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Background Gadolinium-based contrast agents were not approved in the United States for detecting coronary artery disease (CAD) prior to the current studies. Objectives The purpose of this study was to determine the sensitivity and specificity of gadobutrol for detection of CAD by assessing myocardial perfusion and late gadolinium enhancement (LGE) imaging. Methods Two international, single-vendor, phase 3 clinical trials of near identical design, “GadaCAD1” and “GadaCAD2,” were performed. Cardiovascular magnetic resonance (CMR) included gadobutrol-enhanced first-pass vasodilator stress and rest perfusion followed by LGE imaging. CAD was defined by quantitative coronary angiography (QCA) but computed tomography coronary angiography could exclude significant CAD. Results Because the design and results for GadaCAD1 (n = 376) and GadaCAD2 (n = 388) were very similar, results were summarized as a fixed-effect meta-analysis (n = 764). The prevalence of CAD was 27.8% defined by a ≥70% QCA stenosis. For detection of a ≥70% QCA stenosis, the sensitivity of CMR was 78.9%, specificity was 86.8%, and area under the curve was 0.871. The sensitivity and specificity for multivessel CAD was 87.4% and 73.0%. For detection of a 50% QCA stenosis, sensitivity was 64.6% and specificity was 86.6%. The optimal threshold for detecting CAD was a ≥67% QCA stenosis in GadaCAD1 and ≥63% QCA stenosis in GadaCAD2. Conclusions Vasodilator stress and rest myocardial perfusion CMR and LGE imaging had high diagnostic accuracy for CAD in 2 phase 3 clinical trials. These findings supported the U .S. Food and Drug Administration approval of gadobutrol-enhanced CMR (0.1 mmol/kg) to assess myocardial perfusion and LGE in adult patients with known or suspected CAD.

Background Detection of breast cancer in women with high breast densities is a clinical challenge. Purpose To study the influence of different degrees of breast density on the sensitivity of contrast-enhanced breast magnetic resonance imaging (CE-BMRI) versus X-ray mammography (XRM). Material and Methods We performed an additional analysis of two large Phase III clinical trials (G1; G2) which included women with histologically proven breast cancers, called “index cancers.” Additional cancers were detected during image reading. We compared the sensitivity of CE-BMRI and XRM in women with different breast densities (ACR A→D; Version 5). For each study, six blinded readers evaluated the images. Results are given as the “Median Reader.” Results A total of 774 patients were included, 169 had additional cancers. While sensitivity of CE-BMRI for detecting all index cancers was independent of breast density (ACR A→D) (G1: 83%→83%; G2: 91%→91%) the sensitivity of XRM declined (ACR A→D) (G1: 79%→62%; G2: 82%→64%). Thus, the sensitivity difference between both imaging modalities in ACR A breasts of 3% (G1) and 9% (G2) increased to 21% (G1) and 26% (G2) in ACR D breasts. Sensitivity of CE-BMRI for detecting at least one additional cancer increased with increasing breast density (ACR A→D) (G1: 50%→73%, G2: 57%→81%). XRM’s sensitivity decreased (G1: 34%→20%) or remained stable (G2: 24%→25%). Conclusion CE-BMRI showed significantly higher sensitivity compared to XRM.

Purpose To compare the performance of magnetic resonance angiography (MRA) with 1M gadobutrol, a high relaxivity macrocyclic contrast agent, to 2D time-of-flight MRA (ToF-MRA) using computed tomographic angiography (CTA) as the standard of reference. Primary objectives were evaluation for superiority of structural delineation and noninferiority for detection and exclusion of clinically significant disease. Materials and Methods In all, 315 subjects underwent unenhanced and contrast-enhanced MRA with 1M gadobutrol (CE-MRA) and were scanned with 1.5T MRI equipped with an at least 6-element body coil. Evaluations were based on both centralized blinded read (BR) performed by six readers as well as investigator site interpretations for the 292 subjects who completed the study. Quantitative evaluations including percent stenosis and normal vessel measurements were also performed. Secondary endpoints included identification of accessory renal arteries, diagnosis of fibromuscular dysplasia (FMD), diagnostic confidence, and need for additional imaging. Results A total of 292 patients suspected of renal artery disease completed the study. CE-MRA demonstrated statistically significant improvement in assessability of vascular segments compared to ToF: 95.9% vs. 77.6% (P < 0.0001). In the BR, the sensitivity and specificity of CE-MRA were noninferior to ToF-MRA (53.4% vs. 46.6% and 95.1% vs. 85.7%, respectively). There was less error in the CE-MRA stenosis measurements (0.15 mm gadobutrol vs. 0.41 mm ToF, P < 0.05). FMD was correctly diagnosed more frequently, 10% more accessory renal arteries were identified (P < 0.01), diagnostic confidence increased (P < 0.01), and fewer additional imaging studies were recommended (P < 0.01). Conclusion Gadobutrol-enhanced MRA of the renal arteries has superior visualization, more accurate vessel measurements, and may serve as a CTA alternative without any ionizing radiation. Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017.

The aim of this study was to evaluate the diagnostic efficacy of gadobutrol enhanced preoperative breast magnetic resonance imaging (MRI) in 2 prospective studies.Approval of ethics committees and informed consent from patients were obtained. Both Gadobutrol-Enhanced MR Mammography (GEMMA) trials followed a standardized protocol using 1.5 T scanners. After unenhanced scans, patients received 0.1 mmol/kg of gadobutrol for the dynamic study. Six independent blinded readers, 3 for GEMMA1 and 3 for GEMMA2, assessed unenhanced images and, 2 or more weeks apart, contrast-enhanced plus unenhanced breast MRI images (CE-BMRI), using a standard 5-region scheme. Another 6 independent readers (3 for each study) evaluated mammograms alone. Sensitivity was calculated taking into account the identification of regions harboring malignancies (within-patient sensitivity), whereas specificity was based on cancer-free breasts. The first patient from each center was used for site qualification and blinded reader training and excluded from the efficacy analyses. Reference standard was pathology for regions harboring malignancy and a combination of negative pathology, mammography, and ultrasound for cancer-free regions.Of 906 breast cancer patients enrolled in 13 countries in the 2 studies, 865 received gadobutrol and 787 were evaluated for diagnostic performance (390 in GEMMA1 and 397 in GEMMA2). Within-patient sensitivity, that is, the detection rate of malignant disease extent per patient, ranged from 80% to 89% for CE-BMRI and was significantly superior to unenhanced breast MRI alone (37%-73%) and to mammography alone (68%-73%) for all readers in both trials. Specifity of the CE-BMRI ranged from 83% to 95%.In a very large multicenter preoperative setting, gadobutrol-enhanced breast MRI demonstrated high levels of sensitivity and specificity, consistent with published data on breast MRI.

