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Objectives: The oxazolidinone class of antibiotics such as linezolid have a narrow spectrum of activity that targets Gram-positive bacteria. We hypothesized that the poor activity of linezolid in Gram-negative bacteria is in part caused by relatively low intracellular concentration due to efflux., Methods: Using whole cell accumulation assays we estimated the intracellular concentration of linezolid in Escherichia coli and other Enterobacteriaceae. We included test strains with enhanced RND-type multidrug efflux pump activity and with genetic inactivation of the pump or functional inhibition by carbonyl cyanide m-chlorophenylhydrazone as inhibitor of the proton motive force or 1-(1-naphthylmethyl)-piperazine (NMP), an efflux pump inhibitor., Results: Consistent with susceptibility studies, enhanced pump activity caused decreased accumulation, and pump inactivation and inhibition caused increased accumulation, of linezolid. The accumulation levels in test strains of E. coli, Citrobacter freundii and Enterobacter aerogenes with functional pumps were lower than in control strains of Staphylococcus aureus and Enterococcus faecium, but were higher after pump inactivation and correlated with ethidium bromide and pyronin Y accumulation., Conclusions: The intracellular concentration of linezolid is comparatively low owing to efficient efflux of the drug and could be increased substantially by inhibition of RND-type efflux pumps.

Objectives: YhiV (MdtF) is an resistance nodulation division (RND) type efflux pump in Escherichia coli with significant homology to AcrB but usually expressed at a low level in clinical isolates. When overexpressed the pump confers decreased susceptibility to a variety of substances including erythromycin and ethidium bromide (EtBr). We characterized two mutants of E. coli E12 (DeltaacrB DeltaacrF) overexpressing yhiV that showed surprising differences in their spectrum of multidrug resistance (MDR)., Methods: The two mutants obtained after repeated exposure of E. coli E12 to levofloxacin were tested for antimicrobial susceptibility to a variety of agents and for intracellular accumulation of selected pump substrates. Gene expression was studied by quantitative RT-PCR, and yhiV was sequenced. Gene inactivation and replacement were done by phage lambda-based homologous recombination., Results: Mutant DKO20/1 overexpressed yhiV, showed a wild-type yhiV sequence and had >2-fold increased MICs of fluoroquinolones, novobiocin, macrolides/ketolides, EtBr, oxacillin and Phe-Arg-beta-naphthylamide (PAbetaN, a putative efflux pump inhibitor) compared with the E12 parent. A second mutant, strain DKO1/17 that had the Val-610-->Phe point mutation in YhiV differed from DKO20/1 by faster growth, >2-fold increased MICs of linezolid and tetracycline, but >2-fold decreased MICs of PAbetaN, azithromycin and telithromycin. Inactivation of yhiV in DKO1/17 and reintroduction of the wild-type and mutant yhiV sequence confirmed that the differing MICs of most of the drugs were associated with the observed single point mutation. Intracellular drug accumulation studies with linezolid and PAbetaN were consistent with the MIC results., Conclusions: The region around amino acid Val-610 in YhiV appears to be involved in determining recognition and efficiency of export of a number of MDR efflux pump substrates. This single point mutation in the periplasmic loop of the pump can increase resistance to a given drug such as a fluoroquinolone while decreasing resistance to another one.

After several decades of continuously successful antibiotic therapy against bacterial infections, we are now facing a worrying prospect: the accelerated evolution of antibiotic resistance to important human pathogens and the scarcity of new anti-infective drug families under development. Efflux is a general mechanism responsible for bacterial resistance to antibiotics. This active drug transport is involved in low intrinsic susceptibility, cross-resistance to chemically unrelated classes of molecules, and selection/acquisition of additional mechanisms of resistance. Thus, inhibition of bacterial efflux mechanisms appears to be a promising target in order to (i) increase the intracellular concentration of antibiotics that are expelled by efflux pumps, (ii) restore the drug susceptibility of resistant clinical strains, and (iii) reduce the capability for acquired additional resistance. Structurally unrelated classes of efflux pump inhibitors (EPIs) have been described and tested in the last decade, including some analogues of antibiotic substrates and new chemical molecules. Among the current collection of EPIs, only a few compounds have been studied taking into account the structure-activity relationships and the spectrum of activity in terms of antibiotics, pumps and bacteria. While large efforts have characterized an increasing number of bacterial efflux pumps and generated several potentially active EPIs, they have not elucidated the molecular basis of efflux transport and inhibition. Recent studies of pump-substrate complexes, the 3D resolution of the efflux pumps, the synthesis of novel compounds and molecular dynamic studies may generate new clues to decipher and select novel targets inside the efflux mechanisms and, finally, may result in a clinically useful molecule.

Antibiotic use was evaluated in two cohorts of intensive care units (ICUs) in Germany. One cohort included ICUs participating in a surveillance programme (N=34) collecting antibiotic use and bacterial resistance data, with quarterly feedback. The second ICU cohort was from a cross-sectional study and represented a sample from hospitals in South-west Germany (N=58). Two dose definitions were used. These were the World Health Organization/Anatomical Therapeutic Chemical Classification (ATC) 2001 definition of defined daily dose (DDD), and a definition of recommended daily dose (RDD) that better reflected the currently prescribed dosages of parenteral drugs for hospitalized patients. Data were expressed as DDD or RDD per 100 patient-days. It was determined whether hospital size and affiliation, year of study and ICU type had an influence on overall use of antibiotics. Overall use differed between the two ICU cohorts irrespective of the dose definitions used. High use of antibiotics was primarily associated with hospital affiliation (university vs non-university) and hospital size. Mean overall use of antibiotics in non-university hospital ICUs ranged between 106 and 111 DDD/100 (59 and 67 RDD/100) for different hospital size categories, compared with 140 DDD/100 (87 RDD/100) in university hospital ICUs. In conclusion, in order to compare the use of antibiotics between ICU cohorts and to assess trends over time, data adjustment is required for hospital affiliation and size.

