Effectiveness of cloxacillin with and without gentamicin in short-term therapy for right-sided Staphylococcus aureus endocarditis. A randomized, controlled trial

BACKGROUND: It is often difficult to administer extended antibiotic therapy in the hospital for right-sided Staphylococcus aureus endocarditis. Although the effectiveness of single-drug therapy given for 4 to 6 weeks and that of two-drug therapy given for 2 weeks have been shown, no data are available on the effectiveness of short-course single-drug therapy. OBJECTIVE: To compare the efficacy of cloxacillin alone with that of cloxacillin plus gentamicin for the 2-week treatment of right-sided S. aureus endocarditis in intravenous drug users. DESIGN: Open, randomized study. SETTING: An academic tertiary care hospital in Barcelona, Spain. PATIENTS: 90 consecutive intravenous drug users who had isolated tricuspid valve endocarditis caused by methicillin-susceptible S. aureus, had no allergy to study medications, and had no systemic infectious complications that required prolonged therapy. An efficacy subset consisted of 74 of these patients who did not meet an exclusion criterion. INTERVENTION: Cloxacillin (2 g intravenously every 4 hours for 14 days) alone or combined with gentamicin (1 mg/kg of body weight intravenously every 8 hours for 7 days). MEASUREMENTS: Clinical or microbiological evidence of active infection after 2 weeks of therapy, relapse of staphylococcal infection, or death. RESULTS: In an analysis of the efficacy subset, treatment was successful in 34 of the 38 patients who received cloxacillin alone (89% [95% CI, 75% to 97%]) and 31 of the 36 patients who received cloxacillin plus gentamicin (86% [CI, 71% to 95%]). Three patients died: one in the cloxacillin group and two in the combination therapy group. Of the 37 patients who completed 2-week treatment with cloxacillin, 34 (92%) were cured, and 3 (8%) needed prolonged treatment to cure the infection. Of the 34 patients who completed 2-week treatment with cloxacillin plus gentamicin, 32 (94%) were cured and 2 (6%) required treatment for 4 weeks. One patient in the combination group had relapse. CONCLUSIONS: A penicillinase-resistant penicillin used as single-agent therapy for 2 weeks was effective for most patients with isolated tricuspid endocarditis caused by methicillin-susceptible S. aureus. Adding gentamicin did not appear to provide any therapeutic advantages. Additional studies to confirm the therapeutic equivalence of short-course therapy with penicillinase-resistant penicillin alone and therapy with combined regimens are warranted.     

Epidermal cell DNA content and intermediate filaments keratin 10 and vimentin after treatment of psoriasis with calcipotriol cream once daily, twice daily and in combination with clobetasone 17-butyrate cream or betamethasone 17-valerate cream: a comparative flow cytometric study

Calcipotriol and corticosteroids, two therapy modalities frequently prescribed in the treatment of psoriasis, are often used in combination. The aim of the present study was to determine whether the cell biological response pattern of concurrent use of calcipotriol and corticosteroids is different from calcipotriol monotherapy. Forty patients with chronic plaque psoriasis were divided at random in four parallel groups and treated for 8 weeks with: (1) calcipotriol cream (50 micrograms/g once daily); (2) calcipotriol cream twice daily; (3) calcipotriol and clobetasone 17-butyrate (0.5 mg/g) creams; and (4) calcipotriol and betamethasone 17-valerate (1 mg/g) creams. Before and after treatment keratotome biopsies were taken and single cell suspensions prepared for flow cytometric analysis. Flow cytometric multiparameter quantification of markers for proliferation (TO-PRO-3), differentiation (antikeratin 10) and inflammation (antivimentin) was used to evaluate all four therapy modalities. A statistically significant decrease of the percentage of basal cells in S- and G2M-phase (proliferation) was obtained with all therapy modalities, except for calcipotriol monotherapy applied once daily. A significant reduction of the number of vimentin-positive cells (non-keratinocytes) was observed following combined treatment with calcipotriol and clobetasone butyrate. In contrast, monotherapy with calcipotriol had virtually no effect on the number of vimentin-positive cells. It can be concluded that: (i) calcipotriol monotherapy, applied once daily was less antiproliferative compared with twice daily applications of calcipotriol or the combined treatment with corticosteroids and that (ii) the combination of calcipotriol and corticosteroids proved to have a marked effect on the percentage of non-keratinocytes, in contrast to the modest effect of calcipotriol.     