To compare the performance of magnetic resonance angiography (MRA) with 1M gadobutrol, a high relaxivity macrocyclic contrast agent, to 2D time-of-flight MRA (ToF-MRA) using computed tomographic angiography (CTA) as the standard of reference. Primary objectives were evaluation for superiority of structural delineation and noninferiority for detection and exclusion of clinically significant disease.In all, 315 subjects underwent unenhanced and contrast-enhanced MRA with 1M gadobutrol (CE-MRA) and were scanned with 1.5T MRI equipped with an at least 6-element body coil. Evaluations were based on both centralized blinded read (BR) performed by six readers as well as investigator site interpretations for the 292 subjects who completed the study. Quantitative evaluations including percent stenosis and normal vessel measurements were also performed. Secondary endpoints included identification of accessory renal arteries, diagnosis of fibromuscular dysplasia (FMD), diagnostic confidence, and need for additional imaging.A total of 292 patients suspected of renal artery disease completed the study. CE-MRA demonstrated statistically significant improvement in assessability of vascular segments compared to ToF: 95.9% vs. 77.6% (P0.0001). In the BR, the sensitivity and specificity of CE-MRA were noninferior to ToF-MRA (53.4% vs. 46.6% and 95.1% vs. 85.7%, respectively). There was less error in the CE-MRA stenosis measurements (0.15 mm gadobutrol vs. 0.41 mm ToF, P0.05). FMD was correctly diagnosed more frequently, 10% more accessory renal arteries were identified (P0.01), diagnostic confidence increased (P0.01), and fewer additional imaging studies were recommended (P0.01).Gadobutrol-enhanced MRA of the renal arteries has superior visualization, more accurate vessel measurements, and may serve as a CTA alternative without any ionizing radiation.1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:572-581.

We examined the correlation between sputum colour and the presence of potentially pathogenic bacteria in acute exacerbations of chronic bronchitis (AECBs). Data were pooled from six multicentre studies comparing moxifloxacin with other antimicrobials in patients with an AECB. Sputum was collected before antimicrobial therapy, and bacteria were identified by culture and Gram staining. Association between sputum colour and bacteria was determined using logistic regression. Of 4,089 sputum samples, a colour was reported in 4,003; 1,898 (46.4%) were culture-positive. Green or yellow sputum samples were most likely to yield bacteria (58.9% and 45.5% of samples, respectively), compared with 18% of clear and 39% of rust-coloured samples positive for potentially pathogenic microorganisms. Factors predicting a positive culture were sputum colour (the strongest predictor), sputum purulence, increased dyspnoea, male sex and absence of fever. Green or yellow versus white sputum colour was associated with a sensitivity of 94.7% and a specificity of 15% for the presence of bacteria. Sputum colour, particularly green and yellow, was a stronger predictor of potentially pathogenic bacteria than sputum purulence and increased dyspnoea in AECB patients. However, it does not necessarily predict the need for antibiotic treatment in all patients with AECB.

Objectives: To evaluate the efficacy and safety of moxifloxacin in the treatment of acute bacterial rhinosinusitis (ABRS). Study Design: Prospective, multicenter, randomized, double-blind, phase III trial. Methods: Patients with ABRS defined by clinical, radiologic, and bacteriologic criteria were recruited to the study. Study treatments were 400 mg of oral moxifloxacin or a matching placebo daily for 5 days. The primary end point was clinical response at test-of-cure, 1 to 3 days after the end of therapy in the modified intent-to-treat (mITT) population (patients with positive culture for one of five prespecified pathogens). Secondary efficacy variables included patient-reported symptom improvement measured using the Sino-Nasal Outcome Test-16 (SNOT-16), and concomitant medication use. Results: The mITT population consisted of 118 patients (moxifloxacin, n = 73; placebo, n = 45). Clinical success rates were numerically higher for moxifloxacin (78.1%, 57/73) versus placebo (66.7%, 30/45); (P = .189). Significantly greater mean reductions in SNOT-16 scores occurred in moxifloxacin- versus placebo-treated patients (−17.54 vs. −12.83; P = .032). Overall concomitant medication use was lower in moxifloxacin versus placebo patients (38.4%, 28/73 vs. 55.6%, 25/45 respectively). Premature discontinuation due to insufficient therapeutic effect was significantly lower in moxifloxacin- versus placebo-treated patients (8.2%, 6/73 vs. 22.2%, 10/45; P = .031). The rate of treatment-emergent adverse events in the ITT population was similar between arms (moxifloxacin 38.2%, 96/251; placebo 40.7%, 50/123). Conclusions: Although moxifloxacin 5-day therapy for ABRS was not statistically superior to placebo for the primary end point, patients who received moxifloxacin had significantly greater improvements in health outcomes and used fewer concomitant medicines than patients treated with placebo, while experiencing no increase in adverse events. Laryngoscope, 2010

Robert Wilson,1 Antonio Anzueto,2 Marc Miravitlles,3 Pierre Arvis,4 Daniel Haverstock,5 Mila Trajanovic,6 Sanjay Sethi7 1Host Defence Unit, Royal Brompton Hospital, London, UK; 2University of Texas Health Science Center, South Texas Veterans Health Care System, San Antonio, TX, USA; 3Pneumology Department, Hospital Universitari Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 4Bayer HealthCare Pharmaceuticals, Loos, France; 5Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA; 6Bayer HealthCare Pharmaceuticals, Toronto, ON, Canada; 7University atBuffalo, Buffalo, NY, USA Background: Acute exacerbations represent a significant burden for patients with moderate-to-severe chronic obstructive pulmonary disease. Each exacerbation episode is frequently associated with a lengthy recovery and impaired quality of life. Prognostic factors for outpatients that may predict poor outcome after treatment with antibiotics recommended in the guidelines, are not fully understood. We aimed to identify pretherapy factors predictive of clinical failure in elderly (≥60 years old) outpatients with acute Anthonisen type 1 exacerbations.Trial registration: NCT00656747.Methods: Based on the moxifloxacin in AECOPDs (acute exacerbations of chronic obstructive pulmonary disease) trial (MAESTRAL) database, this study evaluated pretherapy demographic, clinical, sputum bacteriological factors using multivariate logistic regression analysis, with internal validation by bootstrap replicates, to investigate their possible association with clinical failure at end of therapy (EOT) and 8 weeks posttherapy.Results: The analyses found that the independent factors predicting clinical failure at EOT were more frequent exacerbations, increased respiratory rate and lower body temperature at exacerbation, treatment with long-acting anticholinergic drugs, and in vitro bacterial resistance to study drug. The independent factors predicting poor outcome at 8 weeks posttherapy included wheezing at preexacerbation, mild or moderate (vs extreme) sleep disturbances, lower body temperature at exacerbation, forced expiratory volume in 1 second

