Showing papers in "Journal of Antimicrobial Chemotherapy in 1999"

Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis isolated in the United States, 1997-1998.

Abstract: A national antimicrobial resistance surveillance study was conducted from December 1997 to May 1998 to determine the prevalence of antimicrobial resistance in 6620 clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. In this centralized study, which involved 163 institutions located in 43 states, we determined MICs for representatives of five antimicrobial classes: beta-lactams (penicillin, co-amoxiclav, cefuroxime, ceftriaxone), macrolides (azithromycin, clarithromycin), co-trimoxazole, glycopeptides (vancomycin) and fluoroquinolones (levofloxacin). In most S. pneumoniae isolates, all antimicrobials were to be found active, but amongst penicillin-resistant isolates (MICs > or = 2 mg/L), resistance to other beta-lactams, macrolides and co-trimoxazole was common. For vancomycin and levofloxacin, however, activity was not associated with penicillin resistance. The prevalence of penicillin-nonsusceptible (intermediate and resistant) pneumococci was highest in the South Atlantic (44%) and East South Central (43%) regions and lowest in the Mid-Atlantic (28%) and New England (28%) regions. Resistance to beta-lactams, macrolides and co-trimoxazole was more commonly found amongst respiratory isolates than blood isolates and in strains from patients < or = 12 years old than from older patients. beta-lactamase, which was detected in 33% of H. influenzae and 92% of M. catarrhalis strains, did not affect the activity of the beta-lactams under study other than ampicillin. Certain agents, such as vancomycin and the fluoroquinolones, remain highly active, and well-designed surveillance systems that monitor MIC distributions would be needed to detect a potential for reduced susceptibility. In addition, surveillance programmes should be designed to collect information about associated resistance as well as differences in prevalence associated with region, specimen source and patient age.

Epidemiology and pathogenesis of influenza.

Abstract: Influenza A, B and C all have a segmented genome, although only certain influenza A subtypes and influenza B cause severe disease in humans. The two major proteins of influenza are the surface glycoproteins-haemagglutinin (HA) and neuraminidase (NA). HA is the major antigen for neutralizing antibodies and is involved in the binding of virus particles to receptors on host cells. Pandemics are a result of novel virus subtypes of influenza A, created by reassortment of the segmented genome (antigenic shift), whereas annual epidemics are a result of evolution of the surface antigens of influenza A and B virus (antigenic drift). The rapid evolution of influenza viruses highlights the importance of surveillance in identifying novel circulating strains. Infectivity of influenza depends on the cleavage of HA by specific host proteases, whereas NA is involved in the release of progeny virions from the cell surface and prevents clumping of newly formed virus. In birds, the natural hosts of influenza, the virus causes gastrointestinal infection and is transmitted via the faeco-oral route. Virulent avian influenza strains, which cause systemic disease, have an HA that is cleaved by proteases present in all cells of the body, rather than by proteases restricted to the intestinal tract. In mammals, replication of influenza subtypes appears restricted to respiratory epithelial cells. Most symptoms and complications, therefore, involve the respiratory tract. However, systemic complications are sometimes observed and other viral genes besides the HA, including the NA, may be involved in determination of virulence of influenza strains in mammals.

A review of the role of antibiotic policies in the control of antibiotic resistance

Abstract: The optimal antibiotic control measures remain to be described and probably vary between institutions. Nevertheless, various control measures have been shown to be useful in reducing costs of therapy and total amounts of prescribing, while maintaining quality of care. More recently, interest has turned to whether antibiotic policies can reduce the spread of resistance and even reverse current high levels. Early studies indicated this was feasible, but mathematical models and the recent discovery of the role of transposons and integrons in multi-drug resistance have both cast doubt on likely future success in this area. Nevertheless, there have been some major successes in recent studies, both in the community and hospital. While cross-infection is a major impediment to control of resistance, there is little doubt that careful antibiotic prescribing can curtail the emergence and reduce the prevalence of resistance.

Inhibitor-resistant TEM beta-lactamases: phenotypic, genetic and biochemical characteristics.

Abstract: Beta-lactamases represent the main mechanism of bacterial resistance to beta-lactam antibiotics. The recent emergence of bacterial strains producing inhibitor-resistant TEM (IRT) enzymes could be related to the frequent use of beta-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam in hospitals and in general practice. The IRT beta-lactamases differ from the parental enzymes TEM-1 or TEM-2 by one, two or three amino acid substitutions at different locations. This paper reviews the phenotypic, genetic and biochemical characteristics of IRT beta-lactamases in an attempt to shed light on the pressures that have contributed to their emergence.

Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration in man

Abstract: The pharmacokinetics of moxifloxacin and its metabolites M1 (sulpho-compound) and M2 (acyl-glucuronide) were characterized in 12 healthy male volunteers in an open, randomized, crossover study. After an overnight fast the volunteers were given a single 400 mg dosage of moxifloxacin either as a tablet or a 1 h infusion with a washout phase of at least 1 week between the two treatments. Multiple plasma, faeces and urine samples were collected for the analysis of moxifloxacin and metabolites using validated HPLC with fluorescence detection. The AUC for both formulations was comparable with bioequivalence criteria fulfilled, with Cmax after oral treatment approximately 31% lower. Following oral administration, absorption was fast with low to medium variability (mean dissolution and absorption time 2.4 h). The absolute bioavailability was 86%. The excretion of moxifloxacin and its metabolites was quantified in a subset of eight subjects. More than 96% of the dose was recovered from urine and faeces after oral dosing, and >98% following i.v. administration of the drug. M1, which is strongly bound to plasma proteins (90%), was mainly eliminated into faeces (approximately 37-38% of the administered dose) and to a minor extent into urine (2.5% of the administered dose) by active tubular secretion. M2 (only 5% bound to plasma protein) was only found in urine, where it amounted to approximately 14% of the dose. Plasma concentrations of the metabolites were much lower than those of the parent compound. Moxifloxacin was well tolerated with few adverse events and no clinically relevant changes in laboratory values.

