Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor.

BACKGROUND: Initial response of small-cell lung cancer (SCLC) to chemotherapy is high, and recurrences occur frequently, leading to early death. This study investigated the prognostic value of circulating tumor cells (CTCs) in patients with SCLC and whether changes in CTCs can predict response to chemotherapy. Patients and methods In this multicenter prospective study, blood samples for CTC analysis were obtained from 59 patients with SCLC before, after one cycle, and at the end of chemotherapy. CTCs were measured using CellSearch systems. RESULTS: At baseline, lower numbers of CTCs were observed for 21 patients with limited SCLC (median = 6, range 0-220) compared with 38 patients with extensive stage (median = 63, range 0-14,040). Lack of measurable CTCs (27% of patients) was associated with prolonged survival (HR 3.4; P ≤ 0.001). CTCs decreased after one cycle of chemotherapy; this decrease was not associated with tumor response after four cycles of chemotherapy. CTC count after the first cycle of chemotherapy was the strongest predictor for overall survival (HR 5.7; 95% CI 1.7-18.9; P = 0.004). CONCLUSION: Absolute CTCs after one cycle of chemotherapy in patients with SCLC is the strongest predictor for response on chemotherapy and survival. Patients with low initial CTC numbers lived longer than those with higher CTCs.

Revised SWAB guidelines for antimicrobial therapy of community-acquired pneumonia.

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.

Steady-state kinetics of the quinolone derivatives ofloxacin, enoxacin, ciprofloxacin and pefloxacin during maintenance treatment with 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.

Inhibition of the oxidative metabolism of theophylline in isolated rat hepatocytes by the quinolone antibiotic enoxacin and its metabolite oxoenoxacin, but not by ofloxacin.

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.

[Optimizing the antibiotics policy in the Netherlands. IV. SWAB- guidelines for antimicrobial therapy of adults with sepsis in hospitals. Foundation Antibiotics Policy Work Group]. / Optimaliseren van het antibioticabeleid in Nederland. IV. SWAB-richtlijnen voor antimicrobiële therapie in het ziekenhuis bij volwassenen met sepsis.

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.

[Optimizing of antibiotics policy in the Netherlands. III. SWAB guidelines for antimicrobial therapy in adults hospitalized with bronchitis. Foundation Antibiotics Policy Work Group]. / Optimaliseren van het antibioticabeleid in Nederland. III. SWAB-richtlijnen voor antimicrobiële therapie bij volwassenen met bronchitis in het ziekenhuis.

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.

[Optimizing antibiotics use policy in the Netherlands. I. The Netherlands Antibiotics Policy Foundation (SWAB)]. / Optimaliseren van het antibioticabeleid in Nederland. I. De Stichting Werkgroep Antibioticabeleid (SWAB).

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.

[Optimization of the antibiotics policy in the Netherlands. II. SWAB guidelines for the antimicrobial therapy of pneumonia in patients at home and as nosocomial infections. The Netherlands Antibiotic Policy Foundation]. / Optimaliseren van het antibioticabeleid in Nederland. II. SWAB-richtlijnen voor antimicrobiële therapie bij thuis opgelopen pneumonie en bij nosocomiale pneumonie.

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 metabolic function of the lung.

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.

Antibacterial treatment in exacerbations of chronic obstructive pulmonary disease. Pitfalls in study design and evaluation.

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.

Interaction between the fluoroquinolones and the bronchodilator theophylline.

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.

Antimicrobial prophylaxis in bowel surgery in The Netherlands.

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.

Antibiotic policies in Dutch hospitals for the treatment of pneumonia.

The guidelines used in Dutch hospitals for the treatment of pneumonia as described in antibiotic formularies are described. A total of 42 formularies were examined. Amoxycillin was the most frequently used agent in the treatment of community-acquired pneumonia and a wide variety of drugs was used for the treatment of nosocomial pneumonia, of which cefuroxime, alone or in combination with an aminoglycoside, was used most often. Benzylpenicillin was the most frequently used drug in community-acquired aspiration pneumonia; this drug, in combination with an aminoglycoside, was also the drug of choice in hospital-acquired aspiration pneumonia. Treatment of pneumonias with known or presumed pathogens was also surveyed and the most usual drugs of choice were benzylpenicillin for pneumococci, flucloxacillin for staphylococci, amoxycillin for Haemophilus influenzae, cefuroxime for Enterobacteriaceae (cefuroxime), cotrimoxazole for Pneumocystis carinii, doxycycline and erythromycin for Mycoplasma pneumoniae and erythromycin for Legionella pneumophila. Relatively wide variations in dosage guidelines were observed for benzylpenicillin and amoxycillin. Only a few formularies gave guidelines for the duration of treatment.

Treatment of urinary tract infections in Dutch hospitals.

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.

Antimicrobial drug use in hospitals in The Netherlands, Germany and Belgium.

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.

Antibiotic policies in Dutch hospitals for the treatment of patients with serious infection.

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 effect of the 4-quinolone enoxacin on plasma theophylline concentrations.

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 influence of quinolone derivatives on theophylline clearance.

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.

Enoxacin decreases the clearance of theophylline in man.

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.