Meropenem versus cefuroxime plus gentamicin for treatment of serious infections in elderly patients

In this multicenter study, the efficacy of and tolerability for meropenem were compared with those for the combination of cefuroxime-gentamicin (+/- metronidazole) for the treatment of serious bacterial infections in patients > or = 65 years of age. A total of 79 patients were randomized; thirty-nine received meropenem (1 g/8 h), and 40 received cefuroxime (1.5 g/8 h) plus gentamicin (4 mg/kg of body weight daily) for 5 to 10 days. Metronidazole (500 mg/6 h) could be added to the cefuroxime-gentamicin regimen for the treatment of intra-abdominal infections (n = 10). Seventy patients were evaluable for clinical efficacy; the primary diagnoses were as follows: pneumonia in 41 patients (20 treated with meropenem, 21 treated with cefuroxime-gentamicin), intra-abdominal infection in 10 patients (7 meropenem, 3 cefuroxime-gentamicin-metronidazole), urinary tract infection (UTI) in 11 patients (6 meropenem, 5 cefuroxime-gentamicin), sepsis syndrome in 7 patients (4 meropenem, 3 cefuroxime-gentamicin), and "other" in 1 patient (cefuroxime-gentamicin). The pathogens isolated from 18 patients with bacteremia were as follows: Staphylococcus spp. (n = 2), Streptococcus spp. (n = 2), members of the family Enterobacteriaceae (n = 11), and Bacteroides spp. (n = 3). A satisfactory clinical response at the end of therapy was achieved in 26 of 37 (70%) and 24 of 33 (73%) evaluable patients treated with meropenem and combination therapy, respectively. Clinical success was achieved in 23 of 31 (74%) and 21 of 28 (75%) evaluable patients with infections other than UTIs, respectively. A satisfactory microbiological response occurred in 15 of 22 (68%) patients in the meropenem group compared with 12 of 19 (63%) treated with combination therapy. Renal failure occurred during therapy in 2 of 39 (5%) meropenem recipients compared with 5 of 40 (13%) of those treated with combination therapy. The findings in this small study indicate that meropenem is as efficacious for and as well tolerated by elderly patients as the combination of cefuroxime-gentamicin (+/- metronidazole).     

Treatment of experimental endocarditis due to Enterococcus faecalis using once-daily dosing regimen of gentamicin plus simulated profiles of ampicillin in human serum

We compared the efficacy of ampicillin, both alone and in combination with gentamicin given once a day (q.d.) or three times a day (t.i.d.), in the treatment of experimental enterococcal endocarditis. Ampicillin was administered by using humanlike pharmacokinetics that simulated the profiles of this drug in human serum. An open one-compartment mathematical model developed in this study was used to estimate the decreasing doses administered with a computer-controlled infusion pump that simulated in rabbits the human serum pharmacokinetics after intravenous administration of 2 g of ampicillin every 4 h. Animals with catheter-induced endocarditis were infected intravenously with 10(8) CFU of Enterococcus faecalis J4 (MICs and MBCs of ampicillin and gentamicin, 2 and 128 and 16 and 64 micrograms/ml, respectively) and were treated for 3 days with ampicillin alone or in combination with gentamicin at 2 mg/kg of body weight subcutaneously t.i.d. or at 6 mg/kg subcutaneously q.d. The serum ampicillin levels and pharmacokinetic parameters of the humanlike pharmacokinetics of ampicillin in rabbits were similar to those found in humans treated with 2 g of ampicillin intravenously. The results of therapy for experimental endocarditis caused by E. faecalis J4 showed that the residual bacterial concentration in aortic valve vegetation was significantly lower in the animals treated with combinations of ampicillin plus gentamicin given q.d. or t.i.d. than in those treated with ampicillin alone (P < 0.01). The dosing interval of gentamicin did not significantly affect (q.d. versus t.i.d.; P = 0.673) the therapeutic efficacy of the combination of ampicillin plus gentamicin.     

