Amorn Leelarasamee

Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial

BACKGROUND Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis. METHODS We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106288. FINDINGS 264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI -5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events--including those that were serious or led to treatment discontinuation--with micafungin than there were with liposomal amphotericin B. INTERPRETATION Micafungin was as effective as--and caused fewer adverse events than--liposomal amphotericin B as first-line treatment of candidaemia and invasive candidosis.

Melioidosis in Southeast Asia.

After the first report of human melioidosis in Burma by Whitmore and Krishnaswami (1912), it took approximately 50 years for the establishment of its endemicity in Southeast Asian countries such as Malaysia, Singapore and Thailand. In other Southeast Asian countries, little is known about the epidemiology although melioidosis is gradually being recognized as an emerging infectious disease in Vietnam (Weber et al., 1969). The septicemic or bacteremic form is the best indicator of its presence since blood isolates generally receive greater attention for proper identification than isolates from other sites. In Thailand, the first case report appeared in 1955 (Chittivej et al., 1955). However, melioidosis was not widely recognized until the Vietnam war when the death of American soldiers due to acute pneumonitis provoked great interest in the disease (Weber et al., 1969). At that time little evidence could be found to substantiate the existence of melioidosis in Thailand. The microorganism could be isolated from soil and water collected from various parts of the country (Finkelstein et al., 1967). The prevalence of a positive serological test was found in 29% of Thai military personnel (Nigg, 1963) but strangely enough, clinical cases could not be identified. In 1975, Sompone Punyagupta and colleagues reported ten cultureproven cases of melioidosis at the meeting of the Infectious Disease Group of Thailand (Punyagupta et al., 1976). Since then clinicians and laboratory personnel in medical schools have been alert to look for the disease. The knowledge and expertise gained from a handful of cases diagnosed at medical schools was passed on to various provincial hospitals. The first national workshop on melioidosis was held 10 years later. It compiled more than 700 reported cases that led to research activities on various aspects of melioidosis. At present, 2000–3000 cases of clinical melioidosis are estimated to occur each year in Thailand with a population of 60 000 000. The incidence rate in highly endemic areas was calculated to be 3.6–5.5 cases per 100 000 population and is seasonal (Suputtamongkol et al., 1994). A multicenter study on the etiology of acute undifferentiated febrile illness from 1991 to 1992 revealed one blood isolate per 1033 cases and 11 (0.9%) cases with a positive serological test among the 1218 cases. Since there are approximately 400 000 cases of acute undifferentiated febrile illness reported to the Division of Epidemiology, Ministry of Public Health each year, 387 cases of bacteremic melioidosis and another 3612 cases with positive serology could be derived according to calculation using this information. In a laboratory survey, total numbers of the isolates were 1131 strains in 1994 and 1165 strains in 1995 (Leelarasamee et al., 1997). When the site of isolation and the annual number of isolates were plotted on a map, it was seen that Burkholderia * Tel.: +66-2-4197785. E-mail address: siall@mahidol.ac.th (A. Leelarasamee)

Severe pneumococcal infection at a Thai hospital.

OBJECTIVES To determine clinical manifestations, prognostic factors, and therapeutic outcomes of severe pneumococcal infection. METHODS Hospitalized patients with specimens cultured positive for Streptococcus pneumoniae were identified retrospectively by reviewing hospital records from 1992 to May 1998 at Siriraj Hospital. RESULTS Of 205 evaluable cases, 130 (63.4%) patients were male. Nineteen (9.3%) patients were less than 2 years old, 29 (14.1%) were between 2 and 13 years, 99 (48.3%) were between 14 and 60 years, and 58 (28.3%) were over 60 years of age. From 1992 to 1997, the average admission rate was highest (36.4%) between January and March (range = 20-45%). Average admission rates during other periods ranged from 20.0% to 23.1%. Pneumonia (50.7%) and acute exacerbation of chronic obstructive pulmonary disease or infected bronchiectasis or bronchopneumonia (21.0%) were the most frequent diagnoses, followed by meningitis (14.6%) and primary sepsis without localized lesion (8. 3%). The mortality rate during the first 7 days of hospitalization was 28.8%, and thereafter, 11.7%. The odds ratios (95% CI) of old age, congestive heart failure, and alcoholism for death were 3.4 (1. 4-8.2), 8.6 (0.97-76.1), and 8.0 (3.1-20.9), respectively. For pneumonitis only, mortality rates among alcoholic and nonalcoholic patients were 76.9% and 39.6%, respectively (P = 0.025). CONCLUSIONS Patients who were alcoholic, over 60 years of age, or had congestive heart failure were vulnerable to severe pneumococcal infection with significant mortality, in spite of proper selection of empirical antimicrobials. Diabetes mellitus and multiple myeloma also contributed to late mortality after 7 days of hospitalization.

