Bioequivalence study of clindamycin phosphate injection (Clinott-P) in Thai healthy volunteers.

BACKGROUND AND OBJECTIVE: Generic clindamycin given intramuscularly, should have identical active ingredient(s), strength, and demonstrable bioequivalence to those of original product. The aim of this investigation was to compare the bioavailability of a single, intramuscular injection, of 2 ml. of 300 mg. of a generic clindamycin (Clinott-P) and the original preparation (Dalacin C). MATERIAL AND METHOD: A randomized, double-blinded, crossover study was conducted. Twenty-four healthy males were recruited at Siriraj Hospital and randomized to receive a single intramuscular injection of either Clinott-P or Dalacin C. Treatment was followed by a two-week washout period. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours after the injection. Plasma samples were analysed for clindamycin by a validated HPLC method at the Faculty of Pharmaceutical Sciences, Chulalongkorn University. RESULTS: Twenty-four volunteers enrolled in and completed the study. They exhibited an average height of 167.92 cm (SD = 5.82), weight of 60.10 kg (SD = 7.36), body mass index of 21.27 (SD = 1.73) and normal blood chemistries. The Cmax of Clinott-P was 3.94225 microg/ml at Tmax 1.75 hours and of Dalacin C, 3.6847 microg/ ml at Tmax 2.09 hours. The AUC0-24 of Clinott-P was 16.32 +/- 6.13 micro.hr/ml and Dalacin C was 17.24 +/- 7.46 microg.hr/ml. Ninety percent confidence intervals of the mean ratios (test/reference) of log transformed of Cmax (93.07-123.43%), AUC(0-24) (82.58-112.31%) and AUC(0-inf), (81.54-110.06%) were all within the standard range (80-125 %) for bioequivalence study. Tenderness after injection around the deltoid area was assessed blindly and was found to be slight (visual basic score < 5) and presented for one or two days after the injection. CONCLUSION: The two brands of clindamycin exhibit comparable pharmacokinetic parameters and volunteers exhibited slight and tolerable tenderness at the injection site.

The prevalence of Chlamydia pneumoniae antibodies in Thai patients with coronary artery disease.

Blood samples were obtained from 243 consecutive coronary artery disease (CAD) patients (177 male, 66 female) aged 35-78 years (mean, 61 years) admitted for coronary angiography because of suspected coronary heart disease, and from 115 blood donors (91 male, 24 female) aged 25-60 years (mean, 47 years). Of the 243 CAD patients, 179 (74%) were positive by an ELISA method for Chlamydia pneumoniae antibodies IgG and 132 (54%) were positive for C. pneumoniae IgA. Among the 115 blood donors, 80 (70%) were positive for C. pneumoniae IgG and 49 (43%) were positive for C. pneumoniae IgA. When IgG antibodies were considered, there was no significant difference between CAD patients and healthy controls (OR = 1.29, 95% CI = 0.79-2.10, p > 0.05). In cases of positive IgA antibodies alone, there was a significant difference between CAD patients and healthy controls (OR = 1.58, 95% CI = 1.01-2.4, p = 0.029). If both IgG and IgA antibodies were positive, OR was increased from 1.58 to 1.80 (95% CI = 0.97-3.36, p = 0.044). In conclusion, C. pneumoniae infection is common in Thai people but chronic C. pneumoniae infection is more common in CAD patients than in middle-aged blood donors.

Prolonged fever due to Mycobacterium avium complex (MAC) disease in advanced HIV infection: a public health concern.

From March 1997 to June 1998, infectious etiologies of prolonged fever was prospectively investigated in 104 advanced human immunodeficiency virus (HIV) infected patients admitted to Siriraj Hospital. The etiology could be identified in 91 cases (87.5%). Of these, blood cultures from 68 patients yielded mycobacteria and fungi. Mycobacterium avium complex was the most common blood isolate in 24 per cent of the patients; followed by Mycobacterium tuberculosis in 20.2 per cent, Cryptococcus neoformans in 5.8 per cent, Penicillium marneffei in 5.8 per cent. During the course of febrile illness, 79 of the 91 patients (86.8%) exhibited focal lesions. Weight loss, elevated serum alkaline phosphatase were often found to be significantly more associated with MAC bacteremia (P < 0.05). Pulmonary involvement significantly correlated more with M. tuberculosis bacteremia than MAC bacteremia (P < 0.05). No cause could be identified in 13 cases. Mycobacterium blood culture alone established the etiologies in 68 cases (65.4%). Of the 25 patients with disseminated MAC (DMAC) infection, nine patients died during hospitalization. Another three cases died within a few months of appropriate anti-MAC chemotherapy. We concluded that the risk of DMAC infection in advanced AIDS patients in Thailand is high when low CD4 lymphocyte count is established. The prolonged fever resulted from DMAC in advanced HIV infection is warrant to be public health concern. Mycobacterium blood culture is a most valuable tool contributing to the diagnosis of infectious agents in this condition. The guidelines of 1997 USPHS/IDSA should be followed to give chemoprophylaxis against DMAC disease in patients with advanced HIV infection and a CD4 count less than 50 cells/mm3.

