Penetration of lomefloxacin into bronchial secretions following single and multiple oral administration.

The bronchial penetration of lomefloxacin, a new difluorinated quinolone, was evaluated in 36 patients who underwent bronchoscopies for diagnostic purposes. Patients were randomized into two groups, with 18 patients (Group I) receiving a single oral dose of 400 mg lomefloxacin and 18 patients (Group II) receiving 400 mg twice daily. Samples of serum and bronchial secretions were collected simultaneously in both groups at 1, 2, or 4 hours after lomefloxacin administration. The results of this study showed that bronchial penetration of lomefloxacin was rapid and yielded high concentrations; the mean bronchial levels of the drug reached 2.78 +/- 3.64 micrograms/mL in Group I 1 hour after the dose, and 2.84 +/- 1.73 micrograms/mL in Group II at the fourth hour. The ratio between bronchial and simultaneous serum concentrations was 89% at the first and second hours after the dose for Group I, and it was 77% 4 hours after oral administration in Group II. In comparing these results to previous reports of lomefloxacin penetration into bronchial mucosa or of concentrations of other new fluoroquinolones into bronchial secretions, it is to be noted that the local concentrations of the newer quinolones are of very similar values, ranging from 2.7 micrograms/mL (ofloxacin) to 4.46 micrograms/mL (pefloxacin). This study confirms that lomefloxacin achieves high tissue concentrations in the respiratory tree; this characteristic, together with lomefloxacin's antibacterial spectrum, indicates promise in the treatment of many respiratory infections.

Cefpodoxime proxetil in upper respiratory tract infections.

Cefpodoxime proxetil is a new third generation oral cephalosporin, which shows potent antibacterial activity against both Gram-positive and Gram-negative bacteria, and high stability in the presence of beta-lactamases. Low concentrations of cefpodoxime inhibit most respiratory pathogens, including Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella (Branhamella) catarrhalis. Cefpodoxime reaches concentrations of 0.24 +/- 0.06 mg/kg in tonsils, 0.89 +/- 0.80 mg/kg in lung parenchyma, and 0.91 +/- 0.01 mg/kg in bronchial mucosa; these values exceed by far the minimum inhibitory concentrations (MICs) of cefpodoxime for respiratory pathogens. Preliminary clinical studies were carried out in 181 patients with upper respiratory tract infections: the results indicated an overall clinical response in 88.4% of patients; in 30% the clinical efficacy was excellent and in 58.5% it was good. Further studies showed clinical cure in 90.3% of patients with pharyngotonsillitis, and clinical efficacy (cure plus improvement) in 95% of those with acute sinusitis. Moreover, bacterial eradication was obtained in 78 to 96.7% of cases, most of which involved H. influenzae, streptococci, or M. catarrhalis. Cefpodoxime appears to be an effective new antibacterial that can be recommended as a drug of first choice in the treatment of most upper respiratory tract infections.

Current guidelines for the treatment and prevention of nosocomial infections.

Nosocomial infections (NIs) are among the most difficult problems confronting clinicians who deal with severely ill patients. The incidence of these hospital-acquired infections varies with the size of hospitals, with specialities of wards, and with many other factors such as length of hospital stay, local trends in antibiotic usage, nursing and hygiene conditions, hospital design and geographical distribution of patients at risk. An average incidence of NI can be estimated at 5 to 10%, with higher rates in large university hospitals, reaching up to 28% in the intensive care unit (ICU). Changing epidemiology of NI and emerging resistance problems have resulted in evolving strategies of antibiotic usage in patients at risk. Several recent antibiotic resistance problems have been identified, for instance in Gram-positive organisms, and have been surveyed, in addition to those previously well known in Gram-negative bacilli. The choice of empiric antibiotic therapy for the treatment of any NI before microbiology is available has become a difficult challenge, requiring: (i) surveillance data on a regular basis of predominant organisms in units at risk; (ii) surveillance of the current resistance patterns of these organisms; (iii) identification of outbreaks involving the prevalent organisms, using modern molecular techniques for typing the strain and assess cross-contamination. In documented infection, monotherapy vs combination therapy has been often discussed in the treatment of serious Gram-negative hospital infections, but these concepts vary with the site of infection, the nature of organism involved and its pattern of resistance, the kind of antibiotic which may more or less quickly select resistant mutants. Antibiotic therapy concepts vary significantly between countries, and combinations either empirical or based on laboratory data are often preferred in European countries than in the US. Frequent collaborative studies and an increasing communication between experts of different countries, make guidelines and consensus conferences, established in a particular country, useful elsewhere and may contribute to improvement in the management of NI. Guidelines for the prevention and the control of NI are well established in many developed countries and they may have resulted in the improvement of the prevention and the treatment of NI. However, there is still potential progress that should be made, including individual preventive practices, improvement in nursing practices, control of antibiotic use, trend to shorten the hospital stay and early discharge from hospital, which results in significant cost savings.