Antibiotic susceptibility assay for Staphylococcus aureus in biofilms developed in vitro

Abstract: Four slime-producing isolates of Staphylococcus aureus were used in an antibiotic susceptibility assay for biofilms developed on 96-well polystyrene tissue culture plates. The study involved 11 antibiotics, two biofilm ages (6 and 48 h), two biofilm growth media (tryptone soy broth (TSB) and delipidated milk) and three antibiotic concentrations (4 x MBC, 100 mg/L and 500 mg/L). ATP-bioluminescence was used for automated bacterial viability determination after a 24 h exposure to antibiotics, to avoid biofilm handling. Under the conditions applied, viability in untreated biofilms (controls) was lower when biofilm growth was attempted in milk rather than in TSB. Various antibiotics had a greater effect on viability when used at higher (> or =100 mg/L) antibiotic concentrations and on younger (6 h) biofilms. Increased antibiotic effect was observed in milk-grown rather than TSB-grown biofilms. Phosphomycin and cefuroxime, followed by rifampicin, cefazolin, novobiocin, vancomycin, penicillin, ciprofloxacin and tobramycin significantly affected biofilm cell viability at least under some of the conditions tested. Gentamicin and erythromycin had a non-significant effect on cell viability. Transmission electron microscopy revealed that cells at the inner biofilm layers tend to remain intact after antibiotic treatment and that TSB-grown biofilms favoured a uniformity of cell distribution and increased cell density in comparison with milk-grown biofilms. A reduced matrix distribution and enhanced cell density were observed as the biofilm aged. The S. aureus biofilm test discriminated antibiotics requiring shorter (3 h or 6 h) from those requiring longer (24 h) exposure and yielded results which may be complementary to those obtained by conventional tests.

Identification and characterization of class 1 integrons in bacteria from an aquatic environment

Abstract: In a survey of 3000 Gram-negative bacteria isolated from an estuarine environment over a 2 month period, the incidence of class 1 integrons was determined to be 3.6%. Of 85 integrons studied further, 11 lacked both the qacEdelta1 and sull genes usually present in the 3' conserved segment of the integron. The qacEdelta1 and sull genes were identified in the 3' conserved segment of 36 integrons. The remaining 38 integrons lacked a sull gene but contained a qacE gene. The variable region of 74 integrons was characterized by PCR and sequence analysis. Forty of the integrons were found to lack integrated gene cassettes, although 21 of these 'empty' integrons were shown to contain inserted DNA which has been tentatively identified as a novel insertion sequence (IS) element. Of the 34 integrons which contained inserted gene cassettes, the aadA1a gene was found to be the most prevalent (74%). Nineteen integrons contained additional or other gene cassettes in their variable region, including those encoding resistance to trimethoprim (dfr1a, dfrIIc, dfrV, dfrVII, dfrXII), chloramphenicol (catB3, catB5), aminoglycosides (aadA2, aacA4, aacC1), beta-lactamases (oxa2) and erythromycin (ereA). This study confirms the occurrence of integrons in bacteria from a natural habitat and suggests that in the absence of continued antibiotic selective pressures, integrons which persist appear to preferentially exist without integrated antibiotic resistance gene cassettes.

A review of the comparative in-vitro activities of 12 antimicrobial agents, with a focus on five new ‘respiratory quinolones’

Abstract: The efficacies of many antimicrobial agents are being threatened by a global increase in the numbers of resistant bacterial pathogens--microorganisms that were once susceptible to some of these agents In particular, antimicrobial resistance amongst strains of Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae has limited the usefulness of first-line agents in some clinical settings Quinolones were introduced in the 1980s and represented a significant therapeutic advancement in the treatment of patients with infectious diseases While these compounds possessed potent in-vitro activities against a wide range of gram-negative pathogens, their activities against some gram-positive and 'atypical' pathogens remained borderline Further advancement in the development of quinolones has overcome some of these problems The 'respiratory quinolones' represent a new generation within this class of molecules and comprise compounds possessing broad spectrum activities against gram-negative, gram-positive and atypical pathogens This review will focus on the in-vitro activities of five new respiratory quinolones (gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin and trovafloxacin), ciprofloxacin and six non-quinolone agents (azithromycin, clarithromycin, amoxycillin, co-amoxiclav, cefuroxime and co-trimoxazole) against a range of bacterial and atypical pathogens, including those that are now resistant to several of these compounds

The prevalence of aminoglycoside resistance and corresponding resistance genes in clinical isolates of staphylococci from 19 European hospitals.

