A Randomized Study of Sequential Intravenous/Oral Moxifloxacin in Comparison to Sequential Intravenous Ceftriaxone/Oral Cefuroxime Axetil in Patients with Hospital-Acquired Pneumonia

Abstract Background: Empiric treatment of hospital-acquired pneumonia (HAP) should be focused on the suspected pathogens. We evaluated the efficacy and safety of moxifloxacin vs ceftriaxone in patients with HAP without risk of infections with Pseudomonas aeruginosa and other non-fermentative Gram-negative bacteria. Patients and Methods: We performed a prospective, randomized, non-blind, multicentric and multinational study to compare the efficacy and safety of moxifloxacin 400 mg IV once daily followed by oral moxifloxacin 400 mg once daily to ceftriaxone 2 g IV once daily followed by oral cefuroxime axetil 500 mg twice daily to treat mild-to-moderate HAP in adult patients requiring initial parenteral therapy. The primary efficacy variable was clinical response 7–10 days after the end of a 7–14-day treatment period, secondary endpoints included clinical and bacteriologic response at different intervals for up to 31 days after treatment. The trial was terminated prematurely due to slow patient recruitment. Results: A total of 161 subjects (87 men, 74 women) between 18 and 95 years of age were enrolled, 120 of whom were eligible for per protocol efficacy analyses (60 each in the moxifloxacin and the comparator groups). Clinical success rates were 87% for moxifloxacin and 83% for the comparator [95% CI (–9.77 to 15.96%)]. The results for secondary endpoints were comparable between groups. Both treatments were safe and well tolerated. Conclusion: Moxifloxacin IV/oral can be considered as a possible alternative for the antibiotic treatment of patients with mild-to-moderate nosocomial pneumonia without risk factors for highly resistant microorganisms.     

Failure of Current Antibiotic First-Line Regimens and Mortality in Hospitalized Patients with Spontaneous Bacterial Peritonitis

Abstract Background:   Increases in Gram-positive infections and infections with Enterobacteriaceae with antimicrobial resistance have been reported in patients with spontaneous bacterial peritonitis (SBP). This study was performed to investigate the rate of treatment failures of recommended empirical therapies and the impact on mortality. Patients and Methods:   A prospectively collected database comprising 101 patients with SBP (70 nosocomial, 31 community acquired) treated at a university hospital between 2002 and 2006 in Munich, Germany, was analyzed. Results:   17 patients initially received a broader than recommended antibiotic regimen. Most of these were treated in the intensive care unit because of severe sepsis/septic shock. Hospital mortality in this group was 82%. A modification of therapy was necessary in 24 of the 84 patients receiving one of the published first-line therapies (cefotaxime, ampicillin/clavulanate, or ciprofloxacin). Mortality was significantly higher in these patients than in those with no change in treatment (66.7% vs 30%, p = 0.002). In 29 patients with positive cultures, mortality was also higher in those with an ineffective first-line treatment (90% vs 45%, p = 0.032). In the multivariable analysis, a modification of antibiotic treatment was an independent risk factor for mortality (odds ratio 5.876, 95% confidence interval 1.826–18.910, p = 0.003). In 41 culture-positive cases, the most commonly cultured pathogens were Escherichia coli (n = 17) and Enterococcus faecium (n = 10). Of the encountered bacterial microorganisms, 14 (33.3%) were resistant to cefotaxime, 17 (38.6%) were resistant to amoxicillin/clavulanate, and 19 (45.2%) were resistant to ciprofloxacin. 29 (64.4%) of the isolates were resistant to one of the recommended firstline antibiotic regimens, and 11 (24.4%) of the isolates were resistant to all three. Conclusion:   Recommended empirical antibiotic regimens fail to achieve the desired effect in a substantial number of hospitalized patients with SBP. This has a negative impact on mortality.     