Bacterial adhesion in human upper gastrointestinal tract.

Small bowel biopsy specimens were taken from 21 patients undergoing gastrointestinal endoscopy to detect a possible adhesion of bacteria to the mucous layer of the upper gastrointestinal tract. In 30 control biopsy specimens taken from 10 patients free from gastrointestinal pathology, no associated bacteria were found, whereas in 23 biopsy specimens taken from eight gastrectomized patients an associated bacterial flora including E. coli or Pseudomonas was grown. Bacterial adhesion was confirmed by means of transmission electron microscopy of the eight patients yielding positive cultures. Bacterial adhesion induced local alterations of the brush border membrane. These results suggest that adherent bacteria may be present in hypochlorhydric patients. Pathophysiologic consequences require further studies.

Novel carbenicillin-hydrolyzing beta-lactamase (CARB-5) from Acinetobacter calcoaceticus var. anitratus.

A strain of Acinetobacter calcoaceticus var. anitratus highly resistant to ticarcillin but susceptible to ticarcillin in combination with clavulanic acid (2 mg/l) was found to produce a constitutive beta-lactamase. This enzyme was periplasmic with a characteristic substrate profile of a carbenicillin-hydrolyzing enzyme. Enzyme inhibition was detected with antiserum (anti-CARB-3), pCMB, cloxacillin, clavulanic acid and sulbactam. This novel enzyme with a molecular mass of 28,000 resembles other plasmid-mediated carbenicillinases (CARB) but differs in its apparent isoelectric point estimated as 6.3 and has been designated CARB-5 on this basis.

Continuous activity of significant antibiotics.

Respiratory tract infections (RTIs) are the primary cause of antibiotic use in general practice. Since the first penicillin was introduced for therapeutic purposes, several classes of antibiotics have been used in the treatment of community-acquired RTIs. The phase when penicillins G and V could be active in RTIs was relatively short lived due to the early emergence of resistant organisms. Ampicillin and amoxicillin have been used successfully for more than 20 years in the treatment of RTIs. In the late 1950s and 1960s, erythromycin, tetracyclines, and co-trimoxazole were also prescribed for RTIs. In the 1970s, other molecules belonging to the cephalosporin class of antibiotics, such as cephalexin, cephaloglycin, cefadroxil, and cephradine, were introduced in general practice for the same indication. Susceptibility of the predominant respiratory pathogens to these antimicrobial agents lasted for many years. However, Haemophilus influenzae responded poorly to erythromycin, and up to 30% of pneumococcal and streptococcal strains are resistant to macrolides, tetracyclines, and co-trimoxazole. Since 1976, increasing percentages of beta-lactamase producers (up to 20% in 1989) were found among Haemophilus species, and Moraxella catarrhalis, a frequent beta-lactamase producer, is increasingly isolated as a respiratory pathogen. These problems have led to the development of additional compounds, most characterized by their stability in the presence of beta-lactamases, such as amoxicillin + clavulanic acid, or exhibiting relative resistance to enzymatic inactivation, such as cefaclor. Treatment today of most RTIs also takes into account the cost-effectiveness relationship of these antibiotics.

Treatment and prevention of antibiotic associated diarrhea.