OBJECTIVE To define and characterize risk factors for the failure of treatment for acute uncomplicated pyelonephritis, as there are few reports available to predict which patients will respond poorly to treatment. PATIENTS AND METHODS Retrospective univariate and multivariate logistic regression analyses were used to assess data from two prospective clinical trials designed to evaluate antibiotic regimens for urinary tract infections. Data from 522 adult patients with acute uncomplicated pyelonephritis were analysed. RESULTS The cure rate was 442/522 (85%) for patients with acute uncomplicated pyelonephritis. Significant independent predictors for treatment failure included hospitalization at baseline (P

In two prospective, randomized studies intravenous (IV)/oral (PO) moxifloxacin (400 mg q.i.d.) was compared to IV/PO antimicrobial comparator agents for the treatment of hospitalized patients with community-acquired pneumonia. Reported here are the pooled data for the sub-population with atypical pathogens. Of 101 intent-to-treat patients with atypical pathogens, a total of 39 moxifloxacin-treated and 47 comparator-treated subjects were microbiologically valid and included in the analysis. Clinical and bacteriological success rates were 95% for the moxifloxacin-treated and 94% for the comparator-treated subjects at the test-of-cure visit. The results indicate IV/PO moxifloxacin (400 mg q.i.d.) is an effective monotherapy for patients with CAP due to atypical pathogens.

BACKGROUND Moxifloxacin is an advanced-generation fluoroquinolone used primarily for the treatment of respiratory tract infections. OBJECTIVE To further investigate moxifloxacin's general and cardiac safety and evaluate its efficacy in the community practice setting in a large surveillance study. METHODS A total of 18 409 outpatients with suspected bacterial episodes of acute sinusitis, acute exacerbation of chronic bronchitis, or community-acquired pneumonia of mild to moderate severity were enrolled at 3377 community practice sites. Patients with sinusitis or pneumonia received once-daily oral moxifloxacin 400 mg for 10 days; those with bronchitis received 5 days' treatment. At follow-up, within 48 hours after the end of treatment, adverse event information was collected. An external safety committee assessed possible cardiac-related events. Efficacy was also evaluated at follow-up via the degree of resolution of clinical signs and symptoms. RESULTS Of 18 374 safety-valid patients, 17.7% experienced adverse events and 14.3% experienced drug-related adverse events. The most common drug-related adverse events were nausea (5.3%), diarrhea (2.2%), and dizziness (2.0%). There was no clinical evidence of increased risk of cardiac arrhythmias with moxifloxacin treatment. Of 17 137 patients included in the efficacy analysis, 92.9% overall experienced clinical cure or improvement (92.8% with sinusitis, 92.9% with bronchitis, 94.1% with pneumonia). CONCLUSIONS Once-daily oral moxifloxacin 400 mg was shown to be safe and effective in this trial for the treatment of respiratory tract infections of suspected bacterial origin in the clinical practice setting.

Background: Trimethoprim/sulfamethoxazole (TMP/SMX) is currently the first choice for empiric therapy of acute uncomplicated urinary tract infection (UTI) in women. In areas where resistance to TMP/SMX is known to be high, ciprofloxacin and other fluoroquinolones are recommended as first-line choices for the empiric therapy of UTI. Objective: This study compared the efficacy and safety profile of once-daily extended-release ciprofloxacin 500 mg (referred to hereafter as ciprofloxacin QD) with those of conventional ciprofloxacin 250 mg BID, each administered orally for 3 days, in the treatment of uncomplicated UTI in women. Methods: In this multicenter, prospective, randomized, double-blind, double-dummy, Phase III trial, adult women with clinical signs and symptoms of acute uncomplicated UTI, pyuria, and a positive pretherapy urine culture (≥10 5 colony - forming units / mL ) received ciprofloxacin QD or ciprofloxacin BID. Bacteriologic and clinical outcomes were assessed at the test-of-cure visit (4–11 days after completion of therapy) and the late follow-up visit (25–50 days after completion of therapy). Results: The intent-to-treat population consisted of 891 patients (444 ciprofloxacin QD, 447 ciprofloxacin BID); 422 patients were evaluable for efficacy (199 ciprofloxacin QD, 223 ciprofloxacin BID). At the test-of-cure visit, bacteriologic eradication was achieved in 94.5% (188/199) of the ciprofloxacin QD group and 93.7% (209/223) of the ciprofloxacin BID group (95% CI, −3.5 to 5.1). Clinical cure was achieved in 95.5% (189/198) of the ciprofloxacin QD group and 92.7% (204/220) of the ciprofloxacin BID group (95% CI, −1.6 to 7.1). Bacteriologic and clinical outcomes at the late follow-up visit were consistent with the test-of-cure findings. The rate of eradication of Escherichia coli , the most prevalent organism, was >97% in each treatment group. Rates of drug-related adverse events were similar with the once- and twice-daily ciprofloxacin regimens (10% and 9%, respectively). Conclusion: Extended-release ciprofloxacin 500 mg given once daily for 3 days was as effective and well tolerated as conventional ciprofloxacin 250 mg given twice daily for 3 days in the treatment of acute uncomplicated UTI in women.

