EXPERIENCE WITH ONCE DAILY DOSING OF GENTAMICIN: CONSIDERATIONS REGARDING DOSING AND MONITORING

Summary: 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.

Comment: The once-daily dosing schedule of gentamicin is justified by the concentration-dependent killing property of aminoglycosides, and by partial attribution of the gentamicin-toxicity to its prolonged serum concentration. In a large study of 2,184 adults treated with once-daily gentamicin, although the therapeutic effect was the same as that observed with the conventional dosing technique at the same hospital, a significant reduction in incidence of nephrotoxicity was seen (1.2% vs. 3-5%). In the developing countries, where the techniques for measuring serum gentamicin level is not widely available, and on account of the pharmacodynamically sound and pharmacoeconomically beneficial results obtained from this therapeutic regimen, once-daily dosing of gentamicin is probably most suitable in the third world patients whenever there is no contraindication.

Farrokh Habibzadeh, M.D., Shiraz.

Source: Christensen S, Ladefoged K, Frimodt-Moller N. Chemotherapy 1997 Nov; 43(6):442-450.

PROTECTIVE IMMUNITY INDUCED BY ORAL IMMUNIZATION WITH A ROTAVIRUS DNA VACCINE ENCAPSULATED IN MICROPARTICLES

Summary: DNA vaccines are usually given by intramuscular injection or by gene gun delivery of DNA-coated particles into the epidermis. Induction of mucosal immunity by targeting DNA vaccines to mucosal surfaces may offer advantages, and an oral vaccine could be effective for controlling infections of the gut mucosa. In a murine model, we obtained protective immune responses after oral immunization with a rotavirus VP6 DNA vaccine encapsulated in poly(lactide-coglycolide) (PLG) microparticles. One dose of vaccine given to BALB/c mice elicited both rotavirus-specific serum antibodies and intestinal immunoglobulin A (IgA). After challenge at 12 weeks postimmunization with homologous rotavirus, fecal rotavirus antigen was significantly reduced compared with controls. Earlier and higher fecal rotavirus-specific IgA responses were noted during the peak period of viral shedding, suggesting that protection was due to specific mucosal immune responses. The results that we obtained with PLG-encapsulated rotavirus VP6 DNA are the first to demonstrate protection against an infectious agent elicited after oral administration of a DNA vaccine.

Comment: Rotavirus, is considered to be the commonest single agent causing acute childhood diarrhea associated with high worldwide and may be mortality rate. Globally, rotavirus causes 130 million or more cases of infantile diarrhea each year, and almost one million deaths. Most of fatal occur in the third World communities where health standards are low. Recently, a rhesus retrovirus tetravalent (RRV-TV) oral vaccine was tested successfully under real-life conditions, in Finland. Development of the newly DNA vaccines, which provides easy transport and maintenance, is promising for the developing countries, where dehydration is one of the most important killers in children.

Mahboobeh Yadollahie, M.D., Shiraz, Iran

Source: Chen SC, Jones DH, Fynan EF, et al. J Virol 1998 Jul 1; 72(7):5757-61.

GLOBAL SURVEILLANCE FOR ANTITUBERCULOSIS-DRUG RESISTANCE, 1994-1997

Summary: Background Drug-resistant tuberculosis threatens efforts to control the disease. This report describes the prevalence of resistance to four first-line drugs in 35 countries participating in the World Health Organization-International Union against Tuberculosis and lung Disease Global Project on Anti-Tuberculosis Drug Resistance surveillance between 1994 and 1997. Methods The data are from cross-sectional surveys and surveillance reports. Participating countries followed guidelines to ensure the use of representative samples, accurate histories of treatment, standardized laboratory methods, and common definitions. a network of reference laboratories provided quality assurance. The median number of patients studied in each country or region was 555 (range, 59 to 14, 344). Results Among patients with no prior treatment, a median of 9.9 percent of Mycobacterium tuberculosis strains were resistant to at least one drug (rang, 2 to 41 percent); resistance to isoniazid (7.3 percent) or streptomycin (6.5 percent) was more common than resistance to rifampin (1.8 percent) or ethambutol (1.0 percent). The prevalence of primary multidrug resistance was 1.4 percent (range, 0 to 14.4 percent). Among patients with histories of treatment for one month or less, the prevalence of resistance to any of the four drugs was 36.0 percent (range, 5.3 to 100 percent), and the prevalence of multidrug resistance was 13 percent (range, 0 to 54 percent). The overall prevalences were 12.6 percent for single-drug resistance (range, 2.3 to 42.4 percent) and 2.2 percent for multidrug resistance (range, 0 to 22.1 percent). Particularly high prevalences of multidrug resistance were found in the former soviet Union, Asia the Dominican Republic, and Argentina. Conclusions Resistance to antituberculosis drugs was found in all 35 countries and regions surveyed, suggesting that it is a global problem.