Mild or severe episodes of antibiotic-associated diarrhea (AAD) are common side effects of antibiotic therapy. The incidence of AAD differs with the antibiotic and varies from 5 to 25%. The major form of intestinal disorders is the pseudomembranous colitis associated with Clostridium difficile which occurs in 10-20% of all AAD. In most cases of AAD discontinuation or replacement of the inciting antibiotic by another drug with lower AAD risk can be effective. For more severe cases involving C. difficile, the treatment of diarrhea requires an antibiotic treatment, with glycopeptides (vancomycin) or metronidazole. Another approach to AAD treatment or prevention is based on the use of non-pathogenic living organisms, capable of re-establishing the equilibrium of the intestinal ecosystem. Several organisms have been used in treatment or prophylaxis of AAD such as selected strains of Lactobacillus acidophilus, L. bulgaricus, Bifidobacterium longum, and Enterococcus faecium. Another biotherapeutic agent, a non-pathogenic yeast, Saccharomyces boulardii has been used. In animal models of C. difficile colitis initiated by clindamycin, animals treated with S. boulardii (at end of vancomycin therapy) had a significant decrease in C. difficile colony-forming units, and of toxin B production. In several clinical randomised trials (versus placebo), S. boulardii has demonstrated its effectiveness by decreasing significantly the occurrence of C. difficile colitis and preventing the pathogenic effects of toxins A and B of C. difficile. It has been shown to be a safe and effective therapy in relapses of C. difficile colitis. A good response has been seen in children with AAD, treated by S. boulardii only. In ICUs prevention of AAD remains based on limitation of antibiotic overuse and spread of C. difficile or other agents of AAD should be prevented by improved hygiene measures (single rooms, private bathrooms for patients, use of gloves and hand washing for personnel). In addition the increasing use of biotherapeutic agents such as S. boulardii should permit the prevention of the major side effect of antibiotics, i.e. AAD in at risk patients.

Interpretation of pharmacologic data in respiratory tract infections.

Few serum pharmacokinetic parameters of antibiotics are predictors of tissue distribution and, for instance, more useful are studies of tissue concentrations in the respiratory tree. Significant antibiotic concentrations can be obtained at various sites of potential infection: lung parenchyma; alveolar macrophages; and bronchial mucosa and secretions. New models using broncho-alveolar lavage allow studies of antibiotic concentrations in epithelial lining fluid that are good predictors of antibiotic activity in lung infections. In studies in human respiratory tissues for superinfected bronchitis, concentrations of macrolides, quinolones or beta-lactans in bronchial secretions, or mucosa, correlated with satisfactory clinical response, and eradication of pathogens. Pulmonary kinetics of aminoglycosides or beta-lactams have been studied using a canine model. Also in murine models of pneumonia, pharmacokinetic parameters have been determined for quinolones and newer macrolides.

The increasing significance of outbreaks of Acinetobacter spp.: the need for control and new agents.

Acinetobacter spp. are Gram-negative non-fermentative bacteria which may be isolated as commensals from human skin, throat and intestine but are also increasingly responsible for hospital infections. Owing to frequent changes in their taxonomy, their pathogenic role in humans has not been clear but today acinetobacter is considered to be a significant nosocomial pathogen in outbreaks of hospital infections predominantly in intensive care units. Nosocomial infections due to acinetobacter include urinary tract infections, bacteraemia, wound and burn infections, but also they are frequently isolated from ventilator-associated nosocomial pneumonia. The frequency of hospital outbreaks of acinetobacter infections has required the development of reliable typing methods. As well as conventional 'phenotypic' methods (serology, biotyping, phage typing), 'genotypic' systems (ribotyping, plasmid profiles, pulsed-field gel electrophoresis) have been utilized for strain identification. These typing systems should allow a better understanding of the epidemiology of acinetobacter in the hospital environment, e.g. sources, modes of transmission, and result in more efficient preventive measures. Acinetobacter infections are difficult to treat owing to their frequent multiple resistance to the antibiotics currently available for the treatment of nosocomial infections; various mechanisms of resistance to beta-lactams and amino-glycosides have been identified in the genus. Combination therapy is usually recommended for treatment of acinetobacter nosocomial infections and active antibacterials include imipenem, ceftazidime, amikacin and the newer fluoroquinolones. Careful in vitro testing of the activity of combinations of these drugs is recommended prior to their use.