Purpose Contrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS) with gadolinium-based contrast agents (GBCAs) is standard of care for CNS imaging and diagnosis because of the visualization of lesions that cause blood–brain barrier breakdown. Gadobutrol is a macrocyclic GBCA with high concentration and high relaxivity. The objective of this study was to compare the safety and efficacy of gadobutrol 1.0 M vs unenhanced imaging and vs the approved macrocyclic agent gadoteridol 0.5 M at a dose of 0.1 mmol/kg bodyweight. Materials and Methods Prospective, multicenter, double-blind, crossover trial in patients who underwent unenhanced MRI followed by enhanced imaging with gadobutrol or gadoteridol. Three blinded readers assessed the magnetic resonance images. The primary efficacy variables included number of lesions detected, degree of lesion contrast-enhancement, lesion border delineation, and lesion internal morphology. Results Of the 402 treated patients, 390 patients received study drugs. Lesion contrast-enhancement, lesion border delineation, and lesion internal morphology were superior for combined unenhanced/gadobutrol-enhanced imaging vs unenhanced imaging ( P < 0.0001 for all). Compared with gadoteridol, gadobutrol was non-inferior for all primary variables and superior for lesion contrast-enhancement, as well as sensitivity and accuracy for detection of malignant disease. The percentage of patients with at least one drug-related adverse event was similar for gadobutrol (10.0%) and gadoteridol (9.7%). Conclusion Gadobutrol is an effective and well-tolerated macrocyclic contrast agent for MRI of the CNS. Gadobutrol demonstrates greater contrast-enhancement and improved sensitivity and accuracy for detection of malignant disease than gadoteridol, likely because of its higher relaxivity.

Ciprofloxacin is a broad-spectrum fluoroquinolone antibiotic used in the treatment of a wide range of mild to moderate gram-positive and gram-negative infections. Although extensive information is available on the safety profile of ciprofloxacin in adults, few published data exist regarding the tolerability and toxicity of this drug in patients agedor = 65 years.The objectives of this retrospective analysis were to compare the safety profile of ciprofloxacin in patients agedor = 65 years versus patients aged65 years and to compare the adverse-event profile of ciprofloxacin with that of other comparator antimicrobial agents used in clinical trials.We retrospectively reviewed 23 prospective, controlled anti-infective clinical trials in the US Bayer ciprofloxacin database that included patients agedor = 65 years. These trials comprised the submission file of the original and supplemental New Drug Application for ciprofloxacin. The incidence of treatment-emergent and drug-related adverse events was assessed.Of the 6863 patients in these 23 clinical trials, 3579 received ciprofloxacin therapy and 3284 received comparator antimicrobial agents. Of the ciprofloxacin-treated patients, 898 (25.1%) were agedor = 65 years; 887 (27.0%) of the patients who received comparator antimicrobial agents were agedor = 65 years. Among ciprofloxacin-treated patients, drug-related adverse events were reported more often in those aged65 years (24.0%) compared with those agedor = 65 years (17.9%). The incidence of drug-related adverse events in the comparator group was also higher in those aged65 years (25.1%) than in those agedor = 65 years (16.8%). Premature discontinuation due to any adverse event was reported in 3.9% (105 of 2681) and 3.7% (33 of 898) of ciprofloxacin-treated patients aged65 years andor = 65 years, respectively. Corresponding rates for the comparator antimicrobial group were 3.9% (93 of 2397) and 3.8% (34 of 887), respectively, for patients aged65 years andor = 65 years. The most common drug-related adverse events reported for ciprofloxacin-treated patients aged65 years andor = 65 years were digestive system-related (18.1% and 11.4%, respectively) and central nervous system-related events (6.6% and 4.9%, respectively).This retrospective analysis suggests that there is no clinically important difference in the safety profile of ciprofloxacin in patients agedor = 65 years versus patients aged65 years.

Chronic bronchitis is common among adults and infectious exacerbations contribute considerably to morbidity and mortality. We aimed to compare the safety and efficacy of moxifloxacin to clarithromycin for the treatment of patients with acute bacterial exacerbations of chronic bronchitis (ABECB) using a prospective, randomized, double-blind, parallel group trial.Between November 21, 1996 and April 7, 1998, 936 patients with acute exacerbations of chronic bronchitis (AECB) were enrolled at 56 centers across the United States of which 491 (52%) had ABECB (i.e. pretherapy pathogen).Patients were randomized to either oral moxifloxacin 400 mg administer once daily, for either 5 or 10 days, or clarithromycin 500 mg bid for 10 days. For the purpose of study blinding, the patients taking moxifloxacin received placebo to maintain uniform dosing.The main outcome measures were bacteriological response at the end of therapy (post-therapy days 0–6) and follow-up (7–17 days post-therapy) visits, as well as overall clinical response, clinical response at the end of therapy and clinical response at follow-up. Two patient populations were analyzed: efficacy-valid (i.e., those with a pretherapy pathogen) and intent-to-treat (i.e., all subjects that took drug).In 420 efficacy valid patients with a pretherapy organism, overall clinical resolution was 89% for 5 days moxifloxacin vs. 91% for 10 day moxifloxacin vs. 91% for 10 day clarithromycin. Bacteriological eradication rates at the end of therapy were 94% and 95% for 5-day moxifloxacin and 10-day moxifloxacin, respectively, and 91% for the clarithromycin group. Eradication rates at follow-up were 89% and 91% for 5-day moxifloxacin and 10-day moxifloxacin respectively, and 85% for the clarithromycin group. Among 926 intent-to-treat patients (312 5-day moxifloxacin, 302 10-day moxifloxacin and 312 clarithromycin), drug-related events were reported for 26%, 30% and 35%, respectively.Moxifloxacin 400 mg once daily, as a 5 or 10 day regimen, was found to be clinically and bacteriologically equivalent to 10 day clarithromycin for the treatment of ABECB. Given its favorable safety and tolerability profile, moxifloxacin administered once daily for 5 days may be as effective and a more convenient treatment than a standard course of clarithromycin for patients with ABECB.