Influence of Moxifloxacin,Comparator Drugs and Some Fractions of Pulmonary Surfactant on Adherence of Some Respiratory Pathogens

Background: This study evaluated the effect of moxifloxacin and comparator drugs with or without some fractions of pulmonary surfactant, as surfactant protein-A (SP-A) and phospholipids, on the adherence of the most common respiratory pathogens. Materials and Methods: The adherence of respiratory pathogens to a bronchial epithelial cell line was tested. Antimicrobials were used at 1/2, 1/4 and 1/8 minimum inhibitory concentration (MIC), SP-A at 1 and 5 μg/ml and phospholipids at 50 μg/ml. Results: At 1/2 MIC moxifloxacin, ciprofloxacin, amoxicillin-clavunalate and ceftriaxone reduced the adherence of Staphylococcus aureus and Streptococcus pneumoniae to values of 40-50%. At the same concentration, cotrimoxazole reduced the adherence values of Moraxella catarrhalis and Haemophilus influenzae to about 50%, while β-lactams showed high efficacy only on H. influenzae, with adherence values of about 40%. The addition of SP-A and/or phospholipids to the tested antibiotics had no effect on bacterial adherence. Conclusion: The non-interference of SP-A and/or phospholipids with the suppressive effect that some antibiotics exert on bacterial adherence could represent a favorable event during antibiotic therapy. Received: March 23, 2001·Revision accepted: May 10, 2002     

Efficacy and safety of IV/PO moxifloxacin and IV piperacillin/tazobactam followed by PO amoxicillin/clavulanic acid in the treatment of diabetic foot infections: results of the RELIEF study

Objective

The aim was to compare the efficacy and safety of two antibiotic regimens in patients with diabetic foot infections (DFIs).

Methods

Data of a subset of patients enrolled in the RELIEF trial with DFIs requiring surgery and antibiotics were evaluated retrospectively. DFI was diagnosed on the basis of the modified Wagner, University of Texas, and PEDIS classification systems. Patients were randomized to receive either intravenous/oral moxifloxacin (MXF, N = 110) 400 mg q.d. or intravenous piperacillin/tazobactam 4.0/0.5 g t.d.s. followed by oral amoxicillin/clavulanate 875/125 mg b.d. (PIP/TAZ–AMC, N = 96), for 7–21 days until the end of treatment (EOT). The primary endpoint was clinical cure rates in the per-protocol (PP) population at the test-of-cure visit (TOC, 14–28 days after EOT).

Results

There were no significant differences between the demographic characteristics of PP patients in either treatment group. At TOC, MXF and PIP/TAZ–AMC had similar efficacy in both the PP and intent-to-treat (ITT) populations: MXF: 76.4 % versus PIP/TAZ–AMC: 78.1 %; 95 % confidence interval (CI) ?14.5 %, 9.0 % in the PP population; MXF: 69.9 % versus PIP/TAZ–AMC: 69.1 %; 95 % CI ?12.4 %, 12.1 % in the ITT population. The overall bacteriological success rates were similar in both treatment groups (MXF: 71.7 % versus PIP/TAZ–AMC: 71.8 %; 95 % CI ?16.9 %, 10.7 %). A similar proportion of patients (ITT population) experienced any adverse events in both treatment groups (MXF: 30.9 % versus PIP/TAZ–AMC: 31.8 %, respectively). Death occurred in three MXF-treated patients and one PIP/TAZ–AMC-treated patient; these were unrelated to the study drugs.

Conclusion

Moxifloxacin has shown favorable safety and efficacy profiles in DFI patients and could be an alternative antibiotic therapy in the management of DFI. Clinical trial: NCT00402727.     

Hungarian Hospital Antibiotic Consumption at the Regional Level, 1996–2005

Abstract Background:   Regional variations in antibiotic consumption in outpatients have been reported previously, but nothing is as yet known about the regional distribution of antibiotic consumption in the hospital sector in Hungary. This study was designed to explore regional variations and investigate determinants of antibiotic consumption in hospital care in Hungary. Materials and Methods:   Regional distribution-based antibiotic sales data were obtained for a 10-year period (1996–2005) for the 20 Hungarian counties. Systemic antibacterial use (Anatomical Therapeutic Chemical code: J01) was expressed as the number of defined daily doses (DDD) per 100 patient-days. The multiple linear regression model was applied to investigate the determinants of regional differences in hospital antibiotic consumption. Independent variables related to health care access, utilization of hospital resources, doctors’ workload, type of hospital care provided, and patient’s characteristics and infections were considered as possible determinants, and data on these variables were obtained for 2 years (2004, 2005). We also tested the association between hospital and ambulatory care antibiotic consumption in Hungarian regions using the Pearson correlation test. Results:   For each year during the 1996–2005 study period, there were large and stable variations in total hospital antibiotic consumption (e.g., min–max₁₉₉₆: 16.0–28.2; min–max₂₀₀₅: 15.2–32.2 DDD per 100 patient-days) depending on the region. In the two developed models (Model 1 and Model 2), the number of reported infections accounted for 53% of the observed regional variations in hospital antibiotic consumption (Model 1), and the number of reported infections together with the case-mix index were responsible for 61% (Model 2) . Total antibiotic consumption in hospitals showed a positive correlation (R = 0.71, p = 0.002) with total antibiotic consumption in ambulatory care. Conclusion:   The case-mix index and the number of reported infections explained some of the observed regional variations. However, the moderate value of the models in explaining these regional variations suggest that determinants which could not be explored in this preliminary study may also contribute to regional differences. Future studies should aim at collecting data for each individual hospital as well as data on possible determinants for hospital antibiotic consumption.     