Hospital infection with Acinetobacter spp.: an increasing problem.

During the last few years, among nosocomial pathogens, Acinetobacter spp. have given rise to an increasing number of nosocomial infections. Acinetobacter strains are widely distributed in nature; in hospitals, the human skin is the likely source for most outbreaks of hospital infections. The organism has been frequently found in the inanimate environment, especially in moist situations and it has been isolated from various types of opportunistic infections (septicaemia, endocarditis, meningitis, pneumonia, skin and wound sepsis and urinary tract infection). For epidemiological studies, various typing methods such as biotyping, bacteriocin typing and serology have been developed. More recently electrophoretic patterns of cell-envelope proteins and plasmid analysis have proved useful in differentiating outbreak strains. Antibiogram typing may be useful but the antibiotic resistance of Acinetobacter spp. has changed rapidly within the last few years and thus antibiotyping must be complemented by other typing systems. New methods such as electrophoretic analysis of isoenzymes, definition of plasmidotype profiles or restriction endonuclease digestion of chromosomal DNA are under investigation.

A study of the relationships between antibiotic resistance phenotypes, phage-typing and biotyping of 117 clinical isolates of Acinetobacter spp.

Two typing systems were used to conduct an epidemiological study of Acinetobacter and to establish their relationship to antibiotic resistance phenotypes. Biotyping was performed with biochemical tests according to the new definition of Acinetobacter baumannii (18 biotypes). Phage typing included two complementary systems: 125 phage-types and 25 subtypes. Resistance phenotype analysis included 11 antibiotics. The results of the study showed that: (1) nine phage-types or subtypes (67%) and two groups of atypical phage-types (5%) or of untypable strains (28%), could be defined; (2) all strains that were resistant to carboxy/ureido-penicillins and cephalosporins (62%) belonged to biotypes 6 or 9; among them 70% belonged to phage-types 17 or 124; (3) imipenem resistance was observed in five isolates of biotype 9 and one of biotype 6; (4) a phenotype including resistance to third generation cephalosporins (but not carboxypenicillins) and to amikacin (but not tobramycin) represented 8.5% of the isolates; 90% of them belonged to biotype 1 and were not phage-typable; (5) 15% of the isolates were not identified as A. baumannii; among them five Acinetobacter haemolyticus strains all had the same resistance phenotype: amikacin-tobramycin-kanamycin-netilmicin resistant; they were however, susceptible to beta-lactams and to gentamicin. There was a clear relationship between biotypes 6 and 9 and phage-types 17 and 124 which were the strains most resistant to beta-lactams and aminoglycosides and were predominant in the survey. The three typing systems were complementary but it seems that antibiotic resistance phenotypes and one of the two other typing systems would be required in parallel to provide suitable information for epidemiological purposes.

[Legionnaires' disease: Legionella pneumophila, an agent in nosocomial infection]. / Maladie des légionnaires: "Legionella pneumophila", agent d'infection nosocomiale.

Legionella pneumophila recently identified in 1977 as responsible for legionnaires' disease, is present in the natural environment. The discovery of the bacteria, the development of suitable complex media ( BCYE ) and of serological techniques improved the knowledge of epidemiologic features of L. pneumophila widely distributed geographically. Legionella has been frequently isolated from the aquatic environment: the organism is able to colonize the condensed water of air-conditioning systems and the water-supply system in public buildings. The presence of Legionella in hospitals constitutes a danger for immunosuppressed patients.

[Medical economics and optimal antibiotic therapy]. / Economie médicale et antibiothérapie optimale.