The aim of this prospective, multicenter, randomized, double-masked clinical trial was to compare the efficacy and safety of moxifloxacin with those of cefuroxime axetil for the treatment of community-acquired acute sinusitis. Five hundred forty-two adult patients with symptoms and radiographic evidence of acute maxillary sinusitis received a 10-day oral regimen of either moxifloxacin (400 mg once daily) or cefuroxime axetil (250 mg twice daily). Acute signs and symptoms at presentation had lasted >7 days but

Five hundred and forty patients with severe infection were enrolled in a multicentre, prospective, randomized, non-blinded study to compare the efficacy and safety of iv ciprofloxacin with iv standard therapy. Five hundred and thirty-one patients received at least one dose of study drug for pneumonia (310), septicaemia (112) or skin and skin structure infection (109). Intravenous ciprofloxacin (400 mg, every 8 h) or iv ciprofloxacin (400 mg, every 8 h) plus a β-lactam were compared with a standard monotherapy (β-lactam) or combination (aminoglycoside plus a β-lactam) therapy. Patients were treated parenterally for a minimum of 2 or 3 days, then at the discretion of the investigator could be switched to oral therapy (ciprofloxacin 750 mg, every 12 h or a standard oral therapy). Patients were randomized in the ratio of 2:1 for the ciprofloxacin and standard therapy treatment groups and stratified to monotherapy if the APACHE II score was ≤20 or to combination therapy if the APACHE II score was 21- 29. Three hundred and ninety-five (74%) patients were valid for the efficacy analysis: these comprised 242 pneumonia (167 ciprofloxacin and 75 standard therapy), 70 septicaemia (47 ciprofloxacin and 23 standard therapy), and 83 skin infections (56 ciprofloxacin and 27 standard). The primary efficacy variable was clinical response and the secondary efficacy assessment was bacteriological response at the end of therapy (2 or 3 days after treatment). The mean duration of therapy for patients receiving only iv monotherapy or combination therapy was shorter (9- 10 days) than for patients receiving sequential iv/po therapy (14- 17 days). At the end of therapy, overall clinical resolution/improvement (success) for monotherapy was 138/166 (83%) for the ciprofloxacin group, compared with 74/87 (85%) for standard-treated patients (95% CI =−11.5% to 7.6%), and for combination therapy the response was 43/51 (84%) for the ciprofloxacin group and 14/20 (70%) for standard-treated patients (95% CI =− 6.3% to 34.9%). For pneumonia, the most frequent infection treated, clinical success rates following monotherapy were 85% for ciprofloxacin and 83% for standard-treated patients and 83% for ciprofloxacin compared with 69% for standard-treated patients in the combination therapy group. Bacteriological eradication/presumed eradication following monotherapy was 85/102 (83%) for ciprofloxacin and 31/46 (67%) for standard-treated patients (95% CI = 1.6% to 30.3%), and that for combination therapy was 29/36 (81%) for ciprofloxacin and 7/10 (70%) for standard-treated patients (95% CI =−18.3% to 39.5%). Drug-related adverse events, primarily diarrhoea and nausea, were reported in 22% of ciprofloxacin-treated patients and 20% of standard-treated patients. In summary, ciprofloxacin administered alone or in combination was found to be effective in treating a wide range of severe infections.

In a multicenter, community-based study involving more than 300 primary care physicians in the United States, the efficacy and safety of ciprofloxacin and clarithromycin were compared in the treatment of patients with complicated or severe acute bacterial exacerbations of chronic bronchitis (i.e., those who had failed previous antibiotic treatment within the prior 2 to 4 weeks; those with susceptibility data suggestive of a resistant pathogen; those having three or more acute exacerbations of chronic bronchitis [AECB] within the past year; and those having three or more comorbid conditions). Patients were randomized to either ciprofloxacin (CIP) 750 mg BID or clarithromycin (CLR) 500 mg BID, both administered for 10 days; all patients were treated on an outpatient basis. Clinical response at the end of therapy was the primary efficacy variable. An interim analysis was performed on the results from 743 patients (369 CIP, 374 CLR) with clinical and bacteriologic evidence of a bronchopulmonary infection who had completed an ongoing study as of the end of May 1997. Three hundred nine pathogens were isolated before therapy, including Haemophilus spp (75 isolates), Moraxella catarrhalis (67 isolates), Staphylococcus aureus (55 isolates), and Streptococcus pneumoniae (23 isolates). Seven hundred eighteen patients (97%) were included in the efficacy-valid population. Clinical success at the end of therapy was observed in 90% (272 of 302) and 88% (274 of 313) of efficacy-valid patients treated with CIP and CLR, respectively (95% confidence interval [CI] = -2.4 to 7.6). Corresponding rates for the intent-to-treat population were also 90% (283 of 314) and 88% (281 of 321), respectively (95% CI = -2.3 to 7.5). The bacteriologic response for efficacy-valid patients at the end of therapy was 98% (119 of 122) for CIP-treated and 93% (103 of 111) for CLR-treated patients (95% CI = -0.8 to 10.2). The eradication rates for the three most commonly isolated gram-negative pathogens were 100% for CIP-treated and 95% for CLR-treated patients and 96% each for the two most commonly isolated gram-positive organisms. Superinfections due to respiratory tract pathogens were more common in the CLR group (10 organisms) than in the CIP group (4 organisms). Seventy-four (20%) CIP-treated and 62 (17%) CLR-treated patients reported 118 and 103 respective study-emergent adverse events. Headache, abdominal pain, diarrhea, nausea, and vomiting in CIP-treated patients and diarrhea, nausea, vomiting, and taste perversion in CLR-treated patients were the most commonly reported adverse events. Treatment of patients with complicated or severe AECB with CIP 750 mg BID was associated with rates of clinical success and bacteriologic eradication similar to those with CLR.

Background. Cystic fibrosis patients have chronic bacterial infections of the respiratory tract, most commonly Pseudomonas aeruginosa. Although controversial, administration of antibiotic therapy during acute pulmonary exacerbations is standard practice. Fluoroquinolones are currently not indicated for use in young children because of the observation of arthropathy and damage to growing cartilage in beagle puppies. Because of its activity against P. aeruginosa and excellent oral bioavailability, ciprofloxacin offers a unique therapeutic alternative for this patient population. Objective. This prospective, randomized, double blind study compared the efficacy and safety of sequential intravenous/oral ciprofloxacin vs. ceftazidime/tobramycin in hospitalized pediatric cystic fibrosis patients with an acute pulmonary exacerbation associated with P. aeruginosa infection. Methods. One hundred thirty patients (ages 5 to 17 years) were randomized to receive either iv ciprofloxacin 10 mg/kg every 8 h for 7 days followed by oral ciprofloxacin 20 mg/kg every 12 h for a minimum of 3 days or iv ceftazidime 50 mg/kg every 8 h plus iv tobramycin 3 mg/kg every 8 h for a minimum of 10 days. Clinical, bacteriologic and safety responses were assessed throughout the study. Results. All 84 patients (median age, 11 years; range, 5 to 17 years) valid for efficacy in both treatment groups demonstrated clinical improvement. Five patients experienced clinical relapses (3 ciprofloxacin, 2 ceftazidime/tobramycin) by the 2- to 4-week follow-up. Intent-to-treat analysis demonstrated similar clinical findings between the two treatment groups at both the end of therapy and follow-up. Clinical improvement correlated with improvement in pulmonary function studies and the acute clinical scoring system but not with bacteriologic eradication of Pseudomonas. DNA profiles demonstrated that irrespective of colony morphology, usually one clonal strain was associated with each patient's pulmonary exacerbation. Treatment-associated musculoskeletal events occurred with equal frequency (22% vs. 21%) in both study drug groups (n = 129), and arthralgias were within the range of rates for cystic fibrosis arthropathy. None of these events required study drug discontinuation. Conclusion. Sequential iv/oral ciprofloxacin monotherapy offers a safe and efficacious alternative to standard parenteral therapy for acute pulmonary exacerbations in pediatric cystic fibrosis patients.