An Audit of Efficacy and Toxicity of Teicoplanin Versus Vancomycin in Febrile Neutropenia: Is the Different Toxicity Profile Clinically Relevant?

Abstract Background: Glycopeptides are often used for persistent fever in neutropenic patients. This study compares efficacy and toxicity of teicoplanin and vancomycin. Patients and Methods: Hundred consecutive neutropenic patients with hematological malignancies and persistent fever after 72 h of first-line antibiotic therapy (91% piperacillin/tazobactam) were treated with teicoplanin (800 mg on day 1, then 400 mg/day) + piperacillin/tazobactam + gentamicin from 08/96 to 09/00 (group T) or with vancomycin (2 g/day) + meropenem + levofloxacin from 10/00 to 04/02 (group V). Success was defervescence (≥ 7 days) in absence of any sign of continuing infection. Nephrotoxicity was monitored daily as increase in serum creatinine. Results: Fifty patients were analyzed in each group. Efficacy was evaluated in patients with piperacillin/tazobactam as first-line therapy only. Treatment was successful in 76% in group T (n = 42) and 59% in group V (n = 49), p = 0.118. Toxicity was evaluated in all patients. The median increase of creatinine was 11% (interquartile range 0%–30%) in group T and 17% (0%–74%) in group V, p = 0.062. In patients who received concomitant amphotericin B (given for 7 days and 6 days, respectively, p = 0.525), median creatinine increased from 0.9 mg/dl (0.8–1.1) to 1.2 mg/dl (0.9–1.5) in group T and from 0.9 mg/dl (0.8–1.08) to 1.55 mg/dl (1.33–2.23) in group V (p < 0.001). This led to a doubling of creatinine in 2/23 (9%) patients of group T and in 9/16 (56%) patients of group V (p = 0.003). A multivariate analysis revealed that concomitant use of amphotericin B (p < 0.001) and treatment with vancomycin (p = 0.002) were independently associated with nephrotoxicity. Conclusion: Teicoplanin and vancomycin were comparably effective in patients with neutropenia and persistent fever, but – if combined with amphotericin B – vancomycin was significantly more nephrotoxic than teicoplanin.     

Molecular forms of serum pancreatic stone protein in acute pancreatitis

Summary Conclusion: Elevation of serum pancreatic stone protein- (PSP) S₁ suggests activation of trypsinogen in the pancreas. This information would prompt the start of intensive treatment and may improve prognosis of acute pancreatitis (AP). Background: PSP exists in two molecular forms, PSP-S_2–5 and PSP-S₁. PSP-S₁ is produced by enzyme cleavage of PSP-S_2–5 by trypsin. Total serum PSP rose in AP, but little is known about its molecular forms. In this study, we characterized the molecular forms of serum PSP in AP. Methods: Sera were taken from 8 patients with severe acute pancreatitis (sAP) and from 11 patients with mild acute pancreatitis (mAP). Serum PSP was characterized by high-performance liquid chromatography (HPLC) followed by the specific enzyme immunoassay (EIA). Results: The total serum PSP in sAP was higher than in mAP, but the difference was not significant. The PSP-S₁ was detected in serum in all (7/7) patients in sAP and in 72% (8/11) of patients in mAP. Serum level of PSP-S₁ was significantly higher in sAP than that in mAP (p<0.05), and the cutoff value to distinguish the two groups was 30 ng/mL. Serum PSP-S₁ did not show significant correlation with total PSP, immunoreactive trypsin, or C-reactive protein.     