Comparative efficacies of oral pefloxacin in uncomplicated cystitis. Single dose or 3-day therapy.

Uncomplicated cystitis (UC) in women is commonly encountered in medical practice. Current short term therapy with 3-day regimens of drugs such as cotrimoxazole (trimethoprimsulfamethoxazole), amoxicillin, norfloxacin and oral cephalosporins has shown efficacies ranging from 68 to 97%.[11 Single dose therapy with comparable efficacy to 3-day or the more common 5-day regimens would obviously be preferable. In a recent review,D1 the efficacies of single dose regimens varied from 47 to 65% with cefadroxil and amoxicillin, respectively, and from 81 to 96% with either cotrimoxazole, amoxicillin or cefonicid. Newer fluoroquinolones with long half-lives were not reviewed at that time. In Thailand, the cheapest treatment for UC is cotrimoxazole, usually administered for either 3 or 5 days. However, cotrimoxazole-resistant uropathogens are increasingly being isolated, and account for about 30 to 40% of Gram-negative urinary isolates. In addition, fixed drug eruption or rash or gastrointestinal upset due to the sulfonamide component are seen in 1 to 5% of patients treated with this agent for cystitis. Thus, there is a need for an alternative drug for those who fail to respond to, or cannot tolerate, cotrimoxazole. A recent study showed that single dose therapy for UC in women may be as effective as 3or 5-day therapy,[2,31 when fluoroquinolones with a long urinary half-life were used. Pefloxacin is one such drug and is well absorbed from the intestine. After a single oral dose of pefloxacin 800mg, concentrations of the active drug and/or its metabolites in urine remained above the MICs for most uropathogens for 3 to 5 days. This randomised single-blind controlled study compared the efficacy of a single oral dose of pefloxacin 800mg with that of a 3-day regimen (400mg twice daily for 3 days) in nonpregnant women with UC at a Bangkok community clinic.

Amoxicillin for fever and sore throat due to non-exudative pharyngotonsillitis: beneficial or harmful?

OBJECTIVES To determine duration of signs and symptoms and adverse reactions after treatment with amoxicillin of patients with fever and sore throat due to non-exudative pharyngotonsillitis. DESIGN This was a randomized, double-blinded, placebo-controlled trial. Outpatients at four medical centers were enrolled. Patients over 5 years of age presented with fever and sore throat for less than 10 days due to non-exudative pharyngotonsillitis. Cases with any of the following symptoms or illness were excluded: earache, nasal discharge with foul smell, rheumatic fever, valvular heart disease, renal disease, and penicillin hypersensitivity. Amoxicillin or identical placebo at the dosage of 50 mg/ kg per day was given three or four times daily for 7 days. RESULTS There were 1217 patients enrolled in this study. Some were lost to follow-up, which is the reason for the variability in number of cases in these analyses. After therapy, duration of fever was 2.46 and 2.48 days (P = 0.78) and of sore throat 3.01 and 3.04 days (P = 0.80) in amoxicillin (n = 431) and placebo (n = 436) groups, respectively. Complications were clinically documented in 13 (2.5%) and 16 (3.0%) cases in amoxicillin (n = 527) and placebo (n = 524) groups (P = 0.56). Two cases (0.46% and 0.46%) from each group (n= 433 and 431) were positive by antistreptolysin O antibody determination. The history of carditis and abnormal urinalysis after treatment were not obtained. CONCLUSIONS Amoxicillin therapy for non-exudative pharyngotonsillitis conferred no beneficial or harmful effect.

Therapeutic Efficacy of Oral Ofloxacin in Acute Diarrhea and Dysentery

The efficacy of 200 mg oral ofloxacin given twice daily for 3 days was evaluated in 98 hospitalized cases with acute diarrhea or dysentery. Sixty cases were female, most of whom were laborers.Vibrio cholerae, Vibrio parahaemolyticus, Shigella flexneri, Shigella boydii, Shigella sonnei, Aeromonas hydrophila, Aeromonas spp., andPlesiomonas shigelloides were isolated from fecal samples in 36 of 86 cases (42%) with diarrhea and 5 of 12 cases (46%) with dysentery.E. coli agglutinated with variousE. coli polyvalent antisera were found in another 25 cases (26%). With the exception ofE. coli, most of the clinical isolates were highly susceptible to ofloxacin and norfloxacin with minimal inhibitory concentrations (MIC90) of 0.047–0.38 and 0.016–0.25 mg/L, respectively. A total cure was achieved in 96.5% of cases with diarrhea and in 100% of cases with dysentery. There was a delayed response in two cases and only one case clinically failed to respond.V. cholerae was repeatedly isolated on day 3 in another case who had recovered on day 2, and 1 case developed gangrenous cholecystitis and ischemic enteropathy after an initial response to ofloxacin.