A Pooled Analysis of Telithromycin in the Treatment of Community-Acquired Respiratory Tract Infections in Adults

Abstract. Background: Thirteen multinational, Phase III studies were conducted to establish the efficacy of telithromycin 800 mg once daily in the treatment of community-acquired respiratory tract infections (RTIs). Patients and Methods: Data were analyzed from 4,743 adult patients participating across four indications: community-acquired pneumonia (CAP) of mild to moderate severity, acute exacerbations of chronic bronchitis (AECB), acute maxillary sinusitis (AMS) and tonsillitis/pharyngitis. Results: Treatment with telithromycin for either 5 days (AECB, AMS and tonsillitis/pharyngitis) or 7–10 days (CAP and AMS) provided high rates of clinical and bacteriologic cure (5-day, 87.0% and 86.0%, respectively; 7 to 10-days, 90.3% and 90.5%, respectively) that were equivalent to those of a 10-day course of comparator antibacterials (86.5% and 86.5%, respectively). The clinical efficacy of telithromycin extended to high-risk CAP and AECB patients and to all key respiratory pathogens, including Streptococcus pneumoniae strains resistant to penicillin or erythromycin and atypical/intracellular pathogens. Telithromycin was generally well-tolerated across patient groups. Conclusion: These findings support the use of telithromycin as an effective therapy for the treatment of community-acquired RTIs.     

Telithromycin is as effective as amoxicillin/clavulanate in acute exacerbations of chronic bronchitis

This randomized, double-blind study evaluated the efficacy and safety of a short, 5-day course of telithromycin, a new ketolide antibacterial, compared with a standard 10-day course of amoxicillin/clavulanate, in the treatment of acute exacerbations of chronic bronchitis (AECB). The study enrolled 325 adult patients with AECB and a history of chronic obstructive pulmonary disease (COPD). Patients received either telithromycin 800 mg once daily (qd) for 5 days (followed by placebo for 5 days) or amoxicillin/clavulanate 500/125 mg three times daily (tid) for 10 days. Clinical cure rates for telithromycin post-therapy (Days 17-21, test-of-cure) and late post-therapy (Days 31-36) were 86.1 and 78.1%, respectively; 82.1 and 75.0% for amoxicillin/clavulanate. Excellent clinical cure rates were also observed for high-risk patients. Bacteriologic outcome was satisfactory for 69.2% of telithromycin recipients vs 70.0% for amoxicillin/clavulanate recipients. Both treatments were generally well tolerated, although the frequency of drug-related adverse events was almost two-fold higher for amoxicillin/clavulanate (25.0 vs. 13.1%). Thus, a 5-day course of telithromycin 800 mg qd is an effective and well-tolerated alternative to a standard 10-day course of amoxicillin/clavulanate 500/125 mg tid for first-line empiric treatment of AECB in adults with COPD.     

Clinical and bacteriologic efficacy of telithromycin in patients with bacteremic community-acquired pneumonia

This retrospective analysis was performed to determine the clinical and bacteriologic efficacy of the ketolide antibacterial telithromycin in patients with community-acquired pneumonia (CAP) with pneumococcal bacteremia. Patients 13 years old with radiologically confirmed CAP and a positive blood culture for Streptococcus pneumoniae at screening were analyzed from eight multicenter Phase III/IV clinical trials. In four open-label, non-comparative studies, patients received telithromycin 800 mg once daily for 7-10 days. In four randomized, controlled, double-blind, comparative studies, patients received telithromycin 800 mg once daily for 5-10 days or a comparator antimicrobial (amoxicillin 1000 mg three times daily, clarithromycin 500 mg twice daily, or trovafloxacin 200 mg once daily) for 7-10 days. In total, 118 patients (telithromycin, 94/1061 [8.9%]; comparator, 24/244 [9.8%]) had documented pneumococcal bacteremia. Those who were treated with telithromycin achieved a clinical cure rate of 90.2% (74/82, per-protocol population); S. pneumoniae was eradicated in 77/82 (93.9%) bacteremic patients who received telithromycin and 15/19 (78.9%) comparator-treated patients. Clinical cure was also observed among telithromycin-treated bacteremic patients who were infected with penicillin- or erythromycin-resistant strains of S. pneumoniae (5/7 and 8/10, respectively). In conclusion, telithromycin achieves high clinical and bacteriologic cure rates in CAP patients with pneumococcal bacteremia.     