Experience with once daily dosing of gentamicin: considerations regarding dosing and monitoring

Plasma concentrations of gentamicin following a fixed dose of 240 mg once daily to patients with normal renal function were measured. The purpose was to establish guidelines to achieve a sufficiently high peak concentration with an appropriately low risk of accumulation. In 40 patients, 1-hour concentrations of plasma gentamicin had a median of 9.3 mg/l (range: 4.5-19.0 mg/l) and 9.7 mg/l (range: 3.6-14.6 mg/l) on days 1 and 3 of gentamicin treatment, respectively. Thirty-nine patients had 1-hour concentrations > 5 mg/l. The 1-hour concentrations varied considerably intra- and interindividually but showed a significant inverse correlation with body weight, surface area and the estimated endogenous creatinine clearance. The plasma gentamicin elimination half-life correlated significantly with age and inversely with body weight and creatinine clearance. There was no increase in the mean plasma creatinine from day 0 to day 4. No patients showed signs of nephrotoxicity, although 2 patients, both elderly and with low body weight, showed signs of beginning gentamicin accumulation. In conclusion, gentamicin treatment with the dose of 240 mg once daily in 3 days to adults with normal kidney function generally does not require adjustment or monitoring. However, the dose should be increased in young patients with an excessive body weight, and decreased doses are needed for old and underweight patients. Monitoring of trough plasma gentamicin concentration is not necessary with treatment duration of 3 days or less.     

Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT)

BACKGROUND: Only 15-20% of patients with chronic hepatitis C achieve a sustained virological response with interferon therapy. The aim of this study was to compare the efficacy and safety of interferon alpha2b in combination with oral ribavirin with interferon alone, for treatment of chronic infection with hepatitis C virus (HCV). METHODS: 832 patients aged 18 years or more with chronic HCV who had not been treated with interferon or ribavirin, were enrolled and randomly allocated one of three regimens: 3 mega units (MU) interferon alpha2b three times a week plus 1000-1200 mg ribavirin per day for 48 weeks; 3 MU interferon alpha2b three times a week plus 1000-1200 mg ribavirin per day for 24 weeks; or 3 MU interferon alpha2b three times a week and placebo for 48 weeks. All patients were assessed for safety, tolerance, and efficacy at the end of weeks 1, 2, 4, 6, and 8, and every 4 weeks during treatment. After treatment was completed patients were followed up on weeks 4, 8, 12, and 24. The primary endpoint was loss of detectable HCV-RNA (serum HCV-RNA <100 copies/mL) at week 24 after treatment. FINDINGS: Sustained virological response at 24 weeks after treatment, was found in 119 (43%) of the 277 patients treated for 48 weeks with the combination regimen, 97 (35%) of the 277 patients treated for 24 weeks with the combination regimen (p=O.055), and 53 (19%) of the 278 patients treated for 48 weeks with interferon alone (p<0.001 vs both combination regimens, intention-to-treat analysis). Logistic regression identified five independent factors significantly associated with response: genotype 2 or 3, viral load less than 2 million copies/mL, age 40 years or less, minimal fibrosis stage, and female sex. Among patients with fewer than three of these factors the odds ratio of sustained response was 2.6 (95% Cl 1.4-4.8; p=0.002) for the 48 week combination regimen compared with 24 weeks of the combination regimen. Discontinuation of therapy for adverse events was more frequent with combination (19%) and monotherapy (13%) given for 48 weeks than combination therapy given for 24 weeks (8%). INTERPRETATION: An interferon alpha2b plus ribavirin combination is more effective than 48 weeks of interferon alpha2b monotherapy and has an acceptable safety profile. Patients with few favourable factors benefit more from extending the duration of combination therapy to 48 weeks.     