Abstract: Aminoglycosides still play an important role in antistaphylococcal therapies, although emerging resistance amongst staphylococci is widespread. To further our understanding of the prevalence of aminoglycoside resistance in Europe, we tested 699 and 249 consecutive unrelated clinical isolates of Staphylococcus aureus and coagulase-negative staphylococci (CNS), respectively, from the SENTRY Antimicrobial Surveillance Program, for susceptibility to gentamicin, tobramycin, kanamycin and streptomycin, and examined the relationship between susceptibility to these antimicrobials and susceptibility to methicillin. Three hundred and sixty-three staphylococcal isolates demonstrated resistance to at least one of the aminoglycosides tested; all of these isolates were screened for the presence of aac(6')-Ie + aph(2"), ant(4')-Ia and aph(3')-IIIa, the genes encoding the most clinically relevant aminoglycoside-modifying enzymes. S. aureus isolates derived from hospital-acquired pneumonia tended to be more resistant to aminoglycosides and methicillin than isolates from blood or wound infections. In S. aureus, resistance to aminoglycosides was closely associated with methicillin resistance. Susceptibility of S. aureus to gentamicin has decreased by 9% from previous European studies to a current level of 77%, while susceptibility of CNS, currently at 67%, has increased by 21%. Geographical variation occurred, correlating with methicillin resistance, although intra-country variation was considerable. aac(6')-Ie + aph(2"), ant(4')-Ia and aph(3')-IIIa were found throughout Europe in 68%, 48% and 14% respectively of staphylococci resistant to at least one aminoglycoside. aph(3')-IIIa was considerably more common in methicillin-susceptible S. aureus and CNS isolates; the reverse was true for the other two resistance genes. The prevalence of ant(4')-Ia and aph(3')-IIIa genes in aminoglycoside-resistant staphylococci was significantly greater than that reported in previous European studies.

Antibiotic resistance in Gram-positive bacteria: epidemiological aspects

Abstract: The emergence and spread of antibiotic resistance in gram-positive bacterial pathogens has become an increasing problem. There has been a dramatic increase in the prevalence of methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci and enterococci. This is mainly due to the clonal dissemination of certain epidemic multiply-resistant strains, for example, those of MRSA and S. pneumoniae, as well as to the spread of resistance genes as exemplified by those causing glycopeptide resistance in enterococci.

The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium

Abstract: A progressive increase in the incidence of vancomycin resistance in strains of Enterococcus faecium (VREF) has severely constrained treatment options for patients with infection caused by this emerging pathogen. Quinupristin/dalfopristin (Synercid), the first injectable streptogramin antibiotic, is active in vitro against VREF, with an MIC90 of 1.0 mg/L. We studied the clinical efficacy and safety of quinupristin/dalfopristin in the treatment of VREF infection. Two prospective studies were conducted simultaneously. The first enrolled only patients with VREF infection; the second included patients with infection caused by other gram-positive bacterial pathogens in addition to VREF. Patients were enrolled if they had signs and symptoms of active infection and no appropriate alternative antibiotic therapy. The recommended treatment regimen of quinupristin/dalfopristin was 7.5 mg/kg i.v. every 8 h for a duration judged appropriate by the investigator. A total of 396 patients with VREF infection were enrolled. The most frequent indications for treatment included intra-abdominal infection, bacteraemia of unknown origin, urinary tract infection, catheter-related bacteraemia, and skin and skin structure infection. This patient population had a high prevalence of severe underlying illness, including a history of diabetes mellitus, transplantation, mechanical ventilation, dialysis, chronic liver disease with cirrhosis and oncological disorders. The mean (+/- S.D.) duration of treatment was 14.5 +/- 10.7 days (range: 1-108). The majority of patients (82.1%) were treated every 8 h, as assessed on day 2 of treatment, while 15.9% were treated every 12 h. The clinical success rate was 73.6% [142/193 clinically evaluable patients; 95% confidence interval (CI): 67.4%, 79.8%], the bacteriological success rate 70.5% (110/156 bacteriologically evaluable patients; 95% CI: 63.4%, 77.7%) and the overall success (both clinical and bacteriological success) rate 65.8% (102/156 bacteriologically evaluable patients; 95% CI: 57.9%, 72.9%). VREF bacteraemia at entry, mechanical ventilation and laparotomy were associated with a worse outcome. Quinupristin/dalfopristin was generally well tolerated. The most common systemic adverse events related to treatment were arthralgias (9.1%) and myalgias (6.6%). Related laboratory abnormalities were infrequent. In these severely ill patients with VREF infection and no other clinically appropriate therapeutic alternatives, quinupristin/dalfopristin demonstrated substantial efficacy and a good nervous system, cardiovascular, gastrointestinal, renal and hepatic tolerability.

Comparative in-vitro activity of voriconazole (UK-109,496) and six other antifungal agents against clinical isolates of Scedosporium prolificans and Scedosporium apiospermum.

Abstract: We report the in-vitro susceptibility of 27 clinical isolates of Scedosporium apiospermum and 43 of Scedosporium prolificans. S. apiospermum was resistant to fluconazole and flucytosine, with variable susceptibility to amphotericin B, itraconazole, ketoconazole and susceptible to miconazole. Voriconazole was much more active than fluconazole and flucytosine, more active than amphotericin B, itraconazole and ketoconazole and was as active as miconazole against S. apiospermum isolates. Voriconazole and the other six antifungal agents showed low activity against S. prolificans isolates.

Current and future antifungal therapy: new targets for antifungal agents

Abstract: Invasive fungal infections are a major problem in immunocompromised patients. The recent expansion of antifungal drug research has occurred because there is a critical need for new antifungal agents to treat these life-threatening invasive infections. The overview of the development of antifungal therapy which is provided herein reflects the increased interest in this very special area of infectious diseases. Although we have newer, less toxic, antifungal agents that are available for clinical use, their clinical efficacy in some invasive fungal infections, such as aspergillosis and fusariosis, is not optimal. Thus, intense efforts in antifungal drug discovery are still needed to develop more promising and effective antifungal agents for use in the clinical arena.