Moxifloxacin versus Standard Therapy in Patients with Pneumonia Hospitalized after Failure of Preclinical Anti-infective Treatment

Abstract The failure rate of primary empirical anti-infective treatment of community-acquired pneumonia is reported to range between 2 and 7%. These patients are subject to a greater risk of intensive medical treatment and a higher mortality rate than patients who respond to primary treatment. We investigated 63 patients in a “real life scenario” who were admitted to the hospital after failure of primary outpatient therapy for community-acquired pneumonia. Thirty-three patients received intravenous standard therapy (betalactam 14, macrolide 3, levofloxacin 6, doxycycline 1, combinations 9 patients) while 30 patients were treated with intravenous moxifloxacin. The oral antibiotic pretreatment that failed most frequently was clarithromycin (n = 25), followed by amoxicillin/clavulanic acid (n = 16), cefixime (n = 10), cefuroxime/axetil (n = 5), doxycycline (3), cefpodoxime, and ciprofloxacin (2 each). There were no differences between the two groups in respect of age, gender, numbers of patients in nursing homes, numbers of patients with different underlying diseases (chronic bronchitis, coronary heart disease, diabetes mellitus, smoking, etc.), severity of pneumonia at the time of admission, numbers of patients requiring intensive care, and lethality. The group that underwent standard therapy experienced failure of the empirical intra-hospital antibiotic therapy more often during therapy [10 (30%) patients vs 2 (6%) in the moxifloxacin group, p = 0.009] and clinical failure of treatment on day 28 after initiation of therapy [7 (21%) patients vs 2 (6%) in the moxifloxacin group, p = 0.003]. In cases of failure of empirical preclinical antibiotic treatment for community-acquired pneumonia, subsequent intrahospital treatment with moxifloxacin is more successful than standard therapy in our study reflecting a "real life scenario".     

In vitro activity of moxifloxacin and piperacillin/sulbactam against pathogens of acute cholangitis

AIM：To analyze the in vitro activity of moxifloxacin and piperacillin/sulbactam against pathogens isolated from patients with acute cholangitis. METHODS： In this prospective study a total of 65 patients with acute cholangitis due to biliary stone obstruction （n = 7）, benign biliary stricture （n = 16）, and malignant biliary stricture （n = 42） were investigated with regard to spectrum of bacterial infection and antibiotic resistance. Pathogens were isolated from bile cultures in all study patients. In 22 febrile patients, blood cultures were also obtained. In vitro activity of moxifloxacin and piperacillin/ sulbactam was determined by agar diffusion. RESULTS： Thirty-one out of 65 patients had positive bile and/or blood cultures. In 31 patients, 63 isolates with 17 different species were identified. The predominant strains were Enterococcus species （26/63）, Ecoli （13/63） and Klebsiella species （8/63）. A comparable in vitro activity of moxifloxacin and piperacillin/sulbactam was observed for E.coli and Klebsiella species. In contrast, Enterococcus species had higher resistances towards moxifloxacin. Overall bacteria showed antibiotic resistances in vitro of 34.9% for piperacillin/sulbactam and 36.5% for moxifioxacin.CONCLUSION： Enterococcus species, E.co/i and Klebsiella species were the most common bacteria isolated from bile and/or blood from patients with acute cholangitis. Overall, a mixed infection with several species was observed, and bacteria showed a comparable in vitro activity for piperacillin/sulbactam and moxifloxacin.     

Penetration of ampicillin and sulbactam into human epididymis and testis

Summary Urologic refertilization microsurgery such as vaso-vasostomy or vaso-epididy-mostomy benefits from perioperative antibiotic prophylaxis. The ability of ampicillin and sulbactam to penetrate sufficiently into mixed epididymis or testis tissue was investigated in nine patients (bodyweights ranged from 58 kg to 92 kg, mean 77.3 kg) undergoing orchiectomy for testicular cancer or advanced prostatic cancer. Each patient received a single infusion of 3 g ampicillin/sulbactam (ratio 2 : 1) preoperatively for antibiotic prophylaxis. The concentrations of both components were determined in serum and in epididymis/testis tissue samples taken 30 min to 65 min after infusion. Ampicillin was determined by bioassay and sulbactam was determined by gas chromatography/mass spectrometry. Mean tissue concentrations of ampicillin were 38.5±15.9 mg/kg. Mean tissue concentrations of sulbactam at the same time were 19.8±5.2 mg/kg. Comparison of the tissue/serum ratios for both agents showed no significant difference. These values indicate that both compounds achieve high concentrations in the scrotal organs. The concentrations exceed the MIC (minimal inhibitory concentration) values of important bacterial pathogens such asStaphylococcus aureus involved in postoperative wound infections. The combination of ampicillin and sulbactam may be effective for perioperative prophylaxis in reconstructive scrotal urologic surgery.