New evidence shows that antibiotic prophylaxis in neutropenic patients reduces mortality, febrile episodes, and bacterial infections. For patients with acute leukemia or those who undergo bone marrow transplantation, prophylaxis with fluoroquinolones diminished the risk of death from any cause by 33% (95% confidence interval [95% CI], 2-54%). Thus, 55 patients who have acute leukemia or who undergo bone marrow transplantation must receive prophylaxis to prevent 1 death. In 4 studies that included patients with solid tumors or lymphoma, prophylaxis reduced the rate of death during the first month (relative risk, 0.51; 95% CI, 0.27-0.97), and 82 patients had to receive prophylaxis to prevent 1 death. The main argument brought against prophylaxis is the induction of resistance. Patients who received prophylaxis did not experience more infections caused by resistant strains than patients in the control group. The recent GIMEMA study was conducted in a population with a nearly 50% resistance to fluoroquinolones in all pathogens and 20% resistance in gram-negative isolates, thus indicating that prophylaxis should be offered in settings with similar or less resistance. Prophylaxis with fluoroquinolones was efficacious in reducing infections caused by gram-positive bacteria. Patients who are treated for acute leukemia should be offered prophylaxis with ciprofloxacin or levofloxacin. Prophylaxis to cover the expected period of neutropenia may be considered for the first cycle of treatment in patients with solid tumors or lymphoma who regularly receive regimens that cause severe neutropenia. Excessive local levels of resistance to fluoroquinolones or high local incidence of infections caused by Clostridium difficile and related to fluoroquinolones should prompt a reconsideration of this policy., (2006 American Cancer Society)

Objective: Outpatient antibiotic use in Germany differs substantially between eastern and southern parts of the country (low use) and the western part (high use). Whether similar regional variation exists in hospital antibiotic consumption is not known. We investigated this issue using a convenience sample of 145 hospitals providing data for the year 2003., Methods: Data on hospital consumption of systemic antibiotics in Anatomical Therapeutic Chemical (ATC) class J01 were obtained from acute care hospitals that participated in an IMS survey and had complete data (dispensed drugs and patient-days per year) for at least one non-pediatric, non-psychiatric department or ward. A total of 275 non-ICU surgical departments/wards, 229 non-ICU non-surgical (general medicine, haematology-oncology, neurology/stroke) departments/wards, and 184 ICUs were analysed. Data were expressed in DDD (WHO/ATC definition version 2003) or daily doses adapted for recommendations in hospitalized patients (RDD) per 100 patient days (DDD/100 and RDD/100)., Findings: The weighted mean over all departments/wards was 49.6 DDD/100 or 31.3 RDD/100, respectively. As expected, ICU antibiotic use density was much higher than use in non-ICU areas, and use in haematology-oncology was higher than in other non-surgical departments/wards. In univariate analyses, region, hospital bed-size category, university affiliation and haematology-oncology as specialty were associated with use density, but these associations were only partly confirmed in multivariate logistic regression analyses of factors associated with excess (> or = 75%) use density which showed university affiliation and haematology-oncology but not hospital location to be independently associated with comparatively high use., Conclusions: Antibiotic use density in German acute care hospitals does not appear to differ significantly between regions. Overall hospital consumption of antibiotics in this country appears to be similar to what has been described from other parts of Europe. In comparative analyses of hospital antibiotic consumption, data need to be adjusted at least for university affiliation and haematology-oncology.

Objective: According to recent surveys, outpatient antibiotic prescribing in Germany has been comparatively low among European countries. We assessed regional variation in outpatient antibiotic use within Germany both for overall use as well as for specific antibiotic drug classes., Methods: Prescription data for the year 2003 covering approximately 90% of the total population were analysed using the ATC/WHO defined daily dose (DDD) methodology. Data were expressed in DDD per 1,000 persons covered by the insurance and day (DID)., Results: Outpatient antibiotic prescribing in 2003 was 13.6 DID and ranged between 9.2 and 17.9 DID in the different regions examined. Low consumption regions were eastern and southern states. High consumption areas were in the west near the French and Belgian border. This regional prescribing pattern was similar for children and adults. Penicillins were the most frequent prescribed drugs, but their use density showed a relatively large regional variation (factor 3.5), with relatively low prescription frequency in the eastern states. In almost all regions quinolones were used more often than trimethoprim-sulfamethoxazole., Conclusion: The regional variation in recent outpatient antibiotic prescribing in Germany is substantial. The relatively high antibiotic use in the western part of the country is remarkable, remains unexplained and requires further study.

Objectives: Recent studies have shown a beneficial impact of fluoroquinolones on infection-related morbidity and mortality for patients with haematological malignancies during neutropenia. Among the fluoroquinolones moxifloxacin currently provides one of the broadest spectra of antibacterial activity and may be suitable for prophylaxis during neutropenia., Patients and Methods: In this controlled before and after observational study, moxifloxacin chemoprophylaxis was used during prolonged neutropenia in haemato-oncological patients (period 2; 282 episodes). Data were compared with two periods with levofloxacin prophylaxis, one preceding period (period 1; 399 episodes) and a post-observational period (period 3; 53 episodes). Endpoints for evaluation were the rates of Gram-negative and Gram-positive bacteraemia and infection-related mortality., Results: We found similar survival rates as compared with levofloxacin. The rate of Gram-negative bacteraemia was higher during prophylaxis with moxifloxacin (11%) when compared with levofloxacin (6% for period 1 and 6% for period 3). In addition we observed a marked increase in diarrhoea associated with Clostridium difficile toxin A (CDAD) after a formula change from levofloxacin to moxifloxacin (attack rate 6% versus 33%). A decrease was attained after changing back to levofloxacin and reinforcing hygienic measures (13%)., Conclusions: During moxifloxacin prophylaxis, we observed a significantly increased incidence of Gram-negative bacteraemia and CDAD. Careful attention must be paid not to trade the particularly beneficial effects of fluoroquinolones in the neutropenic setting for such disadvantageous effects. Until further data are obtained, caution is warranted when applying fluoroquinolones with high anaerobic activity in the neutropenic setting.

We evaluated a highly sensitive quantitative real-time one-step reverse transcription-PCR (RT-PCR) for detection of human cytomegalovirus pp67 transcripts in monitoring of solid-organ transplant recipients. Results were compared with those of pp65 antigen testing and quantitative DNA-PCR. Due to a low clinical sensitivity, the pp67 RT-PCR was not able to replace these assays.

Using a hard X-ray microprobe, we showed recently that in unstimulated peritoneal macrophages from C57BL/6 mice, the phagosome of pathogenic mycobacteria (Mycobacterium tuberculosis and Mycobacterium avium) can accumulate iron. We expanded our studies to the M. avium infection of peritoneal macrophages of Balb/c mice that show a similar degree of M. tuberculosis and M. avium-related chronic disease, but a higher susceptibility towards other intracellular pathogens such as Listeria monocytogenes, Leishmania major, or Brucella abortus as compared to C57BL/6 mice. Similar to C57BL/6 macrophages, the iron concentration in Balb/c macrophages increased significantly after 24 h of infection. A significant increase of the chlorine and potassium concentrations was observed in the Balb/c phagosomes between 1 and 24 h, in contrast with macrophages from C57BL/6 mice. The absolute elemental concentrations of calcium and zinc were higher in the mycobacterial phagosomes of Balb/c mice. We hypothesize that a potassium channel is abundant in the phagosome in macrophages that may be related to microbiocidal killing, similar to the requirement of potassium channels for microbiocidal function in neutrophils.