Antibiotics account for a large proportion of pharmaceutical consumption in France and in the world. Forty years after penicillin was introduced in antimicrobial therapy, the antibiotics constitute the first pharmaceutical class in the world (gross production) with beta-lactam antibiotics at the top. The sociological and economical consequences of their development are considerable: decrease in death-rates in childhood, tuberculosis healing, life lengthening, etc.: the consequences of these improvements on health organisation and structures are difficult to evaluate in terms of economics. The drawbacks of the development of antibiotic therapy besides side-effects or toxicity, are the emergence of resistant strains as a consequence of selective pressure due to uncontrolled use of antibiotics; the expenses increase in hospitals in relation to indiscriminate use of chemotherapeutic agents. For an optimal antibiotic therapy, a rational prescription of antibiotics and a control of appropriate antibiotic usage should be developed. However, the therapeutic efficacy and patients' cure constitute the main objective of an optimal antibiotic therapy.

Interactions among antibiotics, bacteria and the human immune system: the clinical relevance of in vitro testing.

The role of interactions of the host immune system with antibacterial activities of antibiotics is extremely complex and its analysis is still at an early stage. Standard in vitro trests of antibiotic susceptibilities of pathogens provide only limited information since they do not take into account either the potential interaction of immunomodulating activities of antibiotics in vivo or the participation of the host immune response in the infection outcome. The understanding of these complex relationships is of major importance in treating immunocompromised patients, but this approach is still under investigation and much work remains to be done in order to confer more significance on in vitro testing.

Current trends and new perspectives in antibiotic therapy.

During the last ten years, limitless numbers of antimicrobials were produced by the pharmaceutical industry and some have been marketed. The main objectives of new drugs are to overcome the expanding problems of resistant bacteria, to fill the gaps of spectrum of previous agents. These objectives are progressively reached by new beta-lactams, penems, fluoroquinolones; in general practice, new oral cephalosporins are becoming available. To overcome toxicity problems new concepts in antibiotic usage such as intermittent aminoglycoside regimens are suggested. Research in antibiotics, the discovery of new molecules or the re-evaluation of older drugs constitute dynamic trends in antibiotic therapy.

Guidelines on antimicrobial chemotherapy for prevention and treatment of infections in the intensive care unit.

Severe infections (SIs) in Intensive Care Units (ICUs) constitute difficult therapeutic problems confronting clinicians who deal with severely ill patients. Some SIs are opportunistic infections acquired either in the community or in hospitals, particularly in immunodepressed patients. The great majority of ICU infections are of nosocomial origin. Resistant organisms have led to changing antibiotic therapy in ICU infections. Before microbiology is available, empiric therapy is based on: (i) proper identification of bacterial risks in each infection site; (ii) local surveillance of frequent nosocomial organisms/susceptibility patterns in the ICU; (iii) identification of environmental risk factors and the patient's underlying condition. In documented infection, antibiotic therapy must take into account gram-positive vs gram-negative bacteria or mixed infections, pharmacokinetics/pharmacodynamic parameters of chosen antibiotic(s) and concentrations at the infection site, in order to prevent selection of resistant mutants and to provide the most efficient antibiotic therapy. With increasingly sophisticated intensive care measures, invasive exploratory procedures, and surgical procedures, evolving profiles of hospital infections require updated Guidelines for treatment of severe infections in ICUs. Preventive and therapeutic strategies include control of antibiotic use, and suitable antibacterial treatments which result in shortened hospital stay, improved outcome of hospital infections and significant cost savings.

In vitro brodimoprim activity on bacterial strains.

The antibacterial activity of brodimoprim (BDP) was compared to that of trimethoprim (TMP) and to 4 other antibiotics (3 beta-lactams and one macrolide). The 237 tested strains were selected predominantly among bacteria isolated from respiratory tract infections: 133 Gram-negative bacilli and 98 Gram-positive cocci. The study included: determination of minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of all antibiotics of the study for all isolates; kinetics of bactericidal activities for selected susceptible strains; correlation between MICs and inhibition zones (standard agar diffusion technique) of BDP (regression line). The results of the study showed: [1] no significant difference between in vitro activities of BDP and TMP against all tested strains; [2] low MICs of both drugs for Haemophilus influenzae, Legionella pneumophila, Staphylococcus aureus (methi-S and methi-R), Streptococcus pneumoniae (peni-S), streptococci and enterococci; [3] kinetics of bactericidal activities indicating 4 log decrease of inoculum size with BDP for Staph. aureus, S. pneumoniae, H. influenzae, within 7 hours; [4] correlation was established between inhibition zones and MICs of BDP, with a coefficient of correlation r = 0.88 for 182 strains. In conclusion, BDP exhibited in vitro antibacterial and bactericidal activities at least equal to that of reference drugs against most respiratory pathogens; BDP was superior to comparators against methi-R staphylococci and enterococci.