ObjectiveIn a randomized, double-blind, multicenter trial, ciprofloxacin/metronidazole was compared with imipenem/cilastatin for treatment of complicated intra-abdominal infections. A secondary objective was to demonstrate the ability to switch responding patients from intravenous (IV) to oral (PO)

Robert Wilson1, Antonio Anzueto2, Marc Miravitlles3, Pierre Arvis4, Geneviève Faragó5, Daniel Haverstock6, Mila Trajanovic5, Sanjay Sethi71Host Defence Unit, Royal Brompton Hospital, London, England, UK; 2University of Texas Health Science Center at San Antonio, South Texas Veterans HealthCare System, San Antonio, TX, USA; 3Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Ciber de Enfermedades Respiratorias (CIBERES), Hospital Clinic, Barcelona, Spain; 4Bayer HealthCare, Loos, France; 5Bayer Inc, Toronto, ON, Canada; 6Bayer HealthCare Pharmaceuticals, Montville, NJ, USA; 7Division of Pulmonary, Critical Care and Sleep Medicine, University at Buffalo, State University of New York, Buffalo, NY, USAAbstract: Antibiotics, along with oral corticosteroids, are standard treatments for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The ultimate aims of treatment are to minimize the impact of the current exacerbation, and by ensuring complete resolution, reduce the risk of relapse. In the absence of superiority studies of antibiotics in AECOPD, evidence of the relative efficacy of different drugs is lacking, and so it is difficult for physicians to select the most effective antibiotic. This paper describes the protocol and rationale for MAESTRAL (moxifloxacin in AECBs [acute exacerbation of chronic bronchitis] trial; www.clinicaltrials.gov: NCT00656747), one of the first antibiotic comparator trials designed to show superiority of one antibiotic over another in AECOPD. It is a prospective, multinational, multicenter, randomized, double-blind controlled study of moxifloxacin (400 mg PO [per os] once daily for 5 days) vs amoxicillin/clavulanic acid (875/125 mg PO twice daily for 7 days) in outpatients with COPD and chronic bronchitis suffering from an exacerbation. MAESTRAL uses an innovative primary endpoint of clinical failure: the requirement for additional or alternate treatment for the exacerbation at 8 weeks after the end of antibiotic therapy, powered for superiority. Patients enrolled are those at high-risk of treatment failure, and all are experiencing an Anthonisen type I exacerbation. Patients are stratified according to oral corticosteroid use to control their effect across antibiotic treatment arms. Secondary endpoints include quality of life, symptom assessments and health care resource use.Keywords: AECOPD, moxifloxacin, amoxicillin/clavulanic acid, clinical trial design, exacerbation, antibiotic

OBJECTIVE To compare the clinical and bacteriological efficacy and the clinical safety of a 1-day with a 3-day regimen of an extended-release formulation of ciprofloxacin (ciprofloxacin XR) given as antimicrobial prophylaxis to men undergoing transrectal needle biopsy of the prostate (TRNBP). PATIENTS AND METHODS This was a multicentre, prospective, international, double-blind study in patients who required TRNBP. Patients were randomized to receive oral ciprofloxacin XR 1000 mg as either a 1-day or a 3-day regimen. Single doses were given at 24 h before, 2–3 h before, and 24 h after TRNBP. Patients in the 1-day regimen had placebo instead of the first and third doses of ciprofloxacin. RESULTS Of 497 patients enrolled, 247 were randomized to 1-day ciprofloxacin XR and 250 to the 3-day regimen. In the population valid for microbiological efficacy, the final assessment identified bacteriological success (primary efficacy endpoint) in more patients who had the 3-day regimen (98%) than in those who received the 1-day regimen (94.8%, 95% confidence interval, CI, − 6.1%, 0.8%), although the difference was not statistically significant. In this population, the clinical response at the final visit was 98.5% and 96.7% for patients receiving the 3-day and the 1-day regimens, respectively (95% CI − 5.2%, 0.8%). However, in the clinical efficacy population the clinical success rate was significantly greater for the 3-day (99.0%) than for the 1-day regimen (95.8%; 95% CI − 6.4%, − 0.3%). In a multivariate analysis, patients with diabetes mellitus and patients with a history of prostatitis had higher microbiological and clinical failure rates, respectively, than those without such conditions. For these patients, all failures occurred among those treated with the 1-day regimen. CONCLUSION As defined by bacteriological success in the population assessed for microbiological efficacy, prophylaxis with one dose of ciprofloxacin XR was statistically no worse than a 3-day regimen. However, in all efficacy analyses, bacteriological and clinical success rates were consistently lower for the 1-day than for the 3-day treatment. Thus, for selected patients undergoing TRNBP, there might be a role for 3-day preventive therapy with ciprofloxacin XR.