Incidence of Surgical Site Infections in General Surgery in Italy

Abstract Background: Epidemiological study to determine surgical site infection (SSI) rates in surgical patients in Italy using the National Nosocomial Infections Surveillance system (NNIS), to monitor current surgical antimicrobial prophylaxis, and to identify possible modifiable risk factors for SSI. Materials and Methods: Thirty-two general surgeries participated in the study. Main criteria for site inclusion were: > 20 operations per week and amoxycillin/clavulanate among prophylactic options. Each patient operated from April 1st to May 30th 2002 was surveyed until 30 days after the operation. SSI cumulative incidence rates and 95% confidence intervals (95%CI) were calculated. Results: During the study period, 3,066 surgical procedures were performed in 2,972 patients. A total of 158 SSI were diagnosed in 154 patients: 96 (62.3%) were at superficial incision, 23 (14.9%) were at deep incision and 35 (22.7%) were at organ-space site. Incidence of SSI every 100 operations was 5.2% (95% CI 4.4–6.0). Of the 2,437 operated patients with clean or elective clean/contaminated or contaminated surgical procedure, 2,105 (86.4%) received antimicrobial prophylaxis, mainly amoxicillin/clavulanate (28.3%) and ceftizoxime (11.4%). Pre-operative hospital stay ≥ 48 h, diabetes, obesity, and HIV/AIDS infection were statistically significantly associated with increased risk of SSI. Conclusions: The SSI rates found are comparable with European studies and can be a benchmark for national incidence data and for inter- and intra-hospital SSI rate comparisons. The preliminary results of this study were presented at the 14th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) – May 1–4, 2004. Clin Microbiol Infect 2004; 10 (suppl 3): abstr P1521.     

Poor outcomes after fibrinolytic therapy for ST-segment elevation myocardial infarction: Impact of age (A Meta-Analysis of a Decade of Trials)

Background: Fibrinolysis for ST-segment elevation myocardial infarction (STEMI) reduces mortality, but its relative efficacy and risks are age-dependent. We aimed to quantify the outcomes of fibrinolysis and adjunctive antithrombin therapy for STEMI stratified by age. Methods: We performed a meta-analysis of 11 published (1992–2001) randomized clinical trials of fibrinolysis in STEMI (sample size ≥3000, no age limit, no placebo-controlled arms) identified by MEDLINE through June 2005. Event rates and odds ratios (OR) in elderly vs. younger patients were calculated for mortality, intracranial hemorrhage (ICH) and total stroke (CVA). Elderly patients were defined as ≥75 years (GUSTO I, TIMI 9B, GUSTO III, COBALT, ASSENT-2, InTIME-II TIMI-17, ASSENT-3, GUSTO V, and HERO-2), except when defined as >65 or ≥70 years by the study (INJECT and ISIS-3). Results: Elderly (n = 24 531) vs. younger (n = 123 568) patients had increased rates of mortality (19.7% vs. 5.5%), ICH (1.4% vs. 0.5%) and CVA (3.5 vs. 1.2%) by 30–35 days; the excess risk for these events was substantial (OR mortality 4.37, 95% CI 4.16–4.58; ICH 2.83, 2.47–3.24; CVA 2.92, 2.62–3.25; p < 0.001 for all). Conclusions: Despite established mortality reductions with fibrinolysis for STEMI, elderly compared with younger patients, still have a three to four fold increased risk of mortality and adverse events when treated with fibrinolysis and antithrombin therapy in the modern era. These robust estimates of the anticipated rates for mortality, ICH, and CVA can be used as benchmarks to monitor the efficacy and safety of therapies in ongoing and newly completed clinical trials. Abbreviated abstract We aimed to quantify the outcomes of death, intracranial hemorrhage (ICH), and total cerebrovascular accidents (CVA) in elderly compared with younger patients treated with fibrinolysis for STEMI based on a meta-analysis of 11 randomized clinical trials (1992–2001) of more than 3000 patients. Elderly (n = 24 531) vs. younger (n = 123 568) patients had increased rates of mortality, ICH and CVA by 30–35 days; the excess risk was substantial (OR 4.37, 2.83, and 2.92 respectively, p < 0.001 for all). These robust estimates can be used as benchmarks to monitor the efficacy and safety of therapies in ongoing and newly completed clinical trials.     