Human metapneumovirus (HMPV) was isolated from a 63-year-old multiple myeloma patient who had undergone hematopoietic stem cell transplantation and who presented with lower respiratory tract infection several weeks prior to the diagnosis of lung cancer. The isolate was phylogenetically and biologically characterized and compared to HMPV prototypes and recent pediatric isolates. Remarkably, it belonged to the novel genomic subgroup A2b.

Initiation of hepatitis C virus (HCV) infection is mediated by docking of the viral envelope to the hepatocyte cell surface membrane followed by entry of the virus into the host cell. Aiming to elucidate the impact of this interaction on host cell biology, we performed a genomic analysis of the host cell response following binding of HCV to cell surface proteins. As ligands for HCV-host cell surface interaction, we used recombinant envelope glycoproteins and HCV-like particles (HCV-LPs) recently shown to bind or enter hepatocytes and human hepatoma cells. Gene expression profiling of HepG2 hepatoma cells following binding of E1/E2, HCV-LPs, and liver tissue samples from HCV-infected individuals was performed using a 7.5-kd human cDNA microarray. Cellular binding of HCV-LPs to hepatoma cells resulted in differential expression of 565 out of 7,419 host cell genes. Examination of transcriptional changes revealed a broad and complex transcriptional program induced by ligand binding to target cells. Expression of several genes important for innate immune responses and lipid metabolism was significantly modulated by ligand-cell surface interaction. To assess the functional relevance and biological significance of these findings for viral infection in vivo, transcriptional changes were compared with gene expression profiles in liver tissue samples from HCV-infected patients or controls. Side-by-side analysis revealed that the expression of 27 genes was similarly altered following HCV-LP binding in hepatoma cells and viral infection in vivo. In conclusion, HCV binding results in a cascade of intracellular signals modulating target gene expression and contributing to host cell responses in vivo. Reprogramming of cellular gene expression induced by HCV-cell surface interaction may be part of the viral strategy to condition viral entry and replication and escape from innate host cell responses.

Objectives: 1-(1-Naphthylmethyl)-piperazine (NMP) has been shown to reverse multidrug resistance (MDR) in Escherichia coli overexpressing RND-type efflux pumps but there are no data on its activity in non-fermenters like Acinetobacter., Methods: Antimicrobial susceptibility in the absence and presence of NMP and, for comparison, phenyl-arginine-beta-naphthylamide (PAbetaN), another putative efflux pump inhibitor (EPI), was tested in laboratory and mutant strains with differing intracellular dye accumulation and expression of adeB, and in clinical isolates of Acinetobacter baumannii., Results: Based on a 4-fold or greater MIC reduction, the effects of both EPIs at low concentrations (25 mg/L) were limited. PAbetaN had a highly selective action on the reduction in the MIC of rifampicin and clarithromycin. At a higher concentration of the putative EPIs (100 mg/L), NMP was more active than PAbetaN. This effect was not limited to strains with adeB overexpression, but affected the susceptibility to linezolid, chloramphenicol and tetracycline most, and was enhanced in clinical isolates with reduced fluoroquinolone susceptibility., Conclusion: NMP can partially reverse MDR in A. baumannii and differs substantially in its activity from that of PAbetaN.

Systematic reviews and meta-analyses published in recent years have allowed drafting of evidence-based guidelines for antibiotic prophylaxis in orthopedic and trauma surgery. It is important to recognize the limitations of the recommendations derived from the available body of evidence. Since some of the most relevant randomized controlled clinical trials were performed more than 20 years ago, it is sometimes difficult to apply the data to today's clinical practice. In establishing consensus guidelines, it could prove difficult to identify areas for improvement through further research and better compliance. Although recommendations for optimized treatment of orthopedic implant infections are not currently based on first-class evidence, there are very promising new concepts emerging in this field, and we are awaiting more data and decisive conclusions from larger clinical trials.

Background: Hospital antibiotic use can be measured by calculating daily doses as defined by the WHO/ATC index (DDD) divided by the number of patient or occupied bed days. We wondered whether changes in antibiotic use density over time at a university hospital using this data format are similar in order of magnitude when compared with a different, alternative dose definition and the number of admissions rather than the number of patient days as denominator., Methods: Data obtained from the hospital pharmacy for the medical and surgical services of a 1,000-bed university hospital for the period 1992 through 2003 were expressed both in daily doses per 100 patient days and daily doses per admission. A PDD dose definition (prescribed daily doses), defining doses that reflect the usually prescribed dose in adult hospitalized patients with normal renal function was compared with the WHO/ATC 2001 DDD dose definitions. The percent changes using the different data formats between two 3-year averages (1992-1994 and 2001-2003) were calculated., Results and Conclusion: The DDD/100 patient days data format overestimated antibiotic use density changes in this hospital both in medicine (81% vs 48%) as well as in surgery (69% vs 39%) when compared with PDD/100 patient days. Due to changes in the number of admissions and length of stay over the years, the percent change between the two periods expressed in doses per 100 patient days in addition differed substantially from that estimated by using the DDD per admission or PDD per admission data format. Studies evaluating the evolution of hospital antibiotic use need to address the limitations and adequacy of the different data formats.

Combination therapy with a beta-lactam plus an aminoglycoside has been the standard approach for treating febrile neutropenia for many years. More recently, beta-lactam monotherapy has also been shown to be a reliable and safe approach. In the present study, 763 eligible patients with fever and neutropenia received piperacillin-tazobactam monotherapy. On day 3, according to the study protocol, 165 patients with persistent fever who fulfilled the study entry criteria were randomised to receive vancomycin or a placebo. The success rate was 51% in the intention-to-treat analysis and 62% in the per-protocol analysis. The overall mortality rate was 8% (58/763), with only 18 (2.4%) deaths attributed to the initial or subsequent infection. Randomisation had no influence on the study endpoints. The adverse event rate was evaluated only in the patient population not included in the randomised part of the study. Among these patients, adverse events probably or definitely related to piperacillin-tazobactam therapy were uncommon, confirming the favourable safety profile of piperacillin-tazobactam. It was concluded that piperacillin-tazobactam could be considered as monotherapy for patients with high-risk febrile neutropenia.