Burkholderia pseudomallei: the unbeatable foe?

Although melioidosis has been recognized in Thailand for many years and considerable progress in term of diagnosis and treatment was achieved, B. pseudomallei is still "the unbeatable foe", for several reasons as outlined here: under-recognition, high case-fatality rate, unacceptable relapse rate and a "time-bomb" for sero-positive patients. Melioidosis is largely restricted to certain geographical areas. In Thailand, it had long been considered a rare disease in Thailand until ten cases with culture-proven melioidosis were reported by Sompone Punyagupta and his associates at a meeting of the Infectious Disease Group of Thailand. Since then awareness of young physicians and laboratory personnel for melioidosis has been increased. The most dramatic consequence was seen at Sappasitprasong Hospital in Ubon Ratchathani where over 100 strains of B. pseudomallei are isolated each year. But the frequent isolation of B. pseudomallei is surprisingly restricted to some provinces in the northeast, namely Khon Kaen and Ubon Ratchathani provinces and only 1-10 cases or none from adjacent provinces. The discrepancy was well illustrated by mapping the number of isolations by province. Thus many cases of septicemic melioidosis are certain to receive inappropriate chemotherapy and nearly half of them probably leave this world without proper diagnosis in area where under-recognition unfortunately still prevails. Mortality in disseminated septicemic melioidosis used to occur in 82-87% of the patients who were treated with doxycycline, chloramphenicol, cotrimoxazole and kanamycin and in non-disseminated septicemic melioidosis about 20%. With ceftazidime therapy, the mortality rate was cut by half to 35-40%. About 50% of the patients deteriorated rapidly and died within the first few days of fever. Fatalities are related to the speed of positive results of blood culture. Accordingly, awareness of the disease, familiarity of clinical syndrome compatible with septicemic melioidosis, gram-staining of exudate to include or exclude melioidosis, are all crucial factors to lead to proper empiric chemotherapy. Since the addition of anti-cytokine and platelet activating factor receptor antagonist to current antimicrobials failed to lower the mortality rate, we need to find a new antimicrobial such as protegrin-1 which exhibits rapid microbicidal activity, especially against stationary-phase cell. We need to optimize the bactericidal action of currently used antimicrobials by examining their pharmacokinetics. With prolonged maintenance treatment with cotrimoxazole plus doxycycline or co-amoxiclav, relapse occurs in 4 to 23%. Various explanations for the relapse are the ability of the organism to produce glycocalyx, form microcolonies in damaged tissues and survive within phagocytic cells. Again, the bactericidal antimicrobial which is concentration-dependent, may be used to shorten the duration of treatment and reduce relapse. Studies so far can not relate relapse to any defect of host defense mechanism. In endemic areas, seroepidemiological surveys showed that infection, mostly latent, occurred fairly commonly since childhood as 80% of children had antibodies by the age of four years. However, clinical melioidosis is more common in the elderly which in some cases are due to reactivation of primary latent infection. Since the incubation period of the reactivation can vary from weeks to many years, a vaccine or short-course secondary chemoprophylaxis may be possible interventions for the high risk group to get rid of the "time-bomb" reactivation. The vaccine may also be used to reduce the relapse rate. We need to discover the cellular determinants which is critical to awake the host defense to the sleeping bacteria and provoke local inflammatory response to newly born bacteria before dissemination takes place again. Basic research into the pathogenic mechanisms are key to understanding how to make an effective vaccine.

Isolation rates of Burkholderia pseudomallei among the four regions in Thailand.