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Penetration von Ampicillin und Sulbactam in menschliches Nebenhoden- und Hodengewebe

Zusammenfassung Für urologische mikrochirurgische Refertilisationen wie die Vaso-Vasostomie oder die Vaso-Epididymostomie ist eine perioperative antibiotische Prophylaxe notwendig. Die Penetrationsfähigkeit in Nebenhoden- und Hodengewebe von Ampicillin und Sulbactam wurde bei neun Patienten (Körpergewicht 59 kg bis 92 kg, Mittel 77,3 kg) untersucht, die sich einer Orchiektomie aufgrund eines Hodenkarzinoms oder fortgeschrittenen Prostatakarzinoms unterziehen mußten. Die Konzentrationen beider Substanzen wurden im Serum und in Proben aus Nebenhoden/Hodengewebe, die 30 bis 65 Minuten nach einer einzelnen präoperativen Kurzinfusion von 3 g Ampicillin/Sulbactam im Verhältnis 2:1 gewonnen wurden, bestimmt. Ampicillin wurde mittels Bioassay und Sulbactam mittels Gaschromatographie/Massenspektrometrie bestimmt. Die mittlere Gewebekonzentration von Ampicillin betrug 38,5 ± 14,2 mg/kg. Die entsprechende mittlere Gewebekonzentration von Sulbactam betrug 19,8 ± 5,2 mg/kg. Ein Vergleich der Gewebe/Serum Quotienten für beide Substanzen ergab keine signifikanten Unterschiede. Die gemessenen Werte zeigen, daß beide Substanzen hohe Konzentrationen in den Skrotalorganen erreichen. Diese Konzentrationen übersteigen die MHK-Werte (minimalen Hemm-Konzentrationen) der bei postoperativen Wundinfektionen bedeutsamen Erreger. Die Kombination von Ampicillin und Sulbactam scheint für eine präoperative antibiotische Einzeldosisprophylaxe bei rekonstruktiven skrotalen Eingriffen gut geeignet.

     

Efficacy and safety of G-CSF mobilized granulocyte transfusions in four neutropenic children with sepsis and invasive fungal infection

Background: Bacterial and fungal infections are serious complications of cancer therapy. Especially during longstanding neutropenia, patients are at risk for life-threatening infections. The aim of this study was to assess the effect and safety of G-CSF mobilized granulocyte transfusions (GTX) in four neutropenic pediatric patients with sepsis. Patients and Methods: The patients were between 4.6–17.5 years old and their diagnoses included very severe aplastic anemia, non-Hodgkin's lymphoma (NHL) and acute myeloid leukemia. Before GTX, all patients had fever despite antibiotic and antimycotic therapy, neutropenia (absolute neutrophil count ANC < 500/μl), increasing C-reactive protein (CRP) values, hypotension requiring dopamine infusion and three patients needed supplemental oxygen. The granulocyte donors received G-CSF (Neupogen™, 5 μg/kg body weight) 12 h prior to granulocyte apheresis. Results: In total, 40 GTX were performed (range 2–28 per patient). The mean increase of the granulocyte count 1 h after GTX was 1,310/μl (range 200–2,950/μl). Within the period of GTX the CRP values decreased in all patients. During or 24 h after the last GTX, the hypotension resolved and supplemental oxygen was stopped. One GTX was discontinued because of oxygen desaturation. Conclusion: GTX were a safe therapeutic measure with beneficial effects on serious infections in neutropenic children. Received: September 25, 2001 · Revision accepted: March 13, 2002 L. Grigull (corresponding author)     

Mechanisms of resistance to methotrexate in childhood acute lymphoblastic leukemia: circumvention of thymidylate synthase inhibition