Successful mobilization of peripheral blood stem cells in heavily pretreated myeloma patients with G-CSF alone

 We investigated the feasibility of mobilizing peripheral blood stem cells (PBSC) with G-CSF alone in 24 patients with multiple myeloma. The median age was 53 years (range 33–62). All patients had stage II/III disease and responded to standard first-line (n=6) or salvage chemotherapy (n=18). The median number of previous chemotherapy cycles was 7 (4–18) and the median number of prior melphalan-cycles was 6 (0–14). Nine (35%) patients had experienced prior radiation therapy. The patients received either 10 μg/kg G-CSF (n=18) or 24 μg/kg G-CSF (n=7, including one patient with previous 10 μg/kg G-CSF stimulation) daily s.c. for 5 or more consecutive days until completion of harvesting, starting apheresis on the fifth day. G-CSF treatment was well tolerated, with only slight bone pain in half of the patients (51%). After a median of three (range 1–7) apheresis procedures, medians of 3.8 (0.3–17)×10⁶ CD34+ cells/kg, 8.5 (4.5–24)×10⁸ MNC/kg, 2.9 (0.6–39.4)×10⁴ CFU-GM/kg, and 5.6 (0.9–49)×10⁴ BFU-E/kg were harvested. Three patients (12%) with extensive melphalan pretreatment failed the target collection of at least 2.0×10⁶ CD34+ cell/kg. Pretreatment with six or more cycles of melphalan yielded a smaller number of CD34+ cells than pretreatment with fewer than six cycles (2.5 vs 5.3×10⁶/kg;p=0.001). Nineteen patients underwent high-dose chemotherapy consisting of either total marrow irradiation (9 Gy)/busulfan (12 mg/kg) and cyclophosphamide (120 mg/kg) (n=10), or busulfan (14 mg/kg)/cyclophosphamide (120 mg/kg) (n=5), or tandem melphalan (200 mg/m²). The median time for granulocyte (>1.0/nl) and platelet (>50/nl) recovery was 10 and 14 days (ranges 7–12 and 8–40), respectively. G-CSF alone is a safe, alternative approach to mobilizing sufficient PBSC in patients with multiple myeloma and allows an exact prediction of harvest time. G-CSF-mobilized PBSCs ensure rapid engraftment after myeloablative therapy. Melphalan treatment should be avoided in patients who are candidates for high-dose chemotherapy. Received: February 5, 1998 / Accepted: April 14, 1998     

Successful autologous bone marrow rescue in patients who failed peripheral blood stem cell mobilization

 We assessed autologous bone marrow (BM) harvest and hematologic recovery after high-dose chemotherapy (HDCT) in patients who failed to achieve peripheral blood stem cell (PBSC) mobilization. One hundred and ninety-three patients with germ cell tumor, malignant lymphoma, sarcoma or medulloblastoma were scheduled for HDCT. In 123 patients, PBSC were mobilized by disease-specific chemotherapy plus granulocyte colony-stimulating factor (G-CSF). In 110/123 patients (89%) with circulating CD34+ cell counts ≥10/μl, sufficient hematopoietic autografts were collected (group A). In 13/123 patients (11%) with peripheral CD34+ cell counts <10/μl, PBSC harvesting was not performed (group B). These latter patients were classified as "poor mobilizers" and underwent second-line BM harvest at a median of 46 (range 10–99) days after mobilization failure. Seventy patients with first-line BM harvest (group C) acted as historical controls. Ten patients from group B proceeded to HDCT and nine were evaluable for hematopoietic reconstitution. Recovery to neutrophils >0.5×10⁹/l was comparable with group C patients: 16 (range 9–34) days vs 13 (range 8–98) days. However, platelet (PLT) reconstitution >20×10⁹/l was significantly slower, with a median of 35 (range 13–50) days as compared with 19 (range 9–148) days (P=0.0106) for control patients. Supportive care requirements, febrile days and length of hospital stay were not significantly different between the two groups of patients. We conclude that patients who fail to mobilize PBSC should be evaluated for second-line BM harvest. This approach may preserve the therapeutic option of HDCT for these patients. Received: 7 March 2000 / Accepted: 4 May 2000     