In vitro activity of antimicrobial agents against Acinetobacter calcoaceticus.

The aim of this study was to evaluate the in vitro activity of several new microbial agents against 96 Acinetobacter calcoaceticus isolates. Among several new beta-lactams, imipenem, a new, broad-spectrum, highly potent penem, was the most active drug in vitro against these strains, with a geometric mean MIC of about 0.3 mg/l. Ceftazidime and ceftizoxime also demonstrated good in vitro activity with geometric mean MICs of 6 mg/l and 7 mg/l respectively. Among new quinolones, ciprofloxacin, ofloxacin and pefloxacin were substantially active in vitro: geometric means were 0.8, 0.9 and 1.5 mg/l respectively. A progressive increase in resistance to aminoglycosides has been observed and 80 to 90% of isolates were resistant to all but amikacin, tobramycin and habekacin, which showed geometric mean MICs of 7.0, 6.0 and 1.2 mg/l.

Influence of a fluidifying agent (bromhexine) on the penetration of antibiotics into respiratory secretions.

The authors report the results of a study designed to evaluate the possible increase of penetration into bronchial secretions of antibiotics when combined with a fluidifying agent: bromhexine. The study was carried out in a double-blind experiment: erythromycin in 22 patients (group I) or amoxycillin in 26 patients (group II) were administered orally; in both groups several patients were given a placebo, instead of bromhexine. Antibiotics were administered at the usual dosage: 0.5 g X 2 for erythromycin (3 days); 1 g X 2 for amoxycillin (7 days); with the latter, two different doses of bromhexine were administered simultaneously: 48 mg/day and 96 mg/day in ten and eight patients respectively. Samples of bronchial secretions were collected by means of fibreoptic bronchoscopy at the second hour for erythromycin and for amoxycillin; simultaneous serum samples were also collected. The results of the study showed in both groups a significant increase of the ratios between bronchial levels and simultaneous serum concentrations when combined with bromhexine; in patients receiving amoxycillin with 96 mg of bromhexine the percentage penetration was noticeably higher (7.5%) than in those treated with 48 mg bromhexine (4.3%). These results confirm the efficacy of bromhexine as a drug able to disrupt mucopolysaccharides of bronchial secretions and, as a result, to increase the bronchial penetration of antimicrobial drugs as evaluated on the basis of percentage penetration ratio.

Methods for clinical assessment of expectorants: a critical review.

The purpose of the paper is to discuss some aspects of the methods that are most appropriate for the clinical assessment of new expectorants. Expectorants are drugs devised to help in the removal of bronchial secretions. The evaluation of these drugs is aimed at demonstrating, in controlled trials, their efficacy, safety and, if possible, mechanism of action. Unfortunately, there is no universally accepted assessment technique available. Evaluation of symptoms with the use of self-reported measures is imprecise. Studies of quality of life can assist as a means of assessing the usefulness of this class of drug for patients. Lung function tests evaluate only the possible indirect effects of expectorants; the changes observed are often minor and they do not correlate with other methods of evaluation. Mucociliary clearance studies evaluate bronchial drainage by mucociliary transport and cough. They are a useful pharmacological approach but they cannot replace therapeutic trials. In vitro and ex vivo studies of bronchial secretion, while improving knowledge of the mechanisms of bronchial secretion, fail to predict the modifications of bronchial drainage produced in vivo by cough or mucociliary transport. To be considered efficient, expectorants should not only ease the removal of bronchial secretions, but also improve the patient's condition for the duration of treatment.