The antileishmanial activity of novel oxygenated chalcones and their mechanism of action

Abstract: Our previous studies have shown that licochalcone A, an oxygenated chalcone, has antileishmanial and antimalarial activities, and alters the ultrastructure and function of the mitochondria of Leishmania spp. parasites. The present study was designed to investigate the antileishmanial activity and the mechanism of action of a group of new oxygenated chalcones. The tested oxygenated chalcones inhibited the in-vitro growth of Leishmania major promastigotes and Leishmania donovani amastigotes. Treatment of hamsters infected with L. donovani with intraperitoneal administration of two oxygenated chalcones resulted in a significant reduction of parasite load in the liver and the spleen compared with untreated control animals. The oxygenated chalcones also inhibited the respiration of the parasite and the activity of mitochondrial dehydrogenases. Electron microscopic studies illustrated that they altered the ultrastructure of the mitochondria of L. major promastigote. The data clearly indicate that this group of oxygenated chalcones has a strong antileishmanial activity and might be developed into a new antileishmanial drug. The antileishmanial activity of oxygenated chalcones might be the result of interference with function of the parasite mitochondria.

The socio-economic burden of influenza

Abstract: Influenza epidemics and pandemics have a huge impact on society and individuals. The weight and scope of the burden of influenza varies with the age and underlying health of the patient. The disease imposes a significant burden on all individuals, but hospitalization and treatment occur more frequently in high-risk patients (the elderly and those with certain underlying medical conditions); patient populations that are increasing in size. Escalating medical costs have increased the need to quantify the burden of influenza. The first step in any such analysis is to determine the incidence of the disease; with influenza, this is often under-reported, since the illness may be confused with other viral illnesses. In addition to the direct costs of medical care, the indirect costs of influenza are substantial and stem largely from absenteeism and loss of work productivity. Estimates of the cost of influenza in the USA, France and Germany have shown that indirect costs can be five- to 10-fold higher than direct costs. Other intangible costs associated with influenza include impaired performance, which can reduce reaction times, and adverse effects on the quality of life of patients and their families. The costs of interventions should, therefore, be considered in this context. The main approach to the control of influenza and its associated costs is the administration of vaccines. Although vaccines are widely effective, the greatest potential benefits are observed within high-risk groups; vaccination is therefore recommended in many countries for high-risk patients, their carers and healthcare workers. However, the shortcomings of present vaccines, which include manufacturing limitations that prevent guaranteed adequate supply of vaccine, the difficulty in matching vaccines to circulating strains and the need for administration by injection, highlight the need for complementary treatment.

A variety of Gram-positive bacteria carry mobile mef genes

Abstract: The mefE gene codes for a membrane bound efflux protein, which confers resistance to macrolides, and has been identified in Streptococcus pneumoniae. A variety of gram-positive organisms were examined. Twenty-six isolates of S. pneumoniae carried mefE and were resistant to erythromycin (MIC of 2-16 mg/L). Two additional isolates of Emr S. pneumoniae carried both ermB and mefE(MIC of 16-128 mg/L). One Micrococcus luteus, one Corynebacterium jeikeium, three Corynebacterium spp., two viridans streptococci and seven Enterocccus spp. also carried mef genes. It was possible to move the mef gene from all 11 S. pneumoniae tested to susceptible S. pneumoniae and/or Enterococcus faecalis recipients. The addition of DNase (1 g/L) did not affect the gene transfer. It was also possible to move the mef gene from donor Enterococcus spp., viridans streptococci, M. luteus, C. jeikeium and Corynebacterium spp. to E. faecalis recipients. Transconjugant isolates were resistant to erythromycin (MIC = 16 mg/L). Hybridization with a labelled mef oligonucleotide probe against Southern blots and bacterial dot blots confirmed the presence of the mef genes. This is the first time that a mobile mef gene has been identified in four different genera, from three distinct geographical locations.

Pneumococcal macrolide resistance—myth or reality?

Abstract: There is no doubt that owing to the prolific use of the macrolides and azithromycin over the past several years, resistance has developed and is increasing in incidence. I believe we should re-evaluate the use of these antibiotics for our patients and consider parameters other than the negative in-vitro results. Firstly, microbiology laboratories should return to the habit of providing the clinician with MIC values for pathogenic isolates rather than generic susceptibility reports ((S)usceptible, (I)ntermediate, (R)esistant) that are based on standard disc diffusion testing. Although agar dilution MIC testing is a bulky and labour intensive practice, it provides the best data when conducted in the appropriate environment. Secondly, and more importantly, these MIC values need to be compared with in-vivo antibiotic pharmacokinetics and pharmacodynamics. Although it is possible to compare MIC values directly with serum concentrations of beta-lactams and aminoglycosides, this is not a valid practice for azithromycin or the macrolides. MICs of azithromycin and the macrolides must be compared with the infection site and phagocytic cell concentrations to determine the utility, or lack thereof, of one of these agents. Whereas azithromycin cellular penetration allows maximal pharmacodynamics potentially even against moderately or highly resistant pneumococci, the macrolides do so less optimally. Although there are no reports of widespread clinical failures resulting from macrolide/azalide resistance in pneumococci, it is expected that such reports will appear once the isolates become consistently highly resistant. This is likely to affect the macrolides, erythromycin and clarithromycin, before the azalide, azithromycin owing to the differences in pharmacokinetics of these drugs. Until then, it will be important to determine the MICs of not just one macrolide, but of all macrolides and azalides for the isolates. This will allow the clinician to make a pharmacokinetically and pharmacodynamically sound choice. By choosing clinical MIC breakpoints of 4-8 mg/L for oral macrolides and < or = 32 mg/L for oral azithromycin, rather than the present standard breakpoints, the clinician can make a macrolide/azalide choice that will optimize the pharmacodynamics of the drug against the isolated pathogen and result in the best possible clinical outcome. Once data concerning the cellular penetration of intravenous formulations of these drugs becomes available, it will be possible to develop clinical breakpoints for these formulations as well. Only through utilizing good antibiotic prescribing practices and by using the drugs appropriately when they are used, can resistance trends be stemmed. In this way, not only does a clinician treat the patient more effectively, but they also extend the antibiotic's useful life.