Two Different Patterns of Mutations are Involved in the Genotypic Resistance Score for Atazanavir Boosted Versus Unboosted by Ritonavir in Multiple Failing Patients

Abstract Objectives:   The protease inhibitor atazanavir (ATV) can be used either boosted by ritonavir (ATV300/r) or unboosted (ATV400). To date, however, genotypic resistance scores (GRSs) have been developed only for boosted-ATV. We have determined GRS associated with virologic response (VR) for both ATV300/r and ATV400 in highly pre-treated HIV-1 infected patients. Patients and Methods:   We analyzed the results of genotypic tests available 0–3 months before the initiation of an ATV-containing regimen in 159 patients with HIV-RNA ≥ 500 copies/ml (ATV300/r group: 74; ATV400 group: 85) who were enrolled in the CARe study through an Early Access Program. The impact of baseline protease mutations on VR (≥ 1 log₁₀copies/ml HIV-RNA decrease at 12–24 weeks) was analyzed using Fisher’s exact test. Mutated protease amino acid positions (MPP) with p < 0.20 were retained for further analysis. The GRSs were determined by a step-by-step analysis using the χ² test for trend. Results:   The GRSs for ATV300/r and ATV400 revealed differing sets of mutations. For ATV300/r, 12 MPPs (10C/I/V + 32I + 34Q + 46I/L + 53L + 54A/M/V + 82A/F/I/T + 84V + 90M – 15E/G/L/V – 69K/M/N/Q/R/T/Y – 72M/ T/V; p = 1.38 × 10^–9) were the most strongly associated with VR (VR: 100%, 78.3%, 83.3%, 75% and 0% of patients with a score of –2/–1, 0, 1, 2, and ≥ 3, respectively); the last three MPPs (I15/H69/I72) were associated with a better VR. For ATV400, nine MPPs (16E + 20I/M/R/T/V + 32I + 33F/I/V + 53L/Y + 64L/M/ V + 71I/T/V + 85V + 93L/M; p = 9.42 × 10^–8) were most strongly associated with VR (VR: 83.3%, 66.7%, 5.9%, 0% of patients with 0, 1/2, 3, and ≥ 4 MPP, respectively). Differences between GRSs for ATV300/r and ATV400 may be due to different ATV drug levels (boosted vs unboosted), favoring different pathways of escape from antiviral pressure. Conclusions:   Both GRSs were independent predictors of response in a multivariable logistic regression model. Nevertheless, cross-validation of these GRSs on different patient databases is required before their implementation in clinical practice. This work was presented in part at the 15th International HIV Drug Resistance Workshop, Sitges, Spain, 13–16 June 2006 (Abstract 89).     

High-dose chemotherapy with peripheral blood stem cell transplantation for patients with advanced ovarian cancer