Purpose: In about 25% of patients suffering from acute lymphoblastic leukemia (ALL) treatment failures occur that are most likely due to development of resistance to methotrexate (MTX). Blasts from patients with ALL were evaluated for MTX uptake, formation of long-chain MTX polyglutamates (MTX-Glu₅₊₆), cytotoxicity and thymidylate synthase inhibition by MTX and compared to blasts from patients with acute myelogenous leukemia (AML). Methods: Radioactively labeled MTX-Glu _n were analyzed by means of HPLC. Thymidylate synthase activity was measured by a tritium-release assay. Cytotoxicity was determined by trypan blue exclusion. Results: In most ALL blasts (n = 9) large amounts of MTX-Glu₅₊₆ (1.06–7.03 pmol/10⁷cells) and high cytotoxicity (43.5%–92.7%) were found, while in others small amounts of MTX-Glu₅₊₆ (0.0–0.39 pmol/10⁷cells) caused only weak cytotoxicity (6.0%–27.9%) (n = 5, 2 relapsed patients). Resistance to MTX in blasts from AML patients (n = 5) was also caused by reduced synthesis of MTX-Glu₅₊₆ (0.0–0.42 pmol/10⁷cells). In contrast, some ALL blasts (n = 7, 4 relapsed patients) were able to survive MTX treatment despite large amounts of MTX-Glu₅₊₆ (1.5–5.05 pmol/10⁷cells) and extensive thymidylate synthase inhibition. Conclusions: Since the majority of ALL patients were examined at first diagnosis, an inherent mechanism of resistance seems most likely. We propose a mechanism based on the switch of thymidylate synthesis to the salvage pathway. Received: 30 October 1998 / Accepted: 6 April 1999     

Low Rate of Clinical Consequences Derived from Results of Blood Cultures Obtained in an Internal Medicine Emergency Department

Abstract Background: Blood cultures detect bacteremia in individual patients and help define local pathogen and resistance spectra. At the same time, the benefits of blood culture results in the management of individual patients – and therefore their cost–effectiveness – are disputed. Patients and Methods: During 1 calendar year, we conducted a prospective study of emergency department admissions with blood culture draws and at least a 3–day hospitalization afterwards. We prospectively surveyed treating physicians on usefulness of blood culture results for patient management. Results: 428 diagnostic episodes (emergency visits) involving 390 patients occurred during the study period from 10/2002 to 10/2003. The analysis included 188/428 (44%) episodes with blood culture draws performed according to the predefined clinical standard where patients were hospitalized with sufficient duration. Absence of therapeutic consequences in response to blood culture results was reported for 138/142 (97%) of episodes with negative blood culture results, for 16/21 (76%) with blood culture results positive only for skin flora, and for 14/25 (56%) of episodes with blood cultures positive for obligate pathogens. Treating physicians regarded the blood culture results necessary for clarifying the etiology in 34/188 (18%) episodes, and rated blood culture results necessary for their therapeutic decisions in 29/188 (15%) episodes. Conclusion: Negative blood culture results rarely changed the management of medical inpatients. Our study suggests that in settings with broad–spectrum empirical antibiotic therapy positive blood culture results for obligate pathogens trigger adjustment of the antibiotic therapy in only about half of instances. Many blood cultures drawn in the emergency department where considered unnecessary by ward physicians. Guidelines for preventing unnecessary blood culture draws are warranted in order to increase the rate of their meaningful clinical consequences for medical inpatients initially treated with broad–spectrum empirical antibiotics. This paper is dedicated to the founders of the Walter Marget Foundation, D. Adam and F. Daschner, in gratitude for their support of the training in infectious diseases.     

Risk Factors for Colonization with Third–Generation Cephalosporin–Resistant Enterobacteriaceae

Abstract Background and Method: Colonization and infections caused by Enterobacteriaceae resistant to third–generation cephalosporins (CRE) have been observed with increasing frequency in intensive care unit (ICU) patients. In contrast to outbreak investigations, information about risk factors for colonization in an endemic situation are rare. We studied risk factors for colonization with CRE in a case control study including 1,706 patients, admitted to any of the 15 ICUs of Heidelberg University Hospitals. Results: 163 patients carried CRE with Enterobacter spp. representing the predominant species. Independent risk factors for CRE carriage in the multivariate logistic regression analysis were an age of under 2.5 years (OR 4.034), an indwelling central venous catheter (CVC) for more than 3 days (OR 2.640), treatment with second– or thirdgeneration cephalosporin for longer than 3 days (OR 2.260) and any antibiotic therapy before admission to the ICU. Conclusion: Apart from the well–recognized risk factor previous antibiotic treatment, the risk factors age and presence of a CVC might suggest that bacterial overgrowth of the gut either due to an increased susceptibility in younger age or as a consequence of parenteral nutrition is a relevant mechanism for acquiring carriage of CRE in a non–outbreak situation. This paper is dedicated to the founders of the Walter Marget Foundation, D. Adam and F. Daschner, in gratitude for their support of the training in infectious diseases.     