This study aimed to compare the isolation rates of Burkholderia pseudomallei among community-based hospitals located in the central, north, northeast, and south of Thailand. A questionnaire inquiring about the number of isolation of B. pseudomallei from various clinical specimens during 1994-95 were mailed to 141 community-based hospitals. Of these, 125 hospitals (88.6%) responded to the questionnaire. Microbiological laboratory was not available in thirty hospitals. Data from 95 remaining hospitals with capability to do bacterial culture showed that B. pseudomallei was never isolated in 49 hospitals. Eleven, 9, 19 and 7 hospitals where B. pseudomallei has been isolated, are located in the central, north, northeast and south of Thailand respectively. From these 46 hospitals, a total of 1,131 strains of B. pseudomallei were isolated from 407,263 specimens in 1994 and 1,165 strains from 440,541 specimens in 1995. However, the isolation was most frequent in northeastern hospitals, which accounted for 890 and 964 strains in 1994 and 1995 respectively while only 94, 76, 71 and 83, 75, 43 strains were simultaneously isolated during the 2-year period in those located in central, north and south respectively. The isolation rates of B. speudomallei in 1994 and 1995 were 4.2 and 4.1 per 1,000 clinical specimens in northeastern hospitals as compared to 1.1, 1.8, 1.1 and 1.1, 1.2, 0.7 in those located in central, north and south respectively. Ubon Ratchathani, Nakhon Ratchasima, Buri Ram, Khon Kaen and Udon Thani were the five provinces which exhibited the highest isolation rates as follows; 244, 150, 147, 127, 100 and 218, 128, 114, 119, 58, in 1994 and 1995, respectively. It was concluded that B.pseudomallei was most commonly isolated in the northeast of Thailand. Under-recognition of B. pseudomallei may prevail not only in other parts of Thailand but in some areas of the northeast as well.

Streptococcus suis toxic-shock syndrome and meningitis.

Three cases with S. suis bacteremia and meningitis were reported. The first case was a 23-year-old butcher who was a regular drinker of alcohol for two years and developed streptococcal toxic-shock syndrome. The organism was transmitted to him through a minor cut in his right arm. The second cases was a 49-year-old female laborer who had been consuming locally produced alcohol for 20 years and developed fever and meningitis. Unfortunately, she succumbed in seven days despite intensive supportive and cefotaxime treatments. The third case was a 45-year-old regular alcoholic drinker and car painter who was seen at a private hospital due to contusion at his left lateral chest wall. However, fever and confusion due to meningitis was detected upon admission. Irreversible deafness developed within 48 hours of ceftriaxone therapy for meningitis. He finally recovered with deafness. S. suis was isolated from blood and cerebrospinal fluid cultures in all three cases though initially reported to be viridans group of streptococci.

A comparative study of tuberculin skin test reactivity between asymptomatic HIV-1 seropositive subjects and healthy volunteers.

During November 1993-October 1994 tuberculin skin test reactivity (PPD-Thai Red Cross: 0.1 ml of 10 IU) was determined among 399 asymptomatic HIV-1 positive subjects and 405 healthy volunteers, 10% (40/399) had PPD-TRC induration 0-2 mm compared with 4.2% (17/405) (p = 0.001) and 43.4% (173/399) had induration > or = 10 mm compared with 53.8% (218/405) (p = 0.003) of healthy volunteers. However, the percentage of the PPD-TRC induration 5-9 mm was similar among HIV-1 seropositive subjects and healthy volunteers as 37.6% (150/399) vs 34.8% (141/405) (p = 0.4). The mean PPD-TRC reaction of HIV-seropositive subjects were 6.4 +/- 0.9 mm vs. 11.0 +/- 0.5 mm among those with CD4 lymphocyte counts 200-299 cells/mm3 compared with those > or = 300 cells/mm3 (p < 0.001). We provide support for use of induration of > or = 5 mm of PPD-TRC skin reaction for evidence of latent infection with Mycobacterium tuberculosis as the CDC recommendation in asymptomatic HIV-seropositive subjects. Consideration of tuberculosis chemoprophylaxis should have benefit, particularly in areas where M.tuberculosis is highly prevalent such as Thailand. However, among HIV-1 seropositive carriers with negative tuberculin (PPD-TRC) skin tests, there needs to be a careful evaluation and follow-up for evidence of tuberculous infection.