Purpose: We report the results of high-dose chemotherapy (HDC) with peripheral blood stem cell transplantation in twenty-one patients with primarily advanced or relapsed ovarian cancer. Methods: Twenty-five women underwent stem cell collection, and 21 were finally treated with different regimens of HDC containing cyclophosphamide, etoposide, carboplatin, and treosulfan. The patients received cyclophosphamide ± cisplatin and cisplatin + paclitaxel, respectively, followed by G-CSF (n=24) or GM-CSF (n=1) for stem cell mobilization. Results: A mean of 7.2 ± 6.1 × 10⁶ CD34+ cells per kg bw were collected. Thirteen patients received double transplants and one patient received a triple transplant. The median age was 47 years (range 24–61 years) and the mean number of prior regimens was three (range 1–8). Engraftment occurred on time in all patients and there was one treatment-related death resulting in an overall mortality rate of 4.8% among the 21 patients treated with HDC. The response rate was 72% (48% CR, 24% PR) and the mean time to progression and overall survival after HDC were 7 and 32 months, respectively. Conclusion: HDC could be performed safely in patients with advanced ovarian cancer. However, even with a high response rate, the duration of response is short, warranting new treatment approaches to further improve the outcome of this population of patients with unfavorable prognosis. Received: 19 July 2000 / Accepted: 25 August 2000     

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.     

Salvage chemotherapy with mitoxantrone, fludarabine, cytarabine, and cisplatin (MIFAP) in relapsing and refractory lymphoma

Purpose: The aim of the study was to evaluate the feasibility and efficacy of the combination of mitoxantrone, fludarabine, cytarabine, and cisplatin (MIFAP) in patients with prognostically unfavorable recurrent and refractory Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Methods: Forty-six patients (median age 43 years, range 18–63) with relapsed (n=15) or refractory (n=31) malignant lymphoma were enrolled (HD, n=13; low-grade/transformed NHL, n=4; high-grade NHL, n=29). A total of 39 patients (85%) showed multiply relapsed diseases with a duration of prior remission of <12 months (n=8) or had lymphoma being resistant to prior chemotherapy (n=31). The MIFAP therapy consisted of fludarabine (15 mg/m², q. 12 h, day 1–4), cytarabine (50 mg/m² by continuous infusion (CI) over 22 h, day 1–4), cisplatin (25 or 30 mg/m² by CI over 24 h, day 1–4), and mitoxantrone (4 mg/m², day 2–5). Results: Thirteen patients (28%) achieved complete remission (CR) and 15 patients (33%) partial remission (PR), for an overall response (OR) rate of 61%. Twenty-two patients responding to MIFAP (10 CR, 12 PR) have been consolidated by high-dose therapy (HDT) with hematopoietic stem cell transplantation (SCT). After a median follow-up of 12 months, 16 patients are in continuous CR (CCR) (n=14) or CCRu (unconfirmed) (n=2). The median duration of event-free survival (EFS) and overall survival (OS) were 6.5 and 19.3 months, respectively. Probabilities of EFS and OS after 3 years were 19% and 40%. Responders consolidated by subsequent HDT showed rates for 3-year EFS and OS of 40% and 66%, respectively. Unfavorable prognostic factors for EFS by univariate analysis were refractory lymphoma and the presence of B-symptoms. Significant prognostic factors for OS were NHL, refractory lymphoma, B-symptoms, and bone marrow involvement. The major toxicities were leukocytopenia and thrombocytopenia of the World Health Organization (WHO) grade IV in nearly all courses (median duration 10 and 11 days). In contrast, non-hematological side effects were moderate, predominantly of WHO grades I and II. Treatment-related mortality with MIFAP was 4% (two patients with septicemia by Aspergillus fumigatus). Conclusions: MIFAP is an effective salvage protocol for patients with poor-risk recurrent or refractory HD and NHL. The observed toxicity seems to be acceptable considering the unfavorable prognosis and intensive pretreatment. The results in patients responding to MIFAP and afterwards undergoing HDT with autologous stem cell support are even comparable to those published in patients with prognostically more favorable diseases. Received: 12 October 2000 / Accepted: 8 November 2000     

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     

Risk Factors of Nosocomial Infection with Extended-Spectrum Beta-Lactamase-Producing Bacteria in a Neonatal Intensive Care Unit in China