Randomized, placebo-controlled studies of inhaled zanamivir in the treatment of influenza A and B: pooled efficacy analysis

Abstract: Zanamivir, a potent, highly selective inhibitor of influenza virus A and B neuraminidase, has been evaluated in seven, similarly designed, placebo-controlled studies of the treatment of influenza. Patients with typical influenza symptoms were recruited when influenza was known to be circulating in the community. Six of these studies included a zanamivir 10 mg inhaled bd (for 5 days) treatment arm, the dose regimen submitted to regulatory agencies. Pooled analyses were conducted to evaluate efficacy more precisely in terms of the alleviation of symptoms in population subgroups and for secondary endpoints. Median time to alleviation of symptoms, the primary endpoint, was reduced from 6.0 days in the placebo group (n = 1,102) to 5.0 days in the zanamivir group (n = 1,133), P 50 years (n = 263), compared with 1 day (P < 0.001) in patients aged <50 years. In 'high-risk' IP patients (recruited into all treatment studies), there was a treatment benefit of 2.5 days (n = 305, P = 0.006). Pooled analyses of secondary endpoints showed statistically significant reductions in antibiotic use, time to return to normal activities and use of relief medication. In addition, reductions in symptom scores were apparent shortly after commencing zanamivir treatment. By the evening of the second day of treatment, the median total symptom score had fallen by 44% in zanamivir recipients compared with 33% in placebo recipients (P < 0.001). These results highlight the groups likely to show greatest benefit from zanamivir treatment, and confirm the clinical relevance of the treatment benefit.

Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for the treatment of acute exacerbations of chronic bronchitis

Abstract: In this multinational, randomized, double-blind study, the efficacy and safety of a 5 day course of moxifloxacin 400 mg orally od was compared with that of a 7 day course of clarithromycin 500 mg orally bd. in 750 patients with acute exacerbations of chronic bronchitis, characterized by at least two of the symptoms: sputum purulence, increased sputum volume or increased dyspnoea. Seven days after the end of therapy, clinical cure was achieved for 89% (287 of 322) of efficacy-evaluable patients in the moxifloxacin group and 88% (289 of 327) of patients in the clarithromycin group (95% CI, -3.9%, 5.8%). At follow-up (21-28 days post-treatment), the continued clinical cure rates were 89% (256 of 287) for moxifloxacin and 89% (257 of 289) for clarithromycin. A total of 342 pathogenic bacteria were isolated from the sputum of 287 patients. The most common pathogens were Haemophilus influenzae (37%), Streptococcus pneumoniae (31%) and Moraxella catarrhalis (18%). Seven days post-treatment, a successful bacteriological response was obtained for 77% (89 of 115) of patients in the moxifloxacin group and 62% (71 of 114) of patients in the clarithromycin group, indicating superiority of moxifloxacin (95% CI, 3.6%, 26.9%). Both treatments were well tolerated with few adverse events. This study demonstrated that for the treatment of acute exacerbations of chronic bronchitis a 5 day course of moxifloxacin 400 mg od was clinically equivalent and bacteriologically superior to a 7 day course of clarithromycin 500 mg bd.

Treatment of hospitalized patients with complicated Gram-positive skin and skin structure infections: two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin

Abstract: Quinupristin/dalfopristin (Synercid), the first injectable streptogramin antibiotic available for the treatment of complicated gram-positive skin and skin structure infections, was compared with standard comparators (cefazolin, oxacillin or vancomycin) in one USA and one international trial. These two randomized, open-label trials of virtually identical design enrolled a total of 893 patients (450 quinupristin/dalfopristin, 443 comparator). The majority of patients had erysipelas, traumatic wound infection or clean surgical wound infection. Staphylococcus aureus was the most frequently isolated pathogen in both treatment groups and polymicrobial infection was more common in the quinupristin/dalfopristin group than in the comparator group. The clinical success rate (cure plus improvement) in the clinically evaluable population was equivalent between the two treatment groups (68.2% quinupristin/dalfopristin, 70.7% comparator; 95% CI, -10.1, 5.1) despite a shorter mean duration of treatment for quinupristin/dalfopristin patients. In the bacteriologically evaluable population, by-patient and by-pathogen bacteriological eradication rates were somewhat lower for quinupristin/dalfopristin (65.8% and 66.6%, respectively) than for the comparator regimens (72.7% and 77.7%, respectively). The lower bacteriological response rates in the quinupristin/dalfopristin group were, in part, due to a higher rate of polymicrobial infections and a higher incidence of patients classified as clinical failure, a category which included premature discontinuation of treatment because of local venous adverse events. The bacteriological eradication rate for quinupristin/dalfopristin was higher in monomicrobial infections than in polymicrobial infections (72.6% versus 63.3%, respectively), whereas the corresponding rate for the comparator regimens was lower for monomicrobial infections than polymicrobial infections (70.8% versus 83.1%). This finding was not unexpected, since the spectrum of quinupristin/dalfopristin is focused on gram-positive pathogens and additional antibiotics to treat gram-negative bacteria were not required per protocol. The systemic tolerability of both treatment regimens was qualitatively similar. A higher rate of drug-related venous adverse events was reported for quinupristin/dalfopristin (66.2%) than for the comparator regimen (28.4%). Premature discontinuation of study drug was primarily due to adverse clinical events for quinupristin/dalfopristin (19.1%), whereas the most common reason for discontinuation among those receiving the comparator regimens was treatment failure (11.5%). Quinupristin/dalfopristin is an effective alternative for the treatment of hospitalized patients with complicated skin and skin structure infections due to quinupristin/ dalfopristin-susceptible gram-positive organisms, including methicillin- and erythromycin-resistant S. aureus.

Early switch from intravenous to oral antibiotics: guidelines and implementation in a large teaching hospital.

Abstract: In recent years 'switch therapy' has been advocated: short intravenous antibiotic therapy, for 2-3 days, followed by oral treatment for the remainder of the course. Little is known about the number of patients that could benefit from early switch therapy and the consequences of introducing this strategy in everyday practice. We prospectively registered all antibiotic courses on wards for Internal Medicine, Surgery, and Pulmonology during a 2 month period, before (n = 362, inventorial phase) and after (n = 281, implementation phase) the introduction of guidelines for switching therapy. Approximately 40% of all patients who started on iv antibiotics were candidates for an early iv-oral switch. During the inventorial phase, 54% (52/97) of eligible patients were switched to oral treatment, after a median of 6 days (range 2-28 days). After implementation of the guidelines, this percentage rose to 83% (66/80) (difference 29%, 95% CI 16-42%; P 6000 per year. This means a potential annual reduction of dfl.60,000 (c. US$30,000) of administration costs. The potential savings in purchase costs of the antibiotics were dfl.54,000 (US$27,000) annually. In conclusion, a substantial number of patients starting on iv antibiotics were candidates for an early iv-oral switch. The guidelines were well accepted by the physicians and substantial savings in costs and nursing time were achieved.

In-vitro and in-vivo antibacterial activity of BI 397, a new semi-synthetic glycopeptide antibiotic

Abstract: BI 397 (formerly A-A-1) is a semisynthetic derivative of the teicoplanin-like glycopeptide A40926. It was more active in vitro against staphylococci (including some teicoplanin-resistant strains) than teicoplanin and vancomycin. Against streptococci (including penicillin-resistant strains) BI 397 has activity comparable with that of teicoplanin and better than vancomycin. BI 397, when administered to rats by the i.v. route, gives high and long lasting blood levels. It shows excellent activity in models of acute septicaemia in immunocompetent and neutropenic mice. In a rat staphylococcal endocarditis model it is as effective as teicoplanin and vancomycin at reducing bacterial loads in the heart, but at lower dosages and with a reduced number of daily treatments compared with the two glycopeptide controls. BI 397 is highly efficacious in clearing penicillin-susceptible and -resistant pneumococci from lungs of immunocompetent and neutropenic rats. The data from these studies show that BI 397 combines an excellent in-vitro antibacterial activity with favourable pharmacokinetic behaviour resulting in potent in-vivo activity.

The control of hyperendemic glycopeptide-resistant Enterococcus spp. on a haematology unit by changing antibiotic usage

Abstract: The rectal carriage of glycopeptide-resistant Enterococcus spp. (GRE) had been established at approximately 50% in a series of prevalence studies on a busy haematological malignancy unit. The aim of this study was to reduce the chance of patients acquiring GRE. A prospective three-phase sequential study was performed. In Phase 1, the acquisition rate of GRE detectable by rectal swab was measured without any intervention for a period of 4 months. For the following 8 months (Phase 2), the first-line treatment for febrile neutropenic episodes was changed from monotherapy with ceftazidime to piperacillin/tazobactam. In addition, an intense education programme was introduced to improve hygiene to reduce the risk of case-to-case spread. In the final 4 months (Phase 3), ceftazidime was again used as the first-line antimicrobial, while continuing the same level of training in relation to hygiene. The carriage of GRE was measured from rectal swabs done weekly. During the initial 4 months, at any time, 40-50% of patients in the unit were colonized with GRE, and 43 of 75 (57%) new patients initially negative for GRE acquired it within 6 weeks of their admission. In Phase 2, 25 patients out of 129 (19%) acquired GRE, with the acquisition rate falling progressively so that in the last 3 months, only one new patient acquired GRE (logrank comparison of probabilities for cohort 1 vs cohort 2b: P < 0.0001). A return to ceftazidime in Phase 3 was associated with a return of the risk of acquiring detectable GRE colonization, despite continued hygiene teaching and surveillance, with 21 out of 58 patients (36%) acquiring GRE (cohort 1 vs cohort 3: P = 0.08). Glycopeptide usage was not reduced during the period of the study. Clinical cases were seen only in Phases 1 and 3. Although the reduction in the risk of acquiring GRE may have been due in part to hygiene practices as well as to the change in antimicrobial usage, or may have occurred spontaneously for other reasons, the return of the problem with the reintroduction of ceftazidime strongly suggests that this antibiotic was responsible for encouraging the acquisition of detectable GRE.