Haemophilus influenzae is the most common bacterial pathogen associated with acute exacerbations of chronic bronchitis (AECB). This study determined the rate of bacterial eradication of H. influenzae during AECB treated with either macrolides or moxifloxacin. Adult AECB patients with H. influenzae were included in a pooled analysis of four double-blind, multicentre, randomised trials. Patients received either moxifloxacin (400 mg qd for 5-10 days) or macrolides (azithromycin 500 mg/250 mg qd for 5 days or clarithromycin 500 mg bid for 5-10 days). Bacterial eradication and clinical success were recorded at the test-of-cure visit (7-37 days post-therapy). Of 2555 patients in the intent-to-treat population, 910 were microbiologically valid and 292 (32%) had H. influenzae cultured at baseline. Bacterial eradication of H. influenzae was significantly higher with moxifloxacin vs. macrolide-treated patients (93.0% [133/143] vs. 73.2% [109/149], respectively, P = 0.001). Moxifloxacin also demonstrated higher eradication rates compared with azithromycin (96.8% vs. 84.6%, P = 0.019) and clarithromycin (90.1% vs. 64.2%, P = 0.001) analysed separately. Clinical success was 89.5% (128/143) for moxifloxacin vs. 85.2% (127/149) for the macrolide group (P = 0.278); similar results were found when moxifloxacin was compared individually with each macrolide. For patients with AECB due to H. influenzae, moxifloxacin provided superior bacterial eradication rates than macrolide therapy.

Background and objective: As aging is associated with physiological changes, including renal and hepatic insufficiency, and a higher risk of drug interactions, special attention needs to be directed towards the safety of medications in the elderly. The objective of this analysis was to evaluate the safety of oral moxifloxacin in elderly patients who were enrolled in clinical trials and to compare these results to those of other commonly used antibacterials. Methods: Safety data from 27 prospective, randomised, comparative phase II/III trials of oral moxifloxacin included in the Bayer clinical trial database were pooled and analysed by age group (

BACKGROUND Therapy with an aminoglycoside and a beta-lactam remains common empirical therapy for febrile neutropenic patients. Concerns of aminoglycoside-induced ototoxicity and nephrotoxicity have led to studies of alternate regimens. OBJECTIVE To determine whether ciprofloxacin-piperacillin is equivalent to tobramycin-piperacillin as empirical therapy for neutropenic fever. DESIGN Randomized, double-blind multicenter trial. SETTING Seven U.S. university-affiliated hospitals and one private research center. PATIENTS Febrile (temperature >/= 38 degrees C), neutropenic (neutrophil level < 1 x 10(9) cells/L) hospitalized patients who had leukemia, lymphoma, or solid tumors, or were undergoing bone marrow transplantation. INTERVENTIONS Patients received piperacillin, 50 mg/kg of body weight intravenously every 4 hours, and ciprofloxacin, 400 mg intravenously every 8 hours, or tobramycin, 2 mg/kg intravenously every 8 hours. MEASUREMENTS Success was defined as resolution of infection and previously positive cultures without the need to give additional antimicrobial agents. RESULTS 543 febrile episodes were evaluated, of which 471 were clinically evaluable (234 in the ciprofloxacin-piperacillin group and 237 in the tobramycin-piperacillin group). Success rates in the ciprofloxacin-piperacillin group (63 of 234 febrile episodes) and tobramycin-piperacillin group (52 of 237 episodes) were similar (27% vs. 22%, respectively; difference, 5.0 percentage points [95% CI, -2.3 to 12.8 percentage points]), as was survival (96.2% of patients receiving ciprofloxacin-piperacillin versus 94.1% of patients receiving tobramycin-piperacillin; difference, 2.1 percentage points [CI, -2.2 to 6.4 percentage points]). Additions to the initial antimicrobial regimen were the most common reason for treatment failure in both groups (accounting for 67% of failures in the ciprofloxacin-piperacillin group and 72% in the tobramycin-piperacillin group; difference, 5.0 percentage points [CI, -13.8 to 3.7 percentage points]). Fevers resolved faster in patients receiving ciprofloxacin-piperacillin than in patients receiving tobramycin-piperacillin (mean, 5 vs. 6 days) (P = 0.005). No significant differences in adverse events or toxicity were noted (P = 0.083). CONCLUSION Ciprofloxacin-piperacillin is as safe and effective as tobramycin-piperacillin for empirical therapy of neutropenic fever.

Although pulmonary function tests are used to evaluate acute changes in obstructive airway disease in patients with cystic fibrosis (CF), these tests are relatively difficult to perform in young children or severely ill patients and may be costly. Other standard tests (eg, the Shwachman-Kulczycki and National Institutes of Health [NIH] scoring systems) evaluate disease severity and predict prognosis but do not measure day-to-day changes in clinical status. They thus provide little information for assessing the start of acute pulmonary exacerbation. Alternative scoring systems are needed to better identify the start of pulmonary exacerbation, to predict worsening or improvement of respiratory function after intervention, and to distinguish the scores from illness severity scores. This study was undertaken to compare a new 10-component, 50-point-maximum, acute clinical scoring system with forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) variables in children with CF who were experiencing an acute pulmonary exacerbation before antimicrobial therapy was initiated and until the end of therapy. One hundred thirty children aged 5 to 17 years (median age, 11 years) had a median NIH score of approximately 64 (range, 39 to 85) at admission. The cystic fibrosis clinical score (CFCS) at admission was found to correlate highly with the modified NIH score at study entry (r = -.68, P = 0.0001 ). The total CFCS at entry was correlated inversely with both FEV1 (r = -.57, P = 0.0001) and FVC (r = -.55, P = 0.0001) measurements; crackles, dyspnea, sputum production, and respiratory rate were the 4 components most highly associated with either pulmonary function variable. The change in total CFCS from start to end of antimicrobial therapy also correlated with changes in FEV1 (r = -.31, P = 0.0016) and change in FVC (r = -.47, P = 0.0001). Clinical improvement was observed in all patients at the end of therapy, and only 1 patient had an increase in total CFCS. Patients who experienced clinical relapse had a mean increase of 8.5 points in the CFCS from end of therapy to 2- to 4-week follow-up, indicating worsening signs and symptoms of acute exacerbation. These data suggest that the CFCS is a predictive and optional surrogate of pulmonary function in assessing the health of patients with CF. Following further validation, this scoring system could be used to evaluate health status in the outpatient setting, the need for hospitalization, and subsequent improvement during an acute pulmonary exacerbation, as well as to compare the efficacy of therapeutic regimens.