Abstract Background: To study risk factors of neonatal nosocomial infection caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria in a neonatal intensive care unit (NICU). Patients and Methods: A retrospective cohort study was conducted in a university hospital NICU in south China. Medical records of neonatal nosocomial infection caused by Escherichia coli or Klebsiella pneumoniae were reviewed. Twenty-two neonates infected with ESBL-producing bacteria (case patients) were compared with 17 patients infected with non-ESBL producing strains (controls). Univariable and multivariable logistic regression were performed to analyze risk factors for infection with ESBL-producing strains. The spectrum of antimicrobial resistance of ESBL-positive E. coli or K. pneumoniae was also examined. Results: Both univariable and multivariable logistic regression analysis revealed that preterm low birth weight, prolonged mechanical ventilation (≥ 7 days) and prior use of third-generation cephalosporins were risks factors for ESBL-producing E. coli or K. pneumoniae infection (p < 0.05), with an odd ratio of 6.43 (95% CI: 1.51–27.44; p = 0.017), 7.50 (95% CI: 1.38–40.88; p = 0.017) and 9.00 (95% CI: 1.65–49.14; p = 0.008) respectively. However, the length of hospital stay before isolation of pathogens, endotracheal intubation, presence of a central venous catheter, days on third-generation cephalosporins and prior use of beta-lactamase inhibitors were not statistically significant (p > 0.05). Resistance of ESBL-positive strains to piperacillin, tobramycin, aztreonam and cephalosporins was significantly higher than that of ESBL-negative ones (p < 0.05). ESBL-producing strains appeared susceptible to carbapenem, fluoroquinolones, and beta-lactamase inhibitor combination piperacillin-tazobactam. Conclusions: Preterm low birth weight, prolonged mechanical ventilation and prior use of third-generation cephalosporins are risks factors for nosocomial infection with ESBL-producing bacteria in NICU.     

A new quadruple therapy for the eradication of Helicobacter pylori. Effect of pretreatment with omeprazole on the cure rate

To elucidate whether pretreatment with omeprazole decreases the cure rate of Helicobacter pylori infection with a new quadruple therapy, and thus, whether this pretreatment should not be used in clinical practice, we conducted a randomized trial. Ninety patients with chronic peptic ulcer disease and nonulcer dyspepsia, with biopsy-proven H. pylori infection were randomly assigned to the two following regimens: Group 1 (n = 45) received omeprazole 20 mg once daily for 2 weeks (days 1–14), and 500 mg amoxicillin granules and 250 mg metronidazole thrice daily, and roxithromycin 150 mg twice daily for 1 week (days 8–14), Group 2 (n = 45) received the same antibiotic treatment as group 1 for 1 week (days 1–7), in addition to omeprazole treatment for 2 weeks (days 1–14). Four weeks after the treatment ended, endoscopy was repeated, with two biopsy specimens each taken from the antrum and the corpus (total of four specimens) for a urease test, histological analysis, and culture to establish cure of infection. A patient was regarded as cured only if all three methods gave negative results for H. pylori. In the intention-to-treat analysis, 42 of 45 patients (93.3%; 95% confidence intervals [CI], 81.7%–98.6%) in group 1 were cured compared with 43 of 45 patients (95.6%; 95% CI, 84.9%–99.5%) in group 2. In the per-protocol analysis, the corresponding figures were 42/44 (95.5%; 95% CI 84.5%–99.4%) and 43/44 (97.7%; 95% CI, 88.0%–99.9%). There were no significant differences in the cure rate between the two groups on either analysis. All patients, except for one who had an allergic reaction, completed the treatment regimens. Fifty to sixty percent of the patients had no side effects while the rest had mild to moderate side effects. The new quadruple therapy consisting of omeprazole, amoxicillin, metronidazole, and roxithromycin appears suitable for use in clinical practice, as the cure rate was 95% and no severe side effects were observed. Pretreatment with omeprazole did not reduce the cure rate for this new quadruple therapy. (Received Sept. 29, 1997; accepted Jan. 23, 1998)     

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     

Prevalence of Septic Events, Type 1 Hepatorenal Syndrome, and Mortality in Severe Alcoholic Hepatitis and Utility of Discriminant Function and MELD Score in Predicting These Adverse Events

