprofloxacin co-medication. These data demonstrate that in a 500 mg twice per day oral dosage, ciprofloxacin does not influence the metabolic clearance of diazepam in young healthy volunteers.

Nalidixic acid is metabolized by hydroxylation to 7-hydroxymethylnalidixic acid[[ and then by oxidation to 7-carboxynalidixic acid.[[ The half-lives of the two elimination phases of nalidixic acid are 0.75 and 2.5 h. The apparent half-lives of the metabolite 7-hydroxymethylnalidixic acid are 2.5 and 5.5 h. Plasma protein binding of nalidixic acid is 95% and that of 7-hydroxymethylnalidixic acid 65%. The renal clearance of nalidixic acid varies between 2 and 25 ml/min and that of 7-hydroxymethylnalidixic acid between 37 and 162 ml/min. Of nalidixic acid 42% is glucuronidated and 40% hydroxylated. Of the hydroxy metabolite 57% is glucuronidated and 32% excreted unchanged. 7-Carboxynalidixic acid is excreted in the urine and is not glucuronidated. The variations in the glucuronidation/hydroxylation ratio of nalidixic acid and the glucuronidation/renal excretion ratio of the 7-hydroxymethyl metabolite belong to a normal distribution.

After a single oral 600 mg dose, ofloxacin concentrations were measured in lung tissue, whole blood and plasma in 11 patients undergoing thoracotomy for a bronchial malignancy. To correct for blood contamination in the tissue samples, the tissue haemoglobin content was measured using a method based on the binding of haemoglobin by haptoglobin. Ofloxacin concentrations in plasma and whole blood did not differ significantly. The calculated blood content in the tissue samples was 0.12 +/- 0.05 ml/g lung tissue. After correction for blood admixture, the mean lung tissue concentration 2 h after administration of ofloxacin was 17.7 +/- 9.2 micrograms/g. At the same time the mean plasma concentration was 8.7 +/- 4.2 mg/l (P less than 0.02). The high concentration of ofloxacin obtained in lung tissue does not result from the preparation technique. After a single 600 mg dose the tissue concentrations proved to exceed MIC values for most pathogens frequently involved in respiratory tract infections.

In this open, non-comparative study 45 lower respiratory tract infections were treated with the new 4-quinolone, enoxacin. Special attention was paid to infections caused by Pseudomonas aeruginosa. Pseudomonas infections were treated with 600 mg bd. whereas infections caused by other bacteria were treated with 400 mg enoxacin bd. In 43 cases efficacy could be assessed. In six out of 23 cases Pseudomonas spp. were eradicated from the sputum. In 12 of the remaining 17 cases a clear reduction in bacterial numbers and a decrease of sputum volume and purulence were obtained. Clinical improvement or cure was obtained in 20 out of the 23 cases. Most of the causative microorganisms in the other infections were eradicated. In two patients Staphylococcus aureus persisted. Overgrowth with streptococci occurred in three patients. Adverse reactions were frequent and occurred in 29 out of 45 treatment periods. They were mainly related to the gastrointestinal tract and the central nervous system. In 25 out of 30 patients on concomitant treatment with theophylline an elevation of plasma theophylline concentrations occurred. Twelve of these patients developed signs and symptoms possibly related to theophylline toxicity. After treatment with enoxacin the MICs of most persisting Pseudomonas strains were two to four times higher than pre-treatment values.

Pharmacokinetic parameters of the bronchodilator theophylline were assessed in eight patients with chronic obstructive lung disease when administered alone and when comedicated with ciprofloxacin 500 mg twice daily, ofloxacin 400 mg twice daily, or pefloxacin 400 mg twice daily. Compared to the control period, in which only theophylline was administered, the total body clearance of theophylline decreased significantly during ciprofloxacin (30.4%) and pefloxacin (29.4%) coadministration, whereas no change of the renal clearance of theophylline occurred. Ofloxacin did not influence the pharmacokinetic parameters of theophylline. From these observations it is concluded that ciprofloxacin and pefloxacin reduce the metabolic clearance of theophylline.