With increasing antibiotic resistance reported worldwide, there is an urgent need for novel treatments for infections caused by Gram-positive bacteria. Daptomycin is the first in a new class of antibiotic, the cyclic lipopeptides, with activity against a range of Gram-positive pathogens. US approval of daptomycin for the treatment of complicated skin and soft-tissue infections (cSSTIs) caused by Gram-positive bacteria was gained in 2003, with European approval granted in January 2006. Most Gram-positive clinical isolates tested have proved susceptible to daptomycin, including methicillin- and vancomycin-resistant strains. Daptomycin has a novel mode of action, is rapidly bactericidal in vitro and has a low potential for the development of resistance. Two pivotal phase III studies, in a total of 1092 patients with cSSTIs, demonstrated non-inferiority to currently used antibiotics and a comparable tolerability profile. The unique mode of action of daptomycin is described alongside studies demonstrating its potential in the treatment of cSSTIs and other infections caused by Gram-positive bacteria.

Progress has been made in the development and validation of rules that attempt ito predict a low risk (<10%) of severe infection or clinical complications in patients with cancer, fever, and neutropenia. It is uncertain, however, which model is optimal, with respect to test characteristics, applicability, and interinstitutional reliability, and prospective model validation in a multicenter context among outpatients has not been performed. Clinical criteria, such as comorbidities and performance status, remain critical in the risk-assessment process and probably are used by most physicians caring for patients with cancer who are febrile and neutropenic. Clinical prediction rules might be improved in the future by including measurements of inflammatory markers, such as procalcitonin. Reliable prediction of the risk of medical complications may be relevant for decisions regarding parenteral versus oral antimicrobial therapy, but it is definitely needed for decisions regarding site of care. Site-of-care decisions require thorough assessment not only of medical criteria, but also of psychosocial and organizational and/or logistic criteria. If the appropriate infrastructure to provide follow-up is available, home-based therapy with oral (or parenteral) antibiotics is an acceptable option in the care of patients with cancer who have intercurrent febrile neutropenia and a predicted low risk for medical complications.

Objectives: 1-(1-Naphthylmethyl)-piperazine (NMP) has been shown to reverse multidrug resistance (MDR) in Escherichia coli overexpressing resistance-nodulation-cell division type efflux pumps, but there is no data on its activity in clinical isolates of E. coli., Methods: The antimicrobial susceptibility of 60 clinical isolates of E. coli to a variety of antimicrobial agents was determined in the absence and presence of NMP and, for comparison, of Phe-Arg-beta-naphthylamide (PAbetaN), another putative efflux pump inhibitor (EPI). The intracellular accumulation of ethidium bromide was measured to confirm efflux pump inhibition as the likely mechanism of action of NMP., Results: Based on a 4-fold or greater reduction of the MIC after the addition of NMP in >50% of the isolates, significant effects of NMP at a concentration of 100 mg/L were seen for levofloxacin, linezolid and ethidium bromide. The ethidium bromide MIC changes after NMP addition correlated with differences in the ethidium bromide intracellular accumulation as measured by fluorometry in whole cell accumulation experiments. The activity of PAbetaN was different from that of NMP, in particular regarding macrolide resistance reversal, suggesting different modes of action of the two putative EPIs., Conclusions: NMP is moderately active in reversing MDR in clinical isolates of E. coli and can partially restore fluoroquinolone susceptibility through inhibition of efflux pumps.

Objectives: 1-(1-Naphthylmethyl)-piperazine (NMP) has been shown to reverse multidrug resistance (MDR) in Escherichia coli overexpressing RND type efflux pumps, but there is no data on its activity in Enterobacteriaceae other than E. coli., Methods: The antimicrobial susceptibilities of laboratory strains and 167 clinical isolates of Enterobacteriaceae to a variety of antimicrobial agents were determined in the absence and presence of NMP and, for comparison, of Phe-Arg-beta-naphthylamide (PAbetaN), another putative efflux pump inhibitor (EPI). A 4-fold or greater reduction of the MIC after EPI addition was considered significant., Results: NMP consistently reduced the MIC of linezolid in Citrobacter freundii, Enterobacter aerogenes and Klebsiella pneumoniae clinical isolates. Significant effects of NMP addition in >50% of tested isolates were also seen for levofloxacin, tetracycline and chloramphenicol in E. aerogenes, and for levofloxacin and tetracycline in K. pneumoniae, whereas no or minor effects were observed in Serratia marcescens. MDR reversal by NMP was more likely in isolates with decreased susceptibility to fluoroquinolones. In most fluoroquinolone-resistant strains the activity was sufficient to render isolates drug-susceptible at clinically achievable concentrations. The activity of PAbetaN was different from that of NMP, suggesting different modes of action of the two putative EPIs., Conclusion: NMP has moderate activity in reversing MDR in many but not all members of the Enterobacteriaceae family including clinical isolates. Its effects on resistance reversal depend on bacterial species and drug, and are different from those seen with PAbetaN.

Objective: To assess the costs and cost-effectiveness of voriconazole in comparison to conventional amphotericin B (CAB) for the treatment of invasive aspergillosis in Germany., Methods: The cost-effectiveness of voriconazole in comparison to CAB was evaluated with a lifetime Markov model, focusing on the long-term survival of patients treated for invasive aspergillosis. Long-term survival was extrapolated from survival after 12 weeks of treatment, obtained from a randomized aspergillosis study. Information on medical resource consumption and treatment pathways were obtained from this study and an expert committee. With probabilistic analysis the cost-effectiveness of voriconazole compared with amphotericin B was analyzed and expressed in incremental costs per life-weeks gained. The evaluation was performed from a limited societal perspective (both inpatient and outpatient costs) and hospital perspective (only inpatient costs)., Results: Average survival of patients treated with voriconazole was 174.4 life-weeks (95% confidence interval [CI] 159.4-191.3), compared with 119.4 life-weeks (95% CI 106.4-132.3) for amphotericin B. With voriconazole, the mean total costs per patient were 30,026 euros (95% CI 23 euros ,118-37,947) compared with 26,669 euros for amphotericin B (95% CI 21,259-34,263 euros ) from the limited societal perspective. The corresponding incremental cost-effectiveness ratio was 62 euros per life-week gained (i.e., 3224 euros per life-year gained). Hospital costs were approximately 90% of the mean total costs., Conclusions: In the treatment of invasive aspergillosis, voriconazole is cost-effective in comparison to amphotericin B. Hospital costs are comparable for both treatments and are expected to be reimbursed based on the German diagnosis-related groups (DRG) system 2005.