Comparison of ceftibuten once daily and amoxicillin-clavulanate three times daily in the treatment of acute exacerbations of chronic bronchitis

In medical practice, antibiotics are generally given empirically for the treatment of acute exacerbations of chronic bronchitis (AECB). To be effective, antibiotic therapy should be broad in spectrum, and it should also cover the common beta-lactamase-producing pathogens. In this multicenter, randomized, investigator-masked study, 469 patients with AECB were randomized (in a ratio of 2:1) to receive 400-mg oral ceftibuten capsules once daily or 500-mg amoxicillin-clavulanate tablets three times daily for 5 to 15 days. Patients receiving ceftibuten were further divided into those who took the capsule with a meal (fed) and those who took the capsule 1 hour before a meal (fasted). Clinical and microbiologic responses were evaluated after treatment at 0 to 6 days (end of treatment) and 7 to 21 days (follow-up). Overall clinical success was determined by cure/improvement of signs and symptoms of AECB at the end of treatment and at follow-up. Overall microbiologic assessment was graded as eradication, persistence, relapse, reinfection, colonization, superinfection, or unassessable. Tolerability was evaluated by grading observed adverse events. The mean duration of treatment was 10.4 days for patients who received ceftibuten and 10.1 days for patients who received amoxicillin-clavulanate. A total of 252 patients receiving ceftibuten and 117 patients receiving amoxicillin-clavulanate were evaluable for clinical efficacy, and 55 patients were evaluable for microbiologic response. Both treatments improved the signs and symptoms of bronchitis, and overall clinical success rates were equivalent for patients treated with ceftibuten (211 of 252 [84%]) and amoxicillin-clavulanate (93 of 117 [79%]) (95% confidence interval [CI], -4.5% to 13.6%). Overall microbiologic eradication rates were also similar for patients treated with ceftibuten (36 of 37 [97%]) and amoxicillin-clavulanate (12 of 14 [86%]) (95% CI, -5.2% to 21.2%). The most frequently reported treatment-related adverse events were gastrointestinal disturbances, which occurred in 15% (47 of 316) and 24% (36 of 152) of patients treated with ceftibuten and amoxicillin-clavulanate, respectively. No significant difference was observed in the ceftibutenfed and ceftibuten-fasted groups in overall clinical assessments of the clinical efficacy population and safety population. In conclusion, 400 mg oral ceftibuten once daily has a similar clinical success rate to 500 mg amoxicillin-clavulanate three times daily, with a trend toward fewer gastrointestinal side effects, in the treatment of patients with AECB.     

Omeprazole 10 milligrams once daily, omeprazole 20 milligrams once daily, or ranitidine 150 milligrams twice daily, evaluated as initial therapy for the relief of symptoms of gastro-oesophageal reflux disease in general practice

BACKGROUND: The efficacy of omeprazole, 20 mg once daily, in the treatment of reflux oesophagitis and the therapeutic advantages over the histamine H2 receptor antagonists are well documented. This study assessed 20 mg omeprazole daily (OM20), 10 mg omeprazole daily (OM10), and 150 mg ranitidine (RAN) twice daily for symptom relief in gastro-oesophageal reflux disease (GORD). METHODS: Patients (n = 994) presenting with heartburn to their general practitioner underwent endoscopy to exclude peptic ulcer disease and were randomized into a UK, multicentre, parallel-group, double-blind comparison of the three treatments for 4 weeks. Symptoms were assessed at clinic visits after 2 and 4 weeks. RESULTS: Symptom relief after 4 weeks was achieved by 61% (OM20), 49% (OM10), and 40% (RAN) patients (OM20 versus OM10, P < 0.0167; OM20 versus RAN, P < 0.0001; OM10 versus RAN, P < 0.01). Among the patients (32%) with erosive reflux oesophagitis, symptom relief was achieved in 79% (OM20), 48% (OM10), and 33% (RAN) (OM20 versus OM10, P < 0.0001; OM20 versus RAN, P < 0.0001; OM1O versus RAN, NS). CONCLUSION: Omeprazole, 20 mg, is the most effective initial therapy for relief of GORD symptoms.     