A meta-analysis of six double-blinded clinical trials was undertaken to identify risk factors associated with bacteriologic outcome in 3,108 women with acute cystitis. Eleven antibiotic regimens were used, including ciprofloxacin, ofloxacin, norfloxacin, trimethoprim-sulfamethoxazole, and nitrofurantoin. Entry criteria for all studies were identical. Among 2,409 patients who were defined to be valid for efficacy analysis, pathogens included Escherichia coli (78.6%), Staphylococcus saprophyticus (4.4%), Klebsiella pneumoniae (4.3%), Proteus mirabilis (3.7%), and "other" (9%). Causative bacteria were eradicated at the end of treatment in 93% of patients. The following parameters were associated with successful bacteriologic outcome: not using a diaphragm (P = .0041), treatment foror = 3 days (P = .0043), pathogen not "other" (P = .0043), symptom duration of2 days (P = .0096), and African American race (P = .0147). K. pneumoniae (P = .0496) and "other" pathogens (P = .0018) were associated with increased probability of bacteriologic treatment failure. The presence of pyuria (or = 10 WBCs per high-power field) did not correlate with outcome and was inversely correlated with the finding ofor = 10(5) bacterial colony-forming units per mL of urine (P.001). This large database identifies new parameters associated with treatment outcomes of acute cystitis and calls into question current clinical trial guidelines.

In a review of the US Bayer ciprofloxacin (CIP) database, an analysis was undertaken to summarize the effectiveness and tolerability of CIP 750 mg BID in the treatment of patients with acute exacerbations of chronic bronchitis (AECB) and pneumonia. In five controlled studies, comparator (COMP) agents included ampicillin, intravenous cefuroxime/cefaclor, and other unspecified agents. Primary efficacy end points were clinical success (resolution plus improvement) and bacteriologic eradication at the end of therapy. The incidence of adverse events for CIP 750 mg BID was compared with that for COMP and with that in the CIP 500-mg-BID AECB and pneumonia clinical trials database. In five uncontrolled studies, 443 patients received CIP 750 mg BID; in 5 controlled trials comprising 344 patients, 169 received CIP 750 mg BID and 175 received COMP. Clinical success for CIP was 93% (368/396) and 99% (160/162), respectively, in the uncontrolled and controlled studies versus 98% (156/160) for COMP agents. Corresponding bacteriologic eradication rates for CIP 750-mg-BID-treated patients were 77% (273/356) and 95% (122/128), respectively, and 77% (96/125) for COMP agents. Overall bacteriologic eradication by organism for CIP 750 mg BID included Streptococcus pneumoniae 96% (51/53), Haemophilus influenzae 98% (92/94), Haemophilus parainfluenzae 100% (56/56), Moraxella catarrhalis 100% (14/14; 13 of 14 organisms were isolated in patients with AECB), and Pseudomonas aeruginosa 66% (135/204). Drug-related adverse events were reported in 113 (26%) CIP 750-mg-BID-treated patients in uncontrolled trials and in 62 (37%) CIP 750-mg-BID- and 61 (35%) COMP-treated patients in controlled trials. In the combined data from the CIP 750-mg-BID uncontrolled and controlled trials, adverse events occurred with similar frequency compared with COMP except for nausea (CIP 10%, COMP 7%) and diarrhea (CIP 3%, COMP 13%). In conclusion, CIP 750 mg BID provided excellent clinical success rates in the treatment of patients with AECB and pneumonia. CIP 750 mg BID was well tolerated compared with the COMP agents administered.

The role of enterococcus in intraabdominal infection is controversial. This study examines the contribution of enterococcus to adverse outcome in a large intraabdominal infection trial.A randomized prospective double-blind trial was performed to compare two different antimicrobial regimens in combination with surgical or percutaneous drainage in the treatment of complicated intraabdominal infections. A total of 330 valid patients was enrolled from 22 centers in North America.In 330 valid patients, 71 had enterococcus isolated from the initial drainage of an intraabdominal focus of infection. This finding was associated with a significantly higher treatment failure rate than that of patients without enterococcus (28% versus 14%, p0.01). In addition, only Acute Physiology and Chronic Health Evaluation II score and presence of enterococcus were significant independent predictors of treatment failure when stepwise logistic regression was performed (p0.01 and0.03). Risk factors for the presence of enterococcus include age, Acute Physiology and Chronic Health Evaluation II, preinfection hospital length of stay, postoperative infections, and anatomic source of infection. There was no difference between the clinical trial treatment regimens with regard to overall failure, failure associated with enterococcus, or frequency of enterococcal isolation.This study is the first to report enterococcus as a predictor of treatment failure in complicated intraabdominal infections. This trial also identifies several significant risk factors for the presence of enterococcus in such infections.

Purpose Changes in sputum microbiology following antibiotic treatment of acute exacerbations of chronic obstructive pulmonary disease (AECOPD), including patterns of bacteriological relapse and superinfection are not well understood. Sputum microbiology at exacerbation is not routinely performed, but pathogen presence and species are determinants of outcomes. Therefore, we determined whether baseline clinical factors could predict the presence of bacterial pathogens at exacerbation. Bacterial eradication at end of treatment (EOT) is associated with clinical resolution of exacerbation. We determined the clinical, microbiological and therapeutic factors that were associated with bacteriological eradication in AECOPD at EOT and in the following 8 weeks. Methods Sputum bacteriological outcomes (i.e., eradication, persistence, superinfection, reinfection) from AECOPD patients (N = 1352) who were randomized to receive moxifloxacin or amoxicillin/clavulanate in the MAESTRAL study were compared. Independent predictors of bacterial presence in sputum at exacerbation and determinants for bacteriological eradication were analyzed by logistic regression and receiver operating characteristic (ROC) analyses. Results Significantly greater bacteriological eradication with moxifloxacin was mainly driven by superior Haemophilus influenzae eradication (P = 0.002, EOT). Baseline clinical factors were a weak predictor of the presence of pathogens in sputum (AUCROC = 0.593). On multivariate analysis, poorer bacterial eradication was associated with antibiotic resistance (P = 0.0001), systemic steroid use (P = 0.0024) and presence of P. aeruginosa (P = 0.0282). Conclusions Since clinical prediction of bacterial presence in sputum at AECOPD is poor, sputum microbiological analysis should be considered for guiding antibiotic therapy in moderate-to-severe AECOPD, particularly in those who received concomitant systemic corticosteroids or are at risk for infection with antibiotic-resistant bacteria. Electronic supplementary material The online version of this article (doi:10.1007/s15010-015-0833-3) contains supplementary material, which is available to authorized users.