An allogeneic stem cell transplant recipient developed pulmonary infiltrates and Aspergillus antigenemia during prophylactic low-dose liposomal amphotericin B. No response to therapy was observed after increasing the dose of liposomal amphotericin B and addition of caspofungin, and breakthrough candidemia developed. Therapy switch to voriconazole did not prevent the development of lethal septic shock. Shortly before death, Scopulariopsis brevicaulis was cultured from bronchial secretions, and positive blood cultures demonstrated persistent candidemia due to Debaryomyces hansenii, teleomorph of Candida famata.

Background: Previous studies have shown that interleukin-8 serum levels in febrile neutropenic patients are significantly higher in patients with gram-negative bacteremia than in patients with other causes of fever and may indicate unfavorable outcomes. We assessed the value of interleukin-8 serum levels at fever onset to predict clinical complications in order to confirm these earlier findings., Patients and Methods: In a prospective observational study of adult patients receiving cancer chemotherapy, serum samples obtained at the onset of 147 febrile neutropenic episodes were measured by an immunoluminescence assay., Results: Complicated courses of fever including severe sepsis or septic shock, respiratory insufficiency or death were observed in 13 episodes (9%); in six episodes complications had developed within 1 week after fever onset and five of them were associated with bloodstream infections. At an interleukin-8 cutoff level of 1,000 pg/ml, these early complications were predicted with a sensitivity of 83%, a specificity of 97%, a positive predictive value of 50%, and a negative predictive value of 99%, respectively., Conclusion: Interleukin-8 levels at fever onset may be used for the prediction of early medical complications associated with bacteremia and can help identify patients who might benefit from intensive care admission.

Background: A previous study from Germany showed high antibiotic use in university hospitals, particularly in intensive care units (ICU) and hematology-oncology services, but there has been no information about recent antibiotic use in non-university hospitals. In the present study, we collected data from 40 non-university regional general hospitals located in the southwestern part of the country, and analyzed use density in the medical and surgical services of these hospitals., Materials and Methods: Hospital pharmacy records for the calendar years 2001 and 2002 were evaluated. The number of defined daily doses (DDD, definition according to the WHO/ATC 2001 index) and prescribed daily doses (PDD) per 100 patient days (DDD/100 or PDD/100, respectively) were calculated to compare antibiotic use densities in medical and surgical services. Data for surgery included various subspecialties and gynecology., Results: Antibiotic use in the participating hospitals increased minimally between 2001 and 2002 both in medicine as well as in surgery. Use density in internal medicine (ICU areas excluded) in the year 2002 ranged between 13.5 and 93.7 DDD/100 with a weighted mean of 49.9 DDD/100 (corresponding to 28.6 PDD/100, respectively). Values for surgery were lower with a weighted mean of 43.4 DDD/100 (corresponding to 26.1 PDD/100, range, 10 to 65.4 DDD/100), respectively. Hospital size was not a strong predictor of use density, while large differences were observed between intensive care areas and normal wards. Mean use densities in intensive care areas in 2002 were 105.6 DDD/100 (or 49.7 PDD/100) in medical intensive care units, 116.9 DDD/100 (or 61.2 PDD/100) in surgical intensive care units, and 112.7 DDD/100 (or 66.7 PDD/100) in mixed, interdisciplinary intensive care units. Betalactams made up > 50% of all PDDs, while fluoroquinolones were the second most frequently prescribed drugs (15% of all PDDs). Fluoroquinolones were usually given orally. Overall glycopeptide and aminoglycoside use was < 1 PDD/100., Conclusion: This recent data from a large regional nonuniversity acute care hospital sample confirms that hospital antibiotic use density largely depends on patient care areas and less on hospital size. Surprisingly low use was observed for glycopeptides and aminoglycosides. The data may be useful as a benchmark for further pharmaco-epidemiologic evaluation and focused drug use control interventions.

Leishmaniasis is a rare, non-notifiable disease in Germany. Epidemiological and clinical data, therefore, are scarce. Most infections seen in Germany are contracted outside the country. The German surveillance network for imported infectious diseases (Surveillance Importierter Infektionen in Deutschland, or SIPMID) recorded 42 cases of imported leishmaniasis (16 visceral, 23 cutaneous, and 3 mucocutaneous) from January 2001 to June 2004. Although most infections were acquired in European Mediterranean countries, the risk of infection was highest for travelers to Latin America. HIV coinfection was observed significantly more often in patients with visceral leishmaniasis than in patients with cutaneous/mucocutaneous leishmaniasis (31 vs. 4%, p=0.02). The median time to a definitive diagnosis was 85 days in cases of visceral leishmaniasis and 61 days in cases of cutaneous/mucocutaneous leishmaniasis, reflecting the unfamiliarity of German physicians with leishmanial infections. Visceral leishmaniasis was treated most frequently with amphotericin B, whereas cutaneous/mucocutaneous leishmaniasis was treated with a variety of local and systemic therapies. The findings presented here should serve to increase awareness as well as improve clinical management of leishmaniasis in Germany.

Early postoperative infections after transplantation vary according to the transplanted organ. During the subsequent course opportunistic infections such as cytomegalovirus reactivation, Pneumocystis jiroveci pneumonia, invasive pneumococcal infection and mould infections predominate. Reactivated tuberculous infection appears to become more prevalent. Some of the opportunistic infections are preventable by chemoprophylaxis; others can be managed very effectively by monitoring and early preemptive therapy. Physicians caring for patients after organ transplantation need to early consider in the differential diagnosis rare pathogens which are often overlooked with standard diagnostic procedures.

Background: Fluoroquinolone prophylaxis during neutropenia in patients with cancer has been associated with decreased incidence of gram-negative bacteremia. Bacterial antimicrobial resistance is likely to cause a progressive lack of efficacy of fluoroquinolones, but no convincing evidence from clinicoepidemiologic observations has proved this hypothesis., Methods: This prospective observational study assessed the impact of discontinuing fluoroquinolone prophylaxis on the incidences of fever and bacteremia and on mortality among patients with neutropenia, after chemotherapy for hematologic malignancies., Results: After a 12-month baseline period of levofloxacin prophylaxis, a period of discontinuation of fluoroquinolone prophylaxis was planned but was stopped prematurely after 9 neutropenic episodes over 3 weeks, because the mortality rate (33.3%) was higher than that with routine fluoroquinolone prophylaxis (2.9%) (odds ratio [OR], 16.6; 95% confidence interval [CI], 3.6-77.2). Fewer patients had gram-negative bacteremia during the baseline period (4.8%; n=15) than during the discontinuation period (44.4%; n=4) (OR, 16.9; 95% CI, 4.1-70.0). After levofloxacin therapy was reintroduced, the incidence of gram-negative bacteremia and the mortality rate were comparable to those during the first period. Escherichia coli isolated during the discontinuation period was susceptible to levofloxacin in vitro, whereas all E. coli isolates isolated during both prophylaxis periods were resistant. Bloodstream infections were caused by a single agent when the patient had received levofloxacin prophylaxis, whereas most cases of gram-negative bacteremia were polymicrobial after discontinuation., Conclusions: These findings suggest that, despite increasing rates of antimicrobial resistance, levofloxacin prophylaxis during neutropenia may have a beneficial impact on morbidity and infection-related mortality. Continued monitoring of the rate of gram-negative bacteremia is warranted for timely detection of the loss of efficacy of fluoroquinolone prophylaxis.