Once-daily gentamicin versus once-daily netilmicin in patients with serious infections--a randomized clinical trial

Consecutive patients with serious infections were randomized between gentamicin 4 mg/kg once daily i.v. or netilmicin 5.5 mg/kg once daily i.v. (with dosage reduction in case of renal dysfunction). Exclusion criteria were neutropenia or severe renal failure. Median first serum trough and peak concentrations were 0.4/9.5 mg/L and 0.4/12.2 mg/L, for gentamicin and netilmicin respectively. A good clinical response was observed in 50/54 (92.6%) evaluable patients treated with gentamicin and in 48/52 (92.3%) netilmicin-treated patients. Nephrotoxicity (a rise of serum creatinine > or = 45 mumol/L) developed in 5/72 (6.9%) gentamicin patients treated > or = 48 hours and in 10/69 (14.5%) netilmicin patients (difference 7.5%, 95% CI -3.9% to +16.2%). High-tone audiometry was performed when possible; no significant differences were found between the regimens with regard to hearing loss or prodromal signs of ototoxicity. We conclude that with once-daily dosing no benefit of netilmicin over gentamicin regarding nephro- or ototoxicity could be demonstrated.     

Erosive pustular dermatosis of the scalp in skin grafts: report of three cases

The objective of the present prospective, noncomparative, multicenter study was assess the safety and efficacy of gentamicin and doxycycline therapy for human brucellosis. In the first part of the study, a cohort of 17 patients received 100 mg of doxycycline (or 50 mg/kg of body weight per day if the body weight was < 40 kg) orally every 12 h for 45 days (cohort 1). In the second part of the study a subsequent cohort of 35 patients was treated with doxycycline at the same dosage for 30 days (cohort 2). All patients were treated intramuscularly with gentamicin at 240 mg (or 5 mg/kg per day if the body weight was < 50 kg) once daily for the first 7 days. Both cohorts showed a favorable response during therapy, and there were no therapeutic failures. Relapse was noted in 1 (5.9%; 95% confidence interval [95% CI], 0.15 to 28.7%) of the 17 patients in cohort 1 and in 8 (22.9%; 95% CI, 10.4 to 40.1%) of the 35 patients in cohort 2. Nineteen patients (36.5%; 95% CI, 23.6 to 51.0%) had adverse effects, with no differences between cohorts, and no patients had a treatment-limiting adverse effect. The study indicates that the combination of doxycycline for 45 days and gentamicin for 7 days is an effective and well-tolerated therapy for human brucellosis. The relapse rates obtained with doxycycline treatment for 30 days appear to be higher than those obtained with doxycycline treatment for 45 days.     

Therapy of multidrug-resistant typhoid fever with oral cefixime vs. intravenous ceftriaxone

We randomly allocated 80 children with suspected multidrug-resistant tyhpoid fever to therapy with either cefixime or ceftriaxone. Of these, an alternative diagnosis was subsequently made in 10 children and another 10 were excluded because cultures were negative. In 9 cases the typhoidal organisms isolated were susceptible to first-line drugs. In all, 50 children were randomly allocated to receive therapy with either intravenous ceftriaxone (65 mg/kg/day once daily, Group A, n = 25) or oral cefixime (10 mg/kg/day divided every 12 hours, Group B, n = 25) for 14 days. The two groups were comparable in their clinical characteristics, duration and severity of illness at the time of admission. The time to defervescence was comparable in both groups (8.3 +/- 3.7 vs. 8.0 +/- 4.1 days, P = not significant). An equal number (3 in each group) failed to respond and underwent a change in therapy. Three children in Group A and one in Group B relapsed. No adverse effects were seen in either group during the course of therapy. Our data suggest that oral cefixime can be used as effectively as parenterally administered ceftriaxone for management of typhoid fever in children.     