We sought to assess prevalence, and utility of discriminant function (DF) and MELD score in predicting septic events (SE), type 1 hepatorenal syndrome (HRS), and short-term mortality in severe alcoholic hepatitis (AH). Charts of patients with AH (group 1) and cirrhosis without AH (group 2) were retrospectively reviewed. Severe AH, discriminant function (DF) ≥ 32 was treated with pentoxifylline. One hundred ninety-five patients were enrolled in the study and divided into 2 groups: group 1, n=99, and group 2, n=96. Of those with AH, 82% had a DF ≥ 32 at presentation. Group 1 patients had a higher prevalence of SE (38% versus 25%, P=.04), type 1 HRS (30% versus 9%, P=.0003), and short-term mortality (28% versus 7%, P=.0001). In patients with AH, a MELD score ≥20 (but not a DF ≥ 32) at presentation was an independent predictor of a SE (odds ratio [OR] 2.8 [1.0–7.9], P=.04), HRS (OR 4.0, 95% confidence interval [CI] 1.0–16.6, P=0.05), and short-term mortality (OR 6.4, 95% CI 1.1–37.6, P=.03). Kaplan-Meier survival curves confirmed that that a MELD ≥ 20 but not a DF ≥ 32 was associated with a poorer survival (P = .005 and .5, respectively). In conclusion, patients with severe AH have higher prevalence of SE, HRS, and short-term mortality compared to those with cirrhosis without AH. A MELD score ≥20 at presentation is an independent predictor of these adverse events in patients with AH who have been treated with pentoxifylline.     

Markers of renal tubular dysfunction measured annually do not predict risk of microalbuminuria in the first few years after diagnosis of Type I diabetes

Aims/hypothesis. Early detection of risk of microalbuminuria could prevent early renal damage. We investigated whether urine retinol binding protein and N-acetyl-glucosaminidase could predict the risk of microalbuminuria in a large cohort of children followed from diagnosis of Type I (insulin-dependent) diabetes mellitus. Methods. Subjects under 16 years of age within a georaphically defined region were recruited at diagnosis of Type I (insulin-dependent) diabetes mellitus. Annually, albumin-, retinol binding protein- and N-acetyl-glucosaminidase- to creatinine ratios were each measured in 3 urine samples. Results. A total of 511 subjects were followed for a median of 6 years (range: 1–14). Microalbuminuria (males: ≥ 3.5 mg/mmol; females: ≥ 4.0 mg/mmol, in 2 out of 3 urines) developed in 78 subjects (36 male). The cumulative probability of microalbuminuria was 40 % after 12 years duration of diabetes. Retinol-binding-proteinuria (men: ≥ 21 μg/mmol; women ≥ 33 μg/mmol) developed in 217 subjects (152 men). The cumulative probability of retinol-binding-proteinuria was 67 % after 12 years duration of diabetes. The cumulative probability of retinol-binding-proteinuria was 40 % before the onset of microalbuminuria and 59 % in subjects who did not subsequently develop microalbuminuria. Retinol-binding-proteinuria developed at a higher rate with increasing HbA_{1 c} than microalbuminuria. N-acetyl-glucosaminidase-uria (males: ≥ 56 μmol-pnp · h^–1· mmol^–1; females: ≥ 46 μmol-pnp · h^–1· mmol^–1) developed in 477 subjects. The cumulative probability of N-acetyl-glucosaminidase-uria was 98 % after 10 years of diabetes duration. The cumulative probability of N-acetyl-glucosaminidase-uria was 73 % in the years before the onset of microalbuminuria and 97 % in subjects without microalbuminuria. The probability of N-acetyl-glucosaminidase-uria was 99 % with an HbA_{1 c} greater than or equal to 14.5 %. Conclusions/interpretation. Raised amounts of urine retinol binding protein and N-acetyl-glycosaminidase are related to HbA_{1 c} and the duration of diabetes. They occur in the majority of subjects and are not early markers for the risk of microalbuminuria. [Diabetologia (2001) 44: 224–229] Received: 25 July 2000 and in revised form: 29 September 2000     

Revisiting the oral glucose tolerance test criterion for the diagnosis of diabetes