Background: Sales data indicate a major increase in the prescription of antifungal drugs in the last two decades. Many new agents for systemic use that only recently have become available are likely to be prescribed intensively in acute care hospitals. Sales data do not adequately describe the developments of drug use density. Given the concerns about the potential emergence of antifungal drug resistance, data on drug use density, however, may be valuable and are needed for analyses of the relationship between drug use and antifungal resistance., Methods: Hospital pharmacy records for the years 2001 to 2003 were evaluated, and the number of prescribed daily doses (PDD, defined according to locally used doses) per 100 patient days were calculated to compare systemic antifungal drug use density in different medical and surgical service areas between five state university hospitals., Results: The 3-year averages in recent antifungal drug use for the five hospitals ranged between 8.6 and 29.3 PDD/100 patient days in the medical services (including subspecialties and intensive care), and between 1.1 and 4.0 PDD/100 patient days in the surgical services, respectively. In all five hospitals, systemic antifungal drug use was higher in the hematology-oncology service areas (mean, 48.4, range, 24 to 101 PDD/100 patient days, data for the year 2003) than in the medical intensive care units (mean, 18.3, range, 10 to 33 PDD/100) or in the surgical intensive care units (mean, 10.7, range, 6 to 18 PDD/100). Fluconazole was the most prescribed antifungal drug in all areas. In 2003, amphotericin B consumption had declined to 3 PDD/100 in the hematology-oncology areas while voriconazole use had increased to 10 PDD/100 in 2003., Conclusion: Hematology-oncology services are intense antifungal drug prescribing areas. Fluconazole and other azol antifungal drugs are the most prescribed drugs in all patient care areas while amphotericin B use has considerably decreased. The data may be useful as a benchmark for focused interventions to improve prescribing quality.

Several arylpiperazines capable of reversing multidrug resistance (MDR) in Escherichia coli overexpressing acrAB and acrEF but not in pump-deficient mutant strains were identified. 1-(1-Naphthylmethyl)-piperazine, one of the more active compounds, enhanced susceptibility to fluoroquinolones and other agents and increased the intracellular concentration of levofloxacin and ethidium bromide, suggesting efflux pump inhibition as the mechanism of MDR reversal.

The aim of the present study was to investigate the epidemiologic evolution of fluoroquinolone resistance of E. coli clinical isolates from patients admitted to a hematology-oncology service where fluoroquinolone prophylaxis during neutropenia was recommended as the standard of care for many years but was then discontinued in a trial conducted in patients with acute leukemia. Fluoroquinolones had been shown to decrease the incidence of gram-negative bacteremia in cancer patients with neutropenia, yet it was thought that the emergence of resistance in Escherichia coli and other gram-negative bacteria may have caused a progressive lack of efficacy of fluoroquinolone prophylaxis. Epidemiologic surveillance of fluoroquinolone resistance of E. coli clinical isolates at our cancer center since 1992 showed a continuing influx of new clones not previously observed in the population of cancer patients, an increase in the number of cancer patients per year colonized and/or infected by fluoroquinolone-resistant E. coli (1992-1994, 10-16 patients; 1995-1997, 24-27 patients), and a resistance rate of >50% among E. coli bloodstream isolates of hematology-oncology patients. A 6-month fluoroquinolone prophylaxis discontinuation intervention trial in 1998 suggested that despite increasing resistance among E. coli isolates, fluoroquinolone prophylaxis in acute leukemia patients was still effective in the prevention of gram-negative bacteremia (incidence rates, 8% during the pre-intervention period vs. 20% after discontinuation; p<0.01). The resumption of fluoroquinolone prophylaxis in acute leukemia patients thereafter decreased the incidence of gram-negative bacteremia to the pre-intervention level (9%; p=0.03), while the proportion of in vitro fluoroquinolone resistance in E. coli bacteremia isolates again increased (from 15% during the intervention period to >50% in the post-intervention period). Relative rates of resistance thus were a poor indicator of the potential clinical benefits associated with fluoroquinolone prophylaxis in cancer patients.

Objectives: To compare rates of in vitro fluoroquinolone resistance of bacterial isolates obtained from inpatients of two haematology-oncology services with high and low fluoroquinolone consumption., Methods: Two hospitals with consistently high (A) and low (B) fluoroquinolone use in their haematology-oncology services between the years 1999 and 2002 were identified in a hospital antibiotic use surveillance project. Rates of in vitro resistance to fluoroquinolones in inpatients of the services were determined for Escherichia coli and coagulase-negative staphylococcal bloodstream isolates, and also for Pseudomonas aeruginosa and Staphylococcus aureus isolates from any site., Results: Fluoroquinolone resistance of E. coli was significantly higher in hospital A than in hospital B, but there was no such correlation between fluoroquinolone use and resistance rates for P. aeruginosa and staphylococci., Conclusion: The impact of antibiotic consumption on the prevalence of resistance may differ widely between different pathogens. Interventions using ecological analyses of the relationship between hospital antibiotic use and resistance need to consider pathogen-specific dynamics in the emergence and control of bacterial resistance.

Recent transmission of dengue viruses has increased in tropical and subtropical areas and in industrialized countries because of international travel. We describe a case of nosocomial transmission of dengue virus in Germany by a needlestick injury. Diagnosis was made by TaqMan reverse transcription-polymerase chain reaction when serologic studies were negative.