Maintenance treatment for gastro-oesophageal reflux disease. A placebo-controlled evaluation of 10 milligrams omeprazole once daily in general practice

BACKGROUND: Gastro-oesophageal reflux disease (GORD) is a frequent cause for consultation in general practice and is a chronically relapsing disease. METHODS: This general practice study was a 6-month randomized, double-blind parallel-group placebo-controlled assessment of the efficacy and safety of continuous treatment with 10 mg omeprazole every morning after initial symptom control in 495 patients with GORD but without erosive oesophagitis. RESULTS: On the basis of life-table estimates for cumulative relapse rates, patients in the placebo group (52%) were almost twice as likely as those in the omeprazole group (27%) to discontinue therapy before 24 weeks because of inadequate relief of heartburn or for other reasons including adverse events (all-patients-treated analysis, log rank test, P = 0.0001). CONCLUSIONS: This study has shown that 10 mg omeprazole once daily is an effective and well-tolerated treatment strategy in general practice for the long-term management of symptoms of GORD in patients without erosive oesophagitis.     

Meropenem versus ceftazidime plus amikacin in the treatment of febrile episodes in neutropenic patients: a randomized study

BACKGROUND AND OBJECTIVE: Meropenem is the first of a new class of carbapenems which may be administered without cilastatin. This study was performed to assess the clinical efficacy and tolerability of meropenem monotherapy (1 g/8 h) compared with the standard combination of ceftazidime (2 g/8 h) plus amikacin (15 mg/kg/day) for the empirical treatment of infective febrile episodes in neutropenic cancer patients. METHODS: This was a three-center, randomized, non-blind parallel group trial. The primary objective was to compare the clinical efficacy of meropenem monotherapy with that of ceftazidime plus amikacin in the empirical treatment of febrile infective episodes in neutropenic patients. This was evaluated by the number of patients surviving on unmodified therapy at 72 h (primary end point) and by the clinical response at the end of therapy (secondary end point). RESULTS: A total of 93 febrile episodes (46 meropenem, 47 ceftazidime/amikacin) were evaluable. Bone marrow transplant patients accounted for 49.5% of all cases. There was a high incidence of Gram-positive infections but no pseudomonal infections. Microbiologically documented infections, clinically documented infections and unexplained fever accounted for 45%, 10% and 45% of episodes, respectively. There was a similar proportion of patients in the meropenem and ceftazidime/amikacin groups on unmodified empiric therapy at 72 h (80.4% vs 76.6%, p = 0.65,) and cured at the end of therapy (37% vs 36.2%, p = 0.9). No significant difference in tolerability was observed between the groups. Meropenem was well tolerated; of note, there were no cases of nausea/vomiting or seizure related to its use. INTERPRETATION AND CONCLUSIONS: Meropenem monotherapy was well tolerated and produced response rates similar to those obtained with ceftazidime/amikacin. The low overall success rates with both treatments concur with those of other recent studies and are probably due to a combination of several factors, including the adoption of strict assessment criteria.     

Comparison between metoprolol orally osmotic once daily and metoprolol two or three times daily in suppressing exercise-induced and daily myocardial ischemia

Metoprolol is a widely used anti-ischemic drug with a relatively short half-life. To improve patient' compliance and to provide 24-hour coverage, its once daily ORally OSmotic (OROS) formulation was developed. In this multicenter double-blind study, the anti-ischemic effects of metoprolol OROS given once daily at doses of 190 and 285 mg were compared to the regular metoprolol formulation of 100 mg 2 or 3 times daily. Sixty-five patients with stable coronary artery disease, positive exercise tests, and ischemic episodes during daily activity as recorded by ambulatory electrocardiographic monitoring (AEM) were included. In the OROS group, 23 patients completed all 3 treatment periods. In these patients, the number of myocardial ischemic episodes decreased from 239 on placebo to 128 during the 190 mg/day dose (p < 0.0001) and to 86 during the 285 mg/day treatment period (p < 0.0001). In the metoprolol group, there were 204 episodes at baseline and 142 and 140 during the 100 mg 2 or 3 times daily treatment periods (p < 0.0001 for both). During exercise testing, time to 1-mm ST depression increased significantly in the OROS group from 6.3 minutes at baseline to 7.1 and 9.6 minutes during 190- and 285-mg treatment periods. In the metoprolol group, it increased from 5.8 to 7.2 and 8.2 minutes, respectively. Both formulations of metoprolol were well tolerated. The OROS formulation was highly effective in suppressing daily and exercise-induced ischemia and exerted its effect throughout the 24-hour period.     