Susceptibility patterns of clinical bacterial isolates in nineteen selected hospitals in Thailand.

Susceptibility patterns of 3,115 clinical isolates obtained from blood, urine, sputum and pus in 19 hospitals located in each part of Thailand, were studied using ampicillin, ampicillin plus sulbactam, piperacillin, gentamicin, amikacin, cefazolin, cefuroxime, cefotaxime, ceftazidime, ofloxacin and imipenem. E.coli, S.aureus, P. aeruginosa, Klebsiella spp., Acinetobacter spp., Proteus spp. and Salmonella spp., were the seven most common isolates and accounted for 28.3, 15.3, 14.6, 14.5, 5.2, 3.3 and 3.3 per cent of total isolates respectively. Susceptibility percentages of common bacterial isolates from blood to third-generation cephalosporins, amikacin, ofloxacin and imipenem were satisfactory and higher than those of clinical isolates from other specimens. As expected, nosocomial strains were more resistant than community-acquired strains. Isolates from government hospitals were more resistant to gentamicin and amikacin but more susceptible to ampicillin compared with those from private hospitals. Susceptibility to imipenem among isolates from private hospitals was less but did not reach statistical significance.

Antimicrobial resistance of 100 serial gram-negative isolates in two intensive care units.

To determine antimicrobial resistance pattern among gram-negative bacteria isolated from suspected sources of infections in patients hospitalized in two Intensive Care Units (ICUs) at Siriraj Hospital from September 1991 to December 1991, minimal inhibitory concentrations of one-hundred consecutive gram-negative isolates for various antimicrobials were performed using the microbroth dilution method. Of all gram-negative bacterial isolates, 25 per cent were Pseudomonas aeruginosa, 22 per cent Acinetobacter anitratus, 16 per cent Klebsiella pneumoniae, 12 per cent enterobacter, 8 per cent E.coli, 5 per cent non-fermenter, 4 per cent pseudomonas, 3 per cent arizona, 2 per cent A. lwoffii, 1 per cent Aeromonas hydrophila, 1 per cent Aeromonas hydrophila, 1 per cent Proteus rettgeri, and 1 per cent shigella. The in vitro MIC study revealed that 50, 48, 43, 61, 59, 34, 47, 52, 31, 15 per cent of gram-negative isolates were resistant to gentamicin, tobramycin, amikacin, cefotaxime, ceftriaxone, ceftazidime, aztreonam, piperacillin, ciprofloxacin and imipenem respectively. In addition, 64 and 71 per cent of the isolates were resistant to aminoglycosides and cephalosporins being used in the same patients 48 hours before cultures were obtained respectively. The possible spread of resistant gram-negative isolates by cross contamination was not evident by looking at MIC co-variation in sequential isolates of P. aeruginosa. It was concluded that antimicrobial resistance was highly prevalent among gram-negative bacteria isolated from patients already hospitalized in the ICUs. Potent antimicrobials such as imipenem, newer fluoro-quinolones, ceftazidime and amikacin, are often needed for therapy of serious gram-negative bacterial infections in the ICUs.

Thai symptom index for patients in department of medicine.

A symptom indexing and coding was set up in Thai for use in Patient Statistical Report Unit in Department of Medicine. The index consisted of leading symptoms which patients complained to physicians at the Out-patient Department and In-patient Department. The symptoms are subcategorized into anatomical sites and in details wherever they applied to with simple-to-use criteria. The index was then used to relate symptom with final diagnosis using 3,124 in-patient charts review. By this method, frequency of each presenting symptom for a disease was shown and for a given leading symptom, how many diseases should be sorted. This index should be extended to cover various symptoms of patients who seeked medication from other departments. The index is anticipated to be beneficial for medical teaching and planning especially where problem-base-learning is applied, and for planning service and research.

Comparative efficacy of spiramycin and erythromycin in acute exudative tonsillitis in adults: a randomized controlled trial.