Some of the new quinolone derivatives may be of value in the treatment of respiratory tract infections. It has been demonstrated that enoxacin, pefloxacin and ciprofloxacin, but not ofloxacin, decreased the metabolic clearance of the bronchodilator theophylline. This resulted in elevated plasma theophylline concentrations and, in some of the patients, theophylline toxicity. When the pharmacokinetic parameters of enoxacin, pefloxacin, ciprofloxacin and ofloxacin obtained in the present study were compared with those obtained from other studies in healthy volunteers not given concomitant theophylline, there was no evidence of theophylline influencing the clearance of the investigated quinolones.

The quinolones are relatively poorly absorbed from the gastrointestinal tract. The elimination proceeds mainly by renal excretion. The half-life of elimination depends on the molecular structure and varies between 2 and 10 h. Impaired kidney function is expected to increase the half-life of elimination, though this effect is not always observed. Since the 4-oxo-metabolites show a higher renal clearance than the parent drug, renal impairment will result in a cumulation of the metabolites in the body.

In studies aimed at assessing the efficacy and safety of antibacterial agents used in treating infections of the respiratory tract, patients with exacerbations of a chronic obstructive pulmonary disease frequently are included. Both the indication for the prescription of an antibiotic and the evaluation of its effect can be difficult. As a general rule, treatment with steroids, bronchodilators and oxygen supply is indicated in cases of exacerbated pulmonary disease. These interventions will influence the clinical and bacteriological parameters usually used to evaluate the antibacterial effect. In a number of cases, non-antibacterial treatment will restore the bronchopulmonary defence sufficiently so that infection control is reached. In order to design meaningful efficacy studies, it is obligatory to understand the pathophysiological mechanisms in chronic obstructive pulmonary disease, to be aware of the pitfalls in making the diagnosis 'bacterial bronchitis' and to take into account the influence of co-medications on the clinical and bacteriological parameters. Some objections to comparative efficacy trials are raised.

In patients treated concomitantly with theophylline and enoxacin, a broad spectrum antibacterial agent for oral administration, unexpectedly high plasma theophylline concentrations were observed. In six patients receiving intravenous aminophylline under controlled conditions, enoxacin was started in a daily dose of 800 or 1200 mg. Plasma theophylline concentrations increased from 8.4 +/- 2.4 mg/l to 15.0 +/- 5.1 mg/l at day 3 of co-administration. Total body clearance of theophylline decreased significantly, whereas renal clearance and protein binding did not change. When enoxacin, 800 mg daily, was administered to seven patients with a stable chronic obstructive pulmonary disease, who were on long-term theophylline treatment a significant increase in plasma theophylline concentrations occurred as well: elimination half-life was prolonged. It is concluded that the rise of plasma theophylline concentrations is caused by a reduced metabolic clearance of theophylline. If concomitant use of both drugs is necessary, monitoring of plasma theophylline concentration and adjustment of the theophylline dose is recommended, to avoid toxicity.

The pharmacokinetic parameters of theophylline and its major metabolites were measured in two healthy volunteers, after the administration of theophylline alone and during co-medication with ofloxacin, 200 mg twice daily, or enoxacin, 200 mg twice daily. During enoxacin co-medication, elimination half-lives of theophylline increased from 8.7 h to 17.4 h and from 6.1 to 12.3 h, respectively. As the renal clearance of theophylline did not change, the decreased elimination of theophylline during enoxacin co-medication must result from a reduced metabolic clearance. Enoxacin co-medication caused a clearly decreased formation of the metabolites 1-methyluric acid and 3-methylxanthine, formed by N-demethylation, whereas the C-8 oxidation of theophylline was less influenced compared to the blank. Enoxacin's interference with the theophylline disposition is predominantly based on the inhibition of the microsomal N-demethylation. Ofloxacin co-medication did not induce a change in the plasma parameters or renal excretion of theophylline and its metabolites.