OBJECTIVE: The Expert Committee on the Diagnosis and Classification of Diabetes retained the 2-hour glucose concentration on an oral glucose tolerance test of ≥11.1 mmol/L (200 mg/dL) as a criterion to diagnose diabetes. Since glycated hemoglobin levels have emerged as the best measure of long-term glycemia and an important predictor of microvascular and neuropathic complications, we evaluated the distribution of hemoglobin A1C (Hb A1C) levels in individuals who had undergone an oral glucose tolerance test to determine how well 2-hour values could identify those with normal versus increased Hb A1C levels. DESIGN: A cross-sectional analysis of 2 large data sets was performed. We cross-tabulated 2-hour glucose concentrations on an oral glucose tolerance test separated into 4 intervals (<7.8 mmol/L [140 mg/dL], 7.8–11.0 mmol/L [140–199 mg/dL], 11.1–13.3 mmol/L [200–239 mg/dL], and ≥13.3 mmol/L [240 mg/dL]) with Hb A1C levels separated into 3 intervals (normal; <1% above the upper limit of normal; and greater than or equal to the upper limit of normal +1%). RESULTS: Approximately two thirds of patients in both data sets with 2-hour glucose concentrations of 11.1 to 13.3 mmol/L (200–239 mg/dL) had normal Hb A1C levels. In contrast, 60% to 80% of patients in both data sets with 2-hour glucose concentrations ≥13.3 mmol/L (240 mg/dL) had elevated Hb A1C levels. CONCLUSION: Since Hb A1C levels are the best measures presently available that reflect long-term glycemia, we conclude that the 2-hour glucose concentration criterion on an oral glucose tolerance test for the diagnosis of diabetes should be raised from ≥11.1 mmol/L (200 mg/dL) to ≥13.3 mmol/L (240 mg/dL) to remain faithful to the concept that diagnostic concentrations of glucose should predict the subsequent development of specific diabetic complications (e.g., retinopathy). Presented at the American Diabetes Association meeting, San Diego, Calif, June 1999.     

A phase II trial of dose-intensive interleukin-2 in metastatic renal cell carcinoma

Purpose: High-dose bolus interleukin-2 (IL-2) is currently the sole agent approved by the Food and Drug Administration for the treatment of advanced renal cell carcinoma. This phase II study was designed to evaluate the clinical activity and toxicity spectrum of a regime consisting of dose-intensive IL-2 in both previously treated and untreated patients with advanced renal cell carcinoma. Patients and methods: Twenty eligible, sequential patients received IL-2 at a dose of 24 mIU m⁻²dose⁻¹ (1.33 mg m⁻²dose⁻¹) every 8 h on days 1–5 and 15–19, for a maximum of 28 boluses. Patients achieving stable disease or a response were treated every 10 weeks for a maximum of five cycles/year. Results: Out of 20 study participants 8 patients (40%; 95% confidence interval, 18.5%–61.4%) demonstrated a response. Three of these responses were complete (CR; 15%) while 5 were partial (PR; 25%) and about 75% of the responses occurred in patients with extensive tumor burdens. All 3 CR continue to respond after 28+ to 30+ months. With a median follow-up time of 26 months, the median overall survival duration for all patients is 18.0 months (95% confidence interval 12–24 months). Response was observed to correlate significantly with the IL-2 dose intensity. A dose intensity below 1440 mIU m⁻² year⁻¹ and at least 1440 mIU m⁻²year⁻¹ correlated highly with failure to achieve CR and the successful achieving of CR respectively (P < 0.01). An analysis of the present study database in the context of five previous similar trials demonstrated a significant correlation between IL-2 dose intensity and response rate by regression analysis (r ² = 0.89; P < 0.019). Finally, all toxicities were reversible once the dosing had concluded. Conclusions: IL-2 dose intensity appears to represent a significant determinant of successful clinical outcomes. This dose-intensive approach led to a high proportion of durable responses. Further evaluation of this regimen is warranted. Received: 25 September 1998 / Accepted: 13 November 1998