Antimycobacterial activities of riminophenazines

Abstract: Riminophenazines were specifically developed as drugs active against Mycobacterium tuberculosis but extensive research over several decades has shown that these compounds are also active against many other mycobacterial infections, particularly those caused by Mycobacterium leprae and the Mycobacterium avium complex (MAC). Clofazimine, the lead compound in this series, is included in the regimens that are approved by the WHO for the treatment of leprosy and has contributed significantly to the control of that disease, particularly that caused by dapsone-resistant bacteria. Despite early problems, clofazimine has shown clinical efficacy in tuberculosis, in particular that caused by multiple drug resistant strains. Clofazimine does not induce resistance and also inhibits emergence of resistance to isoniazid in M. tuberculosis. The efficacy of clofazimine against MAC is more varied and the availability of better drugs has limited its use. Newer riminophenazines, such as B746 and B4157, not only showed increased anti-mycobacterial activity but also produced less skin pigmentation, which is the main drawback of this group of compounds. The most important virtues of riminophenazines, such as intracellular accumulation in mononuclear phagocytic cells, anti-inflammatory activity, a low incidence of drug resistance and slow metabolic elimination, make them attractive candidates for the treatment of mycobacterial infections. It is essential, however, to investigate the newer analogues clinically, while continuing the pursuit of alternate candidates that demonstrate higher anti-mycobacterial activity and lower rates of skin pigmentation.

Extended-spectrum beta-lactamase-producing strain of Acinetobacter baumannii isolated from a patient in France.

Abstract: Sir, Acinetobacter spp., especially Acinetobacter baumannii, are common opportunistic pathogens in immunocompromised patients and currently cause 10% of nosocomial infections in intensive care unit patients. They tend to be resistant to multiple antibiotics and to produce cephalosporinases. Indeed, hyperproduction of cephalosporinases, together with decreased outer membrane permeability, are the predominant mechanisms of resistance to ceftazidime amongst A. baumannii isolates. Most extended-spectrum -lactamases (ESBLs) are the result of mutations that alter the hydrolytic properties of the restricted spectrum penicillinases, TEM-1 and -2 and SHV-1. These enzymes are principally mediated by plasmids which spread readily amongst Enterobacteriaceae and their presence is detected by the demonstration of synergy between clavulanic acid, which inhibits the lactamase, and a third-generation cephalosporin (most effectively ceftazidime) with the double-disc diffusion test. In the course of routinely assessing all ceftazidime-resistant Acinetobacter spp. isolates by the double-disc diffusion test, we identified a strain of A. baumannii (Ama-1) exhibiting only slight synergy that was most evident when the ceftazidime disc was placed 2 cm from the clavulanic acid disc. The MICs of amoxycillin, ticarcillin, piperacillin, ceftazidime and imipenem for the isolate were determined by the agar dilution method according to recommendations of a working party of the British Society for Antimicrobial Chemotherapy. Ama-1 was resistant to all of the -lactams tested, with the exception of imipenem. In the presence of clavulanic acid at a fixed concentration of 2 mg/L, the MIC of ticarcillin was reduced from 512 mg/L to 256 mg/L and that of ceftazidime from 512 mg/L to 128 mg/L. Similarly, in the presence of sulbactam at a concentration of 4 mg/L, the MIC of ceftazidime fell from 512 mg/L to 256 mg/L. The activity of any -lactamase(s) produced by this isolate is therefore inhibited only minimally by either -lactamase inhibitor. In an attempt to determine the molecular basis of this resistance phenotype, we assayed for a putative ESBL gene by PCR analysis with TEM-specific primers (5 -GTATGGATCCTCAACATTTCCGTGTCG-3 and 5 -ACCAAAGCTTAATCAGTGAGGCA-3 ) and SHVspecific primers (5 -TTATCTCCCTGTTAGCCACC-3 and 5 -GATTTGCTGATTTCGCCG-3 ). Neither gene was demonstrated. However, primers used to detect the gene for the ESBL, PER-1 (5 -ATGAATGTCATTATAAAAGC-3 and 5 -AATTTGGGCTTAGGGCAGAA-3 ), yielded a 925 bp PCR product. The sequence analysis of this product revealed total identity with blaPER-1 which was originally detected in a strain of Pseudomonas aeruginosa. A survey recently carried out in Turkey showed that 46% of Acinetobacter spp. hospital isolates possessed PER1-type -lactamases. In this study, attempts to demonstrate plasmid carriage of blaPER-1 in Ama-1 and to transfer the ESBL resistance phenotype from Ama-1 to Escherichia coli DH10B by mating-out assays and by electroporation (electrotransformation) were unsuccessful. Ama-1 was isolated following culture of a rectal swab obtained from a 90 year old female patient on the intensive care unit. She had previously been admitted to two other hospitals in Paris but, to the best of our knowledge, had not travelled to Turkey, nor had she been in contact with either Turkish patients or travellers to Turkey. PER-1-positive A. baumannii strains were not isolated from the rectal swabs of 16 other patients on the intensive care unit at the same time as the patient from whom Ama-1 was recovered. Moreover, comparison of ApaI-digested genomic DNA extracted from Ama-1 with DNA from four randomly selected PER-1-type -lactamase-positive and one PER1-type -lactamase-negative A. baumannii strains from Turkey by pulsed-field gel electrophoresis (PFGE) revealed different restriction patterns (Figure). Thus, the French isolate was not clonally related to the Turkish strains. This is the first report from outside Turkey of the detection of an ESBL in an Acinetobacter spp. clinical isolate. We believe that it is also the first description of the sequencing-based identification of an ESBL gene in an

Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy

Abstract: The concentrations of moxifloxacin achieved after a single 400 mg dose were measured in serum, epithelial lining fluid (ELF), alveolar macrophages (AM) and bronchial mucosa (BM). Concentrations were determined using a microbiological assay. Nineteen patients undergoing fibre-optic bronchoscopy were studied. Mean serum, ELF, AM and BM concentrations at 2.2, 12 and 24 h were as follows: 2.2 h: 3.2 mg/L, 20.7 mg/L, 56.7 mg/L, 5.4 mg/kg; 12 h: 1.1 mg/L, 5.9 mg/L, 54.1 mg/L, 2.0 mg/kg; 24 h: 0.5 mg/L, 3.6 mg/L, 35.9 mg/L, 1.1 mg/kg, respectively. These concentrations exceed the MIC(90)s for common respiratory pathogens such as Streptococcus pneumoniae (0.25 mg/L), Haemophilus influenzae (0.03 mg/L), Moraxella catarrhalis (0.12 mg/L), Chlamydia pneumoniae (0.12 mg/L) and Mycoplasma pneumoniae (0. 12 mg/L) and indicate that moxifloxacin should be effective in the treatment of community-acquired, lower respiratory tract infections.

Pharmacodynamics of levofloxacin and ciprofloxacin against Streptococcus pneumoniae

Abstract: An in-vitro pharmacokinetic model was used to compare the pharmacodynamics of levofloxacin and ciprofloxacin against four penicillin-susceptible and four penicillin-resistant Streptococcus pneumoniae. Logarithmic-phase cultures were exposed to the peak concentrations of levofloxacin or ciprofloxacin observed in human serum after 500 mg and 750 mg oral doses, human elimination pharmacokinetics were simulated, and viable bacterial counts were measured at 0, 1, 2, 4, 6, 8, 12, 24 and 36 h. Levofloxacin was rapidly and significantly bactericidal against all eight strains evaluated, with eradication of six strains occurring despite area under the inhibitory curve over 24 h (AUIC24) values of only 32-64 SIT(-1) x h (serum inhibitory titre over time). The pharmacodynamics of ciprofloxacin were more variable and the rate of bacterial killing was consistently slower than observed with levofloxacin. Ciprofloxacin eradicated five strains despite having an AUIC24 of only 44 SIT(-1) x h. These data suggest that the increased potency of levofloxacin and more favourable pharmacokinetics compared with ciprofloxacin provide enhanced pharmacodynamic activity against S. pneumoniae. Furthermore, these data suggest that the minimum AUIC required for clinical efficacy against and eradication of S. pneumoniae with levofloxacin and ciprofloxacin may be well below the 125 SIT(-1) x h identified by other studies.

Pharmacokinetics of the 8-methoxyquinolone, moxifloxacin: a comparison in humans and other mammalian species

Abstract: The pharmacokinetics of moxifloxacin was investigated in NMRI mice, Wistar rats, rhesus monkeys, beagle dogs, Gottingen minipigs and healthy human volunteers after i.v. and oral administration of moxifloxacin-HCl (single doses of moxifloxacin 9.2 mg/kg bodyweight) in animals and 100 mg moxifloxacin (1.4 mg/kg bodyweight p.o. and 1.2 mg/kg bodyweight i.v.) in humans. The plasma concentration vs time courses of the unchanged compound (determined by HPLC) and the derived pharmacokinetic parameters were used to evaluate the absorption process, to compare the pharmacokinetics in these species and to perform an interspecies scaling. The results of the pharmacokinetic investigations indicate a clear dependence on the species. Moxifloxacin is absorbed quickly (rats, dogs, humans > monkeys): the major portion of the dose reached the systemic circulation within the first 2 h. In the minipig absorption was slower. Bioavailability was high to moderate (91-52%) in all species. Protein binding (f(u)) was low (55-71%) in all species. The volume of distribution at steady state (Vss) was medium to large (2.0-4.9 L/kg) in all species. There were considerable differences in maximum concentrations (C(max,norm), 0.430-0.070 kg/L) and in AUCnorm values (oral, 6.18-0.184 kg x h/L; i.v., 7.51-0.237 kg x h/L). Total body clearance (CL) decreased with increasing bodyweight (4.21-0.132 L/(h x kg)). The mean residence time (MRT) decreased with decreasing bodyweight (15-0.88 h). The half-life (t(1/2)) decreased with decreasing bodyweight (oral, 12-1.3 h, i.v., 13-0.93 h). There was moderate to low renal excretion (i.v., 20-6.2%), the renal clearance, (CL(R)) was in the range 0.615-0.0222 L/(h x kg). Regarding the pharmacokinetic parameters determined after oral administration, the dog was most similar to the human in terms of Cmax, AUC and t(1/2). There was good correlation between bodyweight and CL (coefficient of correlation (r) = 0.959), Vss (r = 0.990) and MRT (r = 0.943). On the basis of preclinical studies a terminal half-life appropriate for once-daily dosing in humans was predicted and confirmed by Phase I data.