Tolerability of moxifloxacin in patients with antibiotic hypersensitivity

BackgroundAllergic reactions to antibiotics are commonly reported in the clinical practice. The treatment of antibiotic hypersensitivity (AH) consists of suggesting to avoid the offending antibiotics and to use safe alternatives after performing oral provocation tests (OPT). Moxifloxacin is a new fluoroquinolone antibacterial agent with a broad spectrum activity. Allergic reactions to moxifloxacin have rarely been described and therefore it could be tolerated by antibiotic allergic subjects.ObjectivesThe aim of this survey was to investigate the tolerability of moxifloxacin in antibiotic intolerant patients.Materials and methodsA prospective study was conducted in 20 patients diagnosed with AH at our clinic between 1 January 2003 and 31 December 2003. We performed single blind, one day OPT protocol for moxifloxacin with a total dose of 1000 mg.ResultsThe mean age of the patients was 38.05 ± 14.1 and 17 (85 %) of them were females. There were only two patients with accompanying allergic diseases; one with bronchial asthma and the other with chronic urticaria. The rates of common anamnestic antibiotic hypersensitivities were 50% with amoxicillin, 40 % with penicillin, 20 % with sulphonamides, respectively. Urticaria (80 %) was the leading reaction appearing after antibiotic ingestion. Seventeen of 20 patients tolerated moxifloxacin at therapeutic doses without any problem. One patient experienced generalized urticaria 4 hours after ingestion of the first dose of the drug, which resolved spontaneously 5 hours after the onset. Another patient experienced tachycardia (heart rate did not exceed beyond 115 per minute) 2.5 hours after ingestion of first dose of the drug, which resolved spontaneously 2 hours after the onset. And a third one developed severe nausea lasting for two hours.ConclusionGiven the high incidence of hypersensitivity reactions to beta-lactam antibiotics the use of new fluoroquinolone, moxifloxacin might represent a therapeutic alternative.     

Chemotherapy in the treatment of recurrent glioblastoma multiforme: ifosfamide versus temozolomide

Purpose: Despite the progress made in neurosurgery and radiotherapy, the prognosis of glioblastoma multiforme (GB) is poor, due to the lack of an effective salvage therapy. In vitro analysis revealed activity for ifosfamide and temozolomide. The usefulness of these agents in recurrent disease was investigated. Methods: Six adult patients with recurrent GB received one to four courses of 1,500 mg/m² ifosfamide given over 5 days intravenously. Furthermore, temozolomide (100–200 mg/m²) was given orally over 5 days to 14 patients. Results: After ifosfamide treatment, one partial response and two cases of stable disease were observed. The median survival time was 24 weeks (range of 9–52 weeks). Toxicity analysis revealed one paranoid reaction, three grade III leukocytopenia, and one grade I–II nausea, anemia, and hematuria. Temozolomide therapy resulted in three partial responses and four cases of stable disease. The median survival time (Kaplan-Meier) was 21 weeks (range 4–64 weeks). The major toxicities were grade I–II nausea and hematological side effects (one case of grade IV leuko- and thrombocytopenia). Conclusions: Ifosfamide treatment might be a feasible approach, but it necessitates hospitalization. Temozolomide showed promising results. Due to its oral application, the patient's quality of life (time out of hospital) is favorable. Subgroups with improved survival were observed. Received: 7 December 1998 / Accepted: 21 January 1999     

Antibiotic Use in Non–University Regional Acute Care General Hospitals in Southwestern Germany, 2001–2002

Abstract 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 pharmacoepidemiologic evaluation and focused drug use control interventions. *Other members of the MABUSE-INTERREGIO-II project team were: S. Amann (München), Nina Schmid and Susanne Hofmann (Freiburg) This paper is dedicated to the founders of the Walter Marget Foundation, D. Adam and F. Daschner, in gratitude for their support of the training in infectious diseases.     

Antibiotic-Resistant Bloodstream Infections in Hospitalized Patients: Specific Risk Factors in a High–Risk Population?