A randomized control trial was designed to compare the efficacies of spiramycin given one gram twice daily and erythromycin given 500 mg thrice or four times daily in the treatment of acute exudative tonsillitis in adults whose ages were over 13 years old from January 1989 to January 1991 at a community clinic. A total of 120 cases were enrolled in the study. Fifty-three patients received spiramycin while 67 received erythromycin. Group A beta-hemolytic streptococci (GABHS), S. aureus, and positive titer of Mycoplasma pneumoniae were detected in 19, 47 and 8 per cent in spiramycin group and 21, 36 and 11 per cent in erythromycin group respectively. GABHS were totally eradicated on day 3 of treatment in both groups through eradication of S. aureus was slightly slower initially in the spiramycin group. Marked improvement was similarly achieved in both groups after 3 days of therapy. Dyspepsia was felt in 34.4 and 8.2 per cent of erythromycin and spiramycin groups respectively but was tolerable by most patients. We concluded that spiramycin given twice daily was as effectively as conventional erythromycin but spiramycin is more convenient to administer and causes much less gastro-intestinal side-effect.

Evaluation of enzyme-linked immunosorbent assay (ELISA) test in the diagnosis of tuberculous meningitis.

The detection of immunoglobulin G antibody in the CSF to purified protein derivative in patients with tuberculous meningitis and non-tuberculous meningitis patients by enzyme-linked immunosorbent assay (ELISA) were performed at the Department of Medicine, Siriraj Hospital Medical School from 1986 to 1988. Seventeen proven tuberculous meningitis patients showed 14 positive results. This yielded the sensitivity of the test as 82.4 per cent only nine of the thirty non-tuberculous meningitis patients showed a positive result. Thus demonstrating the specificity of the test as 70.0 per cent. The ELISA test for detecting the antibody of tuberculosis in the CSF is a rather sensitive test for diagnosis of tuberculous meningitis but it is not so specific for the condition.

Undetectable anti-bacterial activity of Andrographis paniculata (Burma) wall. ex ness.

Andrographis paniculata (Burma) Wall. ex Ness (AP) is a herbal medicine and has been used for therapy of upper respiratory tract infection (URI) as well as acute diarrhea with reported efficacy of 75-100 per cent. To investigate whether anti-bacterial activity was responsible for the reported therapeutic success of AP, we carried out a number of studies. The first study was a direct assay of anti-bacterial activity of AP suspended in water. The tested pathogens included Salmonella, Shigella, E.coli, gr. A Streptococci and S.aureus. Anti-bacterial activity was not demonstrable even in a solution containing 25,000 mg per litre of crude powder. The second was designed to detect serum bactericidal activity after oral intake of stem and leaves of AP. Ten healthy volunteers were enrolled in the study. They received a single oral dose of AP (1, 2, 3 and 6 g) in a randomized, cross-over manner. The washout period was one week. Blood samples were taken at 0, 1, 2, 4, 8 and 24 hours after ingestion. Serum bactericidal activity was assayed by agar diffusion technique using Bacillus spores and five strains of each pathogen (Shigella, Salmonella typhi, S.aureus and gr. A Streptococci) incubated for 24 hours. Again serum bactericidal activity was not detected in any of the sera tested. In a third study, ninety-six rats were daily fed with high doses of AP ranging 0.12-24 g per kg body wt. for six months before sacrifice. Antibacterial activity was still undetectable when lung parenchyma and liver tissue was placed on culture media containing bacteria tested. In conclusion, anti-bacterial activity of AP is undetectable in our study.

Disseminated strongyloidiasis: report of seven cases.

Disseminated strongyloidiasis with associated infection from various organisms in 7 cases on corticosteroid therapy are reported. Either respiratory or abdominal symptoms or both without other obvious etiological factors are its usual clinical manifestations. The highly motile filariform larvae of Strongyloides stercoralis were demonstrated in sputum, gastric content, peritoneal fluid as well as in stool. Associated infection from various organisms were found in 6 cases and it is believed that these contributed to immediate cause of death since disseminated strongyloidiasis had been eradicated before death. Only one case survived. Thiabendazole therapy in conventional dosage is adequate in eradicating disseminated strongyloidiasis.

Disseminated nocardiosis after pulmonary collapse: a case report.

A 24-year-old Thai woman receiving corticosteroid treatment for systemic lupus erythematosus, developed pulmonary nocardiosis after pulmonary collapse. The correct diagnosis was reached when dissemination had occurred which was characterized by two subcutaneous abscesses and acute uveitis of the right eye. Gram stain of sputum and pus revealed delicate, branching, Gram-positive filamentous mycelia which were identified as Nocardia asteroides on culture. Subcutaneous abscesses and exophthalmos disappeared after one week of therapy and she made an uneventful recovery.