Clinical efficacy of low-dose inhaled budesonide once or twice daily in children with mild asthma not previously treated with steroids

The aim of the present study was to examine the efficacy of low-dose inhaled budesonide (BUD) administered via Turbuhaler once or twice daily on symptoms, lung function and bronchial hyperreactivity in children with mild asthma. One hundred and sixty-three children (mean age 9.9 yrs, 56 females/107 males) with mild asthma (forced expiratory volume in one second (FEV1) 103% of predicted, morning peak expiratory flow (PEF) 87% pred, reversibility in FEV1 3%, fall in FEV1 after exercise 10.4% from pre-exercise value) and not previously treated with inhaled steroids, were included in a double-blind, randomized, parallel-group study. After a two-week run-in period, the children received inhaled BUD 100 microg or 200 microg once daily in the morning, 100 microg twice daily or placebo for 12 weeks. Exercise and methacholine challenges were performed before and at the end of treatment. After 12 weeks of therapy, the fall in FEV1 after an exercise test was significantly less in all three BUD groups (43-5.1%) than in the placebo group (8.6%). Bronchial hyperreactivity to methacholine with the provocative dose causing a 20% fall in FEV1 decreased significantly in the BUD 100 microg twice-daily group compared with placebo (ratio at the end of treatment 156%). Changes in baseline lung function (FEV1 and PEF) were less marked than changes in bronchial responsiveness. In conclusion, low doses of inhaled budesonide, given once or twice daily, provided protection against exercise-induced bronchoconstriction in children with mild asthma and near normal lung function.     

Combination therapy with interferon alpha and ribavirin for chronic hepatitis C virus infection in thalassaemic patients

Hepatitis C virus (HCV) infection is common in multi-transfused thalassaemic patients, and, in combination with transfusional iron overload, can result in progressive liver disease. Therapy with interferon-alpha causes a sustained loss of HCV in only 15-25% of patients, and there is as yet no established effective therapy for those who fail to respond. We have conducted a pilot study of combination anti-viral therapy for patients who failed to respond, or relapsed after an initial response to single-agent interferon-alpha. Patients were treated for 6 months with interferon-alpha 2b, given subcutaneously three mega units thrice weekly, together with ribavirin, orally 1 g daily. 11 patients were enrolled, their median age was 24.9 years. 8/10 evaluable patients had cirrhosis on biopsy, five were infected with HCV type 1 and all but one had initial HCV RNA titres > 10(6) genomes/ml. Five patients (45.5%) had a sustained virological response with loss of serum HCV RNA for > 6 months after finishing therapy. There was no clear association between response to therapy and age, histology, HCV genotype, or HCV RNA titre. Transfusion requirements were significantly increased during the treatment phase, probably due to ribavirin-induced haemolysis, and this necessitated intensification of iron chelation therapy. Serum ferritin levels decreased significantly in those who responded. These results suggest that combination therapy is potent in clearing HCV infection, and may provide effective second-line therapy for thalassaemic patients who have failed to respond to interferon-alpha monotherapy.     

Ceftriaxone in treatment of streptococcal endocarditis

The authors studied efficacy and safety of ceftriaxone given intravenously for 3-4 weeks in a dose 2-4 g/day to patients with streptococcal endocarditis (SE). Of them, 8, 8 and 1 patients were infected with Streptococcus viridans, Streptococcus pyogenes, Pneumococcus, respectively. Hospital trial and follow-up lasted up to 2 years. Cure without surgical correction occurred in 7 patients, valvular replacement was needed in 4 patients, 1 patient died, 4 patients developed recurrences 3 and more months after therapy with ceftriaxone. The drug was safe and well tolerated. 33% of the patients were discharged from hospital with obvious improvement after 2-3 week treatment to continue it outpatiently for 1-2 weeks.     