Isolated rat hepatocytes obtained from Aroclor-pretreated rats were incubated with theophylline in the presence or absence of the quinolone antibiotics enoxacin, its metabolite oxoenoxacin, or ofloxacin. The hepatocytes converted theophylline by cytochrome P-450 activity mainly to two metabolites: 1,3-dimethyluric acid and 3-methylxanthine. Enoxacin inhibited the formation of 1,3-dimethyluric acid by 67% at 1.0 mM. Oxoenoxacin or ofloxacin had no inhibitory effect. The oxidation of theophylline to 3-methylxanthine was not inhibited by any of the three compounds. The quinolones had no effect on cell viability. These results show that the inhibition by enoxacin is not due to the formation of its oxoenoxacin metabolite.

Pharmacokinetic data were obtained from four healthy volunteers after oral administration of a single 400 or 600 mg dose of enoxacin. Enoxacin was absorbed quickly and absorption was increased when enoxacin was ingested after a meal. Renal clearance of enoxacin and 4-oxo-enoxacin decreased after simultaneous administration of probenecid. In addition, pharmacokinetic parameters of enoxacin and its 4-oxo metabolite were determined for plasma and sputum from 19 patients treated with enoxacin, 400 or 600 mg bd, for a respiratory tract infection. The half-life of both enoxacin and 4-oxo-enoxacin was 5-6 h; during treatment with 400 and 600 mg bd, the plasma concentrations exceeded MIC values for most bacteria isolated in respiratory tract infections, including most Pseudomonas aeruginosa strains; Streptococcus pneumoniae was an exception. Diffusion from plasma to sputum was approximately 100%. Of an ingested dose, 60-65% was recovered in the urine in 24 h. In a third study, a single 600 mg dose of enoxacin was given to 15 patients undergoing thoracotomy. Subsequent lung tissue concentrations of enoxacin were significantly higher than plasma concentrations at the same time after ingestion.

In five cases of carbamazepine (CBZ) intoxication, the time curves of the plasma concentration and of the renal excretion rate of carbamazepine and its metabolites carbamazepine 10,11-epoxide (CBZ-epoxide) and trans-10,11-dihydro-10,11-dihydroxy-CBZ (CBZ-diol) were measured. Pseudo-steady-state or plateau-like plasma concentration-time curves were observed when doses of 12 or 18 g of CBZ were ingested. Hemoperfusion lowers the plasma concentration of CBZ and its metabolites by affecting the half-life. The effect of hemoperfusion is reduced by the continuous absorption from the gastrointestinal tract and redistribution from the tissues. The renal clearances of CBZ and of CBZ-epoxide are low (1 and 8 ml/min, respectively); both are flow dependent. The renal clearance of CBZ-diol is approximately 160-350 ml/min and is independent of the urine flow. Although urine stimulation increases the renal clearance of CBZ by 100%, the overall amount excreted increases only 1-2% of the dose. Protein binding of CBZ is approximately 80%, of CBZ-epoxide 50%, and of CBZ-diol 70%.

This review summarizes the available data on the influence of ofloxacin on the metabolic clearance of the bronchodilator theophylline. At the moment, several new fluoroquinolone derivatives, such as ofloxacin, ciprofloxacin, pefloxacin, and enoxacin are being clinically tested in respiratory tract infections. Enoxacin causes a strong and clinically important decrease (60%) of the total body clearance of theophylline. Ciprofloxacin and pefloxacin show the same effect, though to a smaller degree (30%). During treatment with these three agents clinical signs and symptoms of theophylline toxicity have been reported. However, no signs of increased plasma theophylline concentrations have been observed during concomitant treatment with ofloxacin and theophylline. Further research into the mechanism of this interaction has demonstrated that quinolones compete with cytochrome P450 related isoenzymes, resulting in a decreased demethylation of theophylline. Whereas a slight influence on these enzymes could be demonstrated for ofloxacin when the drug was administered in very high concentrations to rats, no significant influence on theophylline metabolic pathways in man has been measured, when ofloxacin was administered in doses up to 800 mg daily.

Whereas the respiratory function of the lung has been studied extensively, there are only scarce data available concerning the lung's drug clearance capabilities in man. Its metabolic function in hormonally active agents has been documented in animals. To gain insight in this non-respiratory function of the lung knowledge of the architecture of the alveolar-capillary unit and the histochemistry of its different cell types is necessary. Some examples of studies with drugs are presented to illustrate the methods that have been used in metabolic and uptake studies of the lung.