In view of increasing rates of antibiotic resistance worldwide and decreased research and development of new antibacterial compounds, programmes helping to better understand the complex relationship between antibiotic consumption and emergence of resistance have gained importance. Consequently, in addition to increased support for research projects that establish prospective surveillance and evaluation of antibiotic resistance and antimicrobial drug use, the EU has passed directives addressing political leadership in this respect. Information on antibiotic use in Germany is now available from databases independent from cost-oriented market research studies. This information allows estimation of antibiotic use in ambulatory and hospital care as compared with to other EU countries. According to results of current projects, the frequency of national antibiotic use in ambulatory care in Germany (4948 defined daily doses per 1000 population per year) falls within the lower third of EU countries. Upper boundaries in regional variation in antibiotic use are still much lower than values for high-use countries like France, Spain and Portugal. Hospital antibiotic use, in contrast, appears to be in the range of that reported for other countries. However, only rough estimates of hospital antibiotic use are available for Germany as well as most other EU countries due to data usually derived from non-representative hospital sampling.

In a pilot study we established a hospital antibiotic use database from which estimates for antibiotic consumption in German hospitals (expressed as defined daily doses per 100 patient days, DDD/100) can be retrieved for both benchmarking and antibiotic use and resistance research purposes. Data from eight university hospitals (1998-2000) showed a mean antibiotic use density of 60.1 DDD/100 in the surgical and 79.3 DDD/100 in the medical services. Antibiotic use was higher in the intensive care units (surgery: 146 DDD/100, medicine: 187 DDD/100) than in haematology-oncology services (110.8 DDD/100) or in other surgical (51.6 DDD/100) and medical (66 DDD/100) service areas. There were major differences in the use of specific antibacterial drug classes between service areas. The established database allows detailed analysis in antibacterial drug use and can be linked to bacterial resistance surveillance databases.

Background: Excessive antibiotic use increases the risk of development and dissemination of bacterial resistance. A comparative analysis of the correlation between hospital antibiotic consumption and rates of bacterial resistance is needed for a better understanding of the complex relationship between antibiotic use and resistance. Apart from economic and market research studies, estimates of antibiotic consumption in German hospitals, however, are not available., Methods: In a pilot project (INTERUNI-II), retrospective data from eight university hospital pharmacies covering the period 1998, 1999, and 2000 were collected to obtain estimates for the antibiotic use densities in the medical services of teaching hospitals. Antibiotic use densities were expressed as prescribed daily doses per 100 occupied bed days (PDD/100). The definition of prescribed daily doses was according to guidelines for antimicrobial therapy in adults with normal renal and hepatic function used in the participant hospitals. Means and ranges of antibiotic use densities were separately assessed for medical intensive care units (MICU), hematology-oncology services (HEMONC), and other medical services (OTHER MED)., Results: Mean antibiotic use density in internal medicine was 55.2 PDD/100 overall, ranging between 39.4 and 75.8 PDD/100 in the eight participant hospitals. In seven hospitals antibiotic use density increased during the years of observation. Antibiotic use was higher in MICU areas (3-year average, 122.3; range, 98-167 PDD/100) than in HEMONC (3-year average, 86.9; range, 67.8-129.4 PDD/100) and OTHER MED areas (3-year average, 42.8; range, 31.7-50.6 PDD/100). There was an increasing use of oral antibiotics resulting in a substantial proportion of oral agents among all antibacterial drugs outside MICU areas (year 2000, HEMONC, range, 36-74% of all PDD; OTHER MED, range, 43-59% of all PDD). beta-lactam antibiotics were the most frequently prescribed drugs (3-year average, 22.6 PDD/100). 56% of beta-lactam PDD belonged to the class of broad-spectrum beta-lactams (ranges, MICU, 49-82%; HEMONC, 61-89%; OTHER MED, 24-58%). Fluoroquinolones were the second most prescribed drug class (3-year average, 13 PDD/100). They were most frequently used in HEMONC (3-year average, MICU, 14.5; HEMONC 26.5; and OTHER MED 8.6 PDD/100, respectively). There was considerable variation between participant hospitals in the use of specific drug classes in given patient care areas., Conclusion: This retrospective study showed significant variation in overall and specific antibacterial drug class use between German teaching hospital medical services and defined patient care areas. Given the variation in the obtained estimates, targeted prospective hospital antibiotic use surveillance with fast data acquisition and analysis might offer an excellent opportunity to evaluate the impact of differences in antibiotic use and of revised therapy guidelines on the evolution of nosocomial bacterial resistance.

Background: A previous study has shown considerable variation in glycopeptide use from 1992 through 1994 among four university hospitals in southern Germany. Active antimicrobial management in one of the hospitals was associated with the containment of glycopeptide consumption in the medical and surgical service at < 1.5 defined daily doses (DDD)/100 patient days in the subsequent period. In the present study, more recent data on comparative glycopeptide use in German university hospitals were analyzed., Materials and Methods: Hospital pharmacy records from 1998 through 2000 were evaluated. The number of DDD (definition according to the World Health Organization [WHO]/Anatomic and Therapeutic Classification [ATC] index) per 100 patient days was calculated to compare glycopeptide use in different medical and surgical service areas between eight German university hospitals., Results: The 3-year averages in recent glycopeptide use for the eight hospitals ranged between 1.3 and 8.8 DDD/100 patient days in the medical services, and between 0.7 and 1.8 DDD/100 patient days in the surgical services. Only one of the eight hospitals showed medical service glycopeptide use of < 1.5 DDD/100 patient days. In most hospitals, glycopeptide use was higher in the medical intensive care units (ICU) (median 8.6; range 4.3 to 12 DDD/100 patient days, data for the year 2000) than in the surgical ICUs (median 6.7; range 1.2 to 8.6 DDD/100 patient days, data for the year 2000). High use was also observed for hematology-oncology services (median 7.5; range 2.7 to 15.7 DDD/100 patient days, data for the year 2000)., Conclusion: These recent data from a larger hospital sample confirm large variations in glycopeptide use, identify hematology-oncology services as a significant prescribing source along with ICUs, and indicate areas of probable overuse of glycopeptide antibiotics. The data may be useful as a benchmark for further focused drug use control interventions., (Copyright Urban and Vogel)

A 64-year old farmer developed cough, dyspnoea on exertion, and recurrent febrile episodes. X-ray and CT scan revealed bilateral lower lobe opacities in his lungs. A transbronchial biopsy was performed and histopathological findings were interpreted as consistent with a pulmonary necrotizing clear-cell carcinoma and later as a Pneumocystis carinii pneumonia. Due to persistence of symptoms, six months later another lung biopsy was performed and a mould was cultured which was identified by 18S rDNA sequencing as Emmonsia sp. The patient showed some improvement under itraconazole treatment. This is the first description of a human infection with Emmonsia sp. in Germany.