Candida fungemia in neonates treated with fluconazole: report of forty cases, including eight with meningitis

PURPOSE OF THE STUDY: To assess efficacy and safety of fluconazole in neonates with Candida fungemia. STUDY DESIGN: Multicenter prospective protocol of all fungemias appearing between January 1, 1993, and December 31, 1997, in four major university hospitals. RESULTS: Forty neonates, 28 of them with very low birth weight (<1500 g; 30.5 median gestation week), with documented Candida albicans fungemia were treated with intravenous fluconazole in a daily dosage of 6 mg/kg once daily for 6 to 48 days. Thirty-four received fluconazole as monotherapy and 6 received it in combination with amphotericin B. Thirty-two (80%) were cured; 4 of them relapsed despite at least 14 days of therapy, but they were ultimately cured without sequelae. Eight other neonates died, 4 because of fungal infection and 4 because of prematurity or hemorrhage or lung failure, with fungemia (20% overall and 10% attributable mortality). Two neonates had elevated liver enzymes during fluconazole therapy and 2 others had elevated serum creatinine during fluconazole monotherapy. In none of them did these abnormalities necessitate discontinuation of antifungal therapy. In 8 neonates fungal meningitis developed as a complication of fungemia. All but 3 fungemias were C. albicans; 3 were Candida parapsilosis. CONCLUSIONS: Fluconazole was safe and effective antifungal therapy even in complicated or Candida fungemia in neonates and in infants with very low birth weight.     

Low-dose reserpine/thiazide combination in first-line treatment of hypertension: efficacy and safety compared to an ACE inhibitor

The concept of initiating treatment of mild-to-moderate hypertension with a low-dose combination of reserpine and the thiazide clopamide in comparison to monotherapy with an ACE inhibitor was investigated. A total of 127 adult outpatients with diastolic blood pressure between 100 and 114 mmHg were randomized into this double-blind, parallel group study. After a 2-week wash-out period and a subsequent 2-week placebo run-in period, they were allocated to once-daily treatment with 0.1 mg reserpine plus 5 mg clopamide (R/C), or 5 mg enalapril. If diastolic blood pressure was not normalized after 3 weeks of therapy (i.e. DBP < 90 mmHg), the dosage was doubled from week 4 to 6. The primary efficacy variables were the change from baseline in mean sitting diastolic and systolic blood pressure (DBP/SBP) after 3 weeks of therapy. Secondary variables included the change in DBP and SBP after 6 weeks of therapy, the BP normalization rates at 3 and 6 weeks and, concerning tolerability, the rates of adverse events after 6 weeks of therapy. An intent-to-treat analysis was performed. The reserpine/ clopamide and enalapril groups did not differ with regard to demographic and baseline characteristics (mean age 57 or 58 years, respectively; 63% or 56% males, respectively; mean SBP/DBP after the 2-week placebo period = 156 mmHg/104 mmHg in both groups). After 3 weeks of treatment with one capsule daily, mean SBP/DBP reduction from baseline (24 h after last medication intake) in the R/C combination group was -19.6/ -17.0 mmHg, in the enalapril group -6.1/ -9.5 mmHg (between-group comparison: 2p < 0.01 for both parameters). The normalization rates for DBP (< 90 mmHg) were 64.1% (R/C) and 28.6% (enalapril) (2p < 0.01). Adverse events that were considered possibly or definitely drug-related by the investigator were noted in 11 patients (17.2%) in the R/C group and in 9 patients (14.3%) in the enalapril group (NS). Two patients in the enalapril group discontinued the study prematurely due to adverse events (cough; skin eruption). In the treatment of mild-to-moderate hypertension, a low-dose combination of reserpine and clopamide once a day is considerably more effective than, and as tolerable as, 5-10 mg of enalapril once a day. These findings suggest that treatment with a combination of different antihypertensives with different modes of action in low doses is a rational alternative to conventional monotherapy in the first-line treatment of hypertension. Besides, the "old" reserpine-diuretic regimen also in these days appears to be a rational alternative to "modern" monotherapies.