Abstract Background: The aim of this study was to explore characteristics that are associated with bloodstream infections due to specific multiresistant microorganisms (methicillinresitant Staphylococcus aureus, MRSA; vancomycin–resistant enterococci, VRE; third–generation cephalosporin–resistant Enterobacteriaceae) or Candida spp. in hospitalized patients. Patients and Methods: All patients who experienced a bloodstream infection with one of the aforementioned pathogens between September 1999 and October 2001 were included into a statistical analysis of independent risk factors. The possible impact of previous antibiotic and antifungal therapies was evaluated. Results: Of the study population, 22% had two or more episodes with different pathogens. In the 314 patients with a single bloodstream infection MRSA was isolated in 189 patients, VRE in 31, Enterobacteriaceae in 13, and Candida spp. in 80 patients. Crude mortality was high in the study population (overall 40%) and varied between 33% (MRSA bacteremia only) and 58% (VRE bacteremia only). Patients who yielded more than one of the pathogens under surveillance had crude mortalities ranging from 41% to 83% (all four pathogens). In this group of high–risk patients, the following factors were independently associated with the individual pathogen: prior chemotherapy (OR 4.88 CI₉₅ 1.50–15.87) and bronchoscopy (OR 3.17 CI₉₅ 1.05–9.52) for VRE patients; burns (OR 4.50 CI₉₅ 0.90–22.73), presence of a tracheostomy (OR 4.22 CI₉₅ 1.15–15.38) and acute dialysis (OR 3.62 CI₉₅ 0.99–13.16) for patients with Enterobacteriaceae; and an underlying malignant disease (OR 1.98 CI95 0.99–3.97), performance of a bowel endoscopy (OR 2.80 CI₉₅ 1.27–6.13) and presence of a central venous catheter (CVC) (OR 12.34 CI₉₅ 1.63–90.91) for patients with candidemia. Conclusion: Patients with bacteremia due to VRE, Enterobacteriaceae or Candida spp. had more severe risk factors associated with the respective pathogen than patients with MRSA bacteremia. This paper is dedicated to the founders of the Walter Marget Foundation, D. Adam and F. Daschner, in gratitude for their support of the training in infectious diseases.     

Procalcitonin and C-Reactive Protein Levels in Community-Acquired Pneumonia: Correlation with Etiology and Prognosis

Summary Background: The diagnostic value of admission serum levels of procalcitonin (PCT) and C-reactive protein (CRP) as indicators of the etiology and prognosis was prospectively investigated. Patients: 96 patients, 50–85 years of age, treated in the hospital for community-acquired pneumonia (CAP). Results: On admission, all patients had elevated CRP levels (> 10 mg/l), but only 60 patients (54%) had elevated PCT levels (> 0.1 μg/l). The severity of disease measured by APACHE II score was strongly associated with admission levels of PCT (p = 0.006), but not with CRP. Eight of nine patients with pneumonia caused by atypical agents had PCT levels < 0.5 μg/l compared with 6/27 patients with pneumonia caused by classical bacterial pathogens, mainly Streptococcus pneumoniae (p = 0.03). No such correlation between CRP levels and etiology was found. Conclusion: Our data indicate that in patients admitted to the hospital with CAP, measurement of PCT gives information about the severity of the disease, and may aid the physician to differentiate typical bacterial etiology from atypical etiology, and thereby to choose appropriate initial antibiotic treatment. Received: June 7, 1999 · Revision accepted: January 17, 2000     

CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer

Purpose As risk-modifiers of alcohol and tobacco effects, metabolic genes polymorphisms were investigated as susceptibility candidates for squamous cell carcinoma of the head and neck (SCCHN). Methods A total of 210 cases and 245 hospital controls, age and gender matched, were genotyped for CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms. A measurement of the biological interaction among two risk factors was estimated by the attributable proportion (AP) due to interaction and its 95% confidence interval (CI). Results SCCHN risk was associated with high-levels of alcohol intake [OR = 3.50 (95%CI: 1.93–6.35) and OR = 6.47 (95%CI: 2.92–14.35) for 19–30 g/day and >30 g/day, respectively], cigarette smoking [OR = 3.47 (95%CI: 1.88–6.41) and OR = 7.65 (95%CI: 4.20–13.90) for 1–25 and >25 pack-years of smoking, respectively] and low-fruit and vegetables consumption (OR = 2.45; 95%CI: 1.53–3.92). No differences were observed for the genotypes or haplotypes distributions among cases and controls, and no biological interaction emerged from gene–gene and gene–environment interaction analyses. An attributable proportion (AP) due to biological interaction of 0.65 (95%CI: 0.40–0.90) was detected for heavy drinkers with a low intake of fruit and vegetables, and an AP of 0.40 (95%CI: 0.10–0.72) resulted forever smokers with low fruit and vegetables consumption. Conclusions Even in presence of high alcohol consumption or cigarette smoking, a high intake of fruit and vegetables might prevent the development of around one quarter of SCCHN cases. The lack of interaction between the studied polymorphisms and the environmental exposures suggests that chronic consumption of tobacco and alcohol overwhelm enzyme defences, irrespective of genotype.