Patients developing fever in neutropenia are at high risk of infection-related complications. Their outcome is influenced by the degree of severity (sepsis, severe sepsis and septic shock). Sepsis describes clinical syndromes resulting from systemic inflammatory response. Diagnosis of sepsis is based on simple clinical criteria. Treatment of neutropenic patients with sepsis does not differ from sepsis treatment in non-neutropenic patients. A variety of treatment options have failed (e.g. anti-cytokine strategies, anti-endotoxin antibodies), however, in recent years successful targeted treatment, the use of activated protein C or the substitution of hydrocortisol has been shown to reduce mortality rates. The outcome of neutropenic sepsis is influenced by the underlying disease as well, however survival rates of neutropenic patients treated on the intensive care unit have improved during the past decade. This paper focuses on pathophysiology, diagnosis and treatment of sepsis. Evidence based medicine (EBM) criteria are used to grade treatment recommendations [50].

Cytostatic chemotherapy of hematological malignancies is often complicated by neutropenia, which increases the risk of infections, especially if the neutrophil count is below 500/microl. Frequently, fever is the first, and in most patients the only, sign of an infection. Unexplained fever is defined as follows: temperature of >/=38.3 degrees C or >/=38.0 degrees C for at least 1 h, or measured twice within 12 h, if the neutrophil count is <500/microl or <1000/microl with predicted decline to 500/microl. Different risk categories can be identified according to the duration of neutropenia: low risk /=10 days. An empirical mono- or duotherapy with antipseudomonal and antistreptococcal agents should be initiated immediately. In the low risk patient group, oral therapy with cipro-, levo-, or ofloxacin combined with amoxicillin/clavulanic acid is permissible. For standard and high risk patients, monotherapy can be carried out with either ceftazidime, cefepime, piperacillin with tazobactam or a carbapenem. In duotherapy, a single dose of an aminoglycoside is combined with acylaminopenicillin or a cephalosporin of the third or fourth generation. The addition of glycopeptides in empirical therapy should only be considered in the presence of severe mucositis, or if a catheter-associated infection is suspected. If fever persists after 72-96 h of first-line therapy with antibiotics, the regimen should be modified (with the exception of e.g. coagulase-negative staphylococci infections, because these infections take longer to respond). Intermediate risk patients should additionally receive an aminoglycoside after monotherapy (penicillin or a cephalosporin). If a carbapenem was administered for monotherapy, this can be followed by a quinolone and/or a glycopeptide. In the high risk group, the same modifications should be made as in the intermediate risk group but with additional systemic antifungal treatment. In the presence of unexplained fever, fluconazole can be administered at first, but if this fails, amphotericin B (conventional or liposomal), itraconazole, voriconazole or caspofungin should be started. After defervescence to <38 degrees C, treatment should be continued for 7 days if the neutrophil count is <1000/microl, and for 2 days if the neutrophil count is >1000/microl.

Approximately 85% of patients with acute leukemia undergoing intensive antileukemic treatment develop infections and/or fever during neutropenic phases; in about 50% of these patients clinical, microbiological or clinical and microbiological evidence of infections can be obtained. The response rate is significantly lower in documented infections than in fever of unknown origin (FUO). Evidence-based recommendations for diagnosis and treatment procedures are presented, reflecting study results and expert opinions.

This prospective, double-blind trial assessed whether the addition of a glycopeptide would be able to reduce the time to defervescence in neutropenic patients with cancer who had persistent fever 48-60 h after the initiation of empirical piperacillin-tazobactam monotherapy. Of 763 eligible patients, 165 with persistent fever were randomized to receive piperacillin-tazobactam therapy plus either vancomycin therapy or placebo. Defervescence was observed in 82 (95%) of 86 patients in the vancomycin group and in 73 (92%) of 79 patients in the placebo group (P=.52). The distributions of the time to defervescence were not statistically significant between the 2 groups (estimated hazard ratio, 1.03; 95% confidence interval, 0.75-1.43; P=.75). The number of additional episodes of gram-positive bacteremia and the percentage of patients for whom amphotericin B was empirically added to their therapy regimen were also similar in both groups. This study failed to demonstrate that the empirical addition of vancomycin therapy to the treatment regimen is of benefit to persistently febrile neutropenic patients with cancer.

Background: Excessive use of glycopeptide antibiotics may enhance the risk of glycopeptide resistance among enterococci and staphylococi, but there is little data on the use of these antibiotics in German hospitals., Methods: Hospital pharmacy records for the years 1992 to 1994 were evaluated. The number of defined daily doses (DDD) per 100 patient days was calculated to compare glycopeptide use between four state university hospitals. At one of the hospitals with comparatively low glycopeptide usage but an active antimicrobial management program, data were prospectively evaluated for 1995 to 2000 to assess the variation of glycopeptide use over time., Results: The 3-year averages in glycopeptide use for the four hospitals ranged between 1.03 and 3.14 DDD/100 patient days. In all four hospitals, glycopeptide use was higher in the medical service (range, 1.59-7.26) than in the surgical service (range, 0.66-4.39). Active antimicrobial management in one of the hospitals was associated with containment of glycopeptide consumption in the medical and surgical service at < 1.5 DDD/100 patient days in the last 3 years., Conclusion: Glycopeptide use differs considerably at tertiary care hospitals in southern Germany, but use of < 1.5 DDD/100 patient days in both surgical as well as medical tertiary care hospital departments appears achievable.

Nocardia species isolated from seven patients with clinical infection were investigated by conventional biochemical methods and 16S rRNA gene sequencing. Three isolates were identified as recently described species (i.e., N. paucivorans, N. abscessus and N. veterana). We provide data on the epidemiology, clinical significance and antimicrobial susceptibility of these newly described Nocardia species.

Background: Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis., Methods: In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome., Results: A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematopoietic-cell transplantation, acute leukemia, or other hematologic diseases. At week 12, there were successful outcomes in 52.8 percent of the patients in the voriconazole group (complete responses in 20.8 percent and partial responses in 31.9 percent) and 31.6 percent of those in the amphotericin B group (complete responses in 16.5 percent and partial responses in 15.0 percent; absolute difference, 21.2 percentage points; 95 percent confidence interval, 10.4 to 32.9). The survival rate at 12 weeks was 70.8 percent in the voriconazole group and 57.9 percent in the amphotericin B group (hazard ratio, 0.59; 95 percent confidence interval, 0.40 to 0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events, but transient visual disturbances were common with voriconazole (occurring in 44.8 percent of patients)., Conclusions: In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B., (Copyright 2002 Massachusetts Medical Society)