Comment: Anti-tuberculosis treatment failure and drug resistance have been dreaded possibilities over the last decades at least fifty years. The outbreak of multi-drug resistant tuberculosis HIV positive patients took alarming proportions the past decade. In many developing countries, in addition to HIV infection, other reasons implicated for drug resistance include non-compliance, and irregular drug supply with subsequent erratic drug use. This cross-sectional multi-center study evaluates the results of coordinated surveillance reports conducted with supervision of World Health Organization International Union Against Tuberculosis. The main emphasis has been to study the prevalence of multi-drug resistance to anti-tuberculosis drugs.

In this study the disproportionately high prevalence of multi-drug resistance in certain developing countries has been attributed to weakness in the local tuberculosis-control programs, malnutrition, immigration from endemic regions, and the increasing number of HIV-infected patients. The high prevalence of resistance in certain regions of the former Soviet Union has been attributed to non-standardized regimens. An interesting finding has been the rather low prevalence of drug resistance in the African countries, despite the relatively high prevalence of HIV infections and poor socio-economic condition. This has been attributed to relatively late introduction of rifampin, and also the limitation of anti-tuberculosis drug usage to particular supervised treatment programs.

One may conclude that although the relationship between the quality of governmental control programs and decrease in drug resistance is far from "linear" and possibly rather complex, nevertheless control programs, however, can be implemental to lower the resistance rates by rendering particular attention to the following parameters as possible contributors: malnutrition, immigration from endemic regions, tuberculosis among HIV-infected patients, non-standardized regimens, and unsupervised use of anti-tuberculosis drugs.

It is noteworthy that although the prevalence of resistance in Asia and certain Middle-Eastern regions is expected to be rather high, none of the Middle-Eastern countries has been included in this 35-country survey, and only four regions in Asia (three southeastern Asian countries and Delhi in India) have been included.

Nasrollah Ghahramani, M.D., Shiraz, Iran

Source: Pablos-Mendez A, Raviglione MC, Laszlo A, et al. N Engl J Med 1998; 338:1641-9.

RAPID ACCURATE FIELD DIAGNOSIS OF INDIAN VISCERAL LEISHMANIASIS

Summary: Background A firm diagnosis of visceral leishmaniasis (kala-azar) requires demonstration of the parasite in organ aspirates or tissue biopsy samples. The aim of this prospective study was to assess the diagnostic usefulness of non-invasive testing for antibody to the leishmanial antigen K39 by means of antigen-impregnated nitrocellulose paper strips adapted for use under field conditions. Methods One drop of peripheral blood is applied to the nitrocellulose strip. Three drops of test buffer (phosphate-buffered saline plus bovine serum albumin) are added to the dried blood. The development of two visible bands indicates presence of IgG anti-K39. 323 consecutive patients with suspected kala-azar referred to two specialist units in India, and 25 healthy controls, provided fingerstick blood samples for the test. Spleen aspirates were taken from 250 patients. Findings Kala-azar was confirmed by microscopy of spleen-aspirate smears in 127 patients. The K39 strip test was positive in all 127; the estimated sensitivity was therefore 100% (95% CI 98-1000). Four patients had positive strip test but negative aspirate smear; all four responded to treatment for leishmaniasis. 217 individuals, including the 25 healthy controls, 73 patients with malaria or tuberculosis, and 119 spleen-negative patients who had presumed malaria or cirrhosis (79) or no final diagnosis (40), had negative strip-test results. None of the 119 aspirate-negative patients developed evidence of kala-azar during 3-6 months of follow-up. The estimated specificity of the strip test was 98% (95-100; 217/221). Interpretation Detection of anti-K39 by immunochromatographic strip testing is a rapid and non-invasive method of diagnosing kala-azar, which has good sensitivity and specificity and is well studied for use in field conditions.

Comment: Visceral leishmaniasis is a disseminated infection in tropical and subtropical regions of the world and associated with potential mortality in children. In many developing countries Visceral Leishmaniasis occur in distant urban and tribal regions lacking proper laboratory facilities. Kala-azar is diagnosed by observing parasites on the smear or tissue culture, but this requires invasive procedures and qualified personnel. Serologic studies either require fluorescent microscopes or the ELISA equipment which is not available everywhere. Direct agglutination test (DAT) can be easily used on the field, but on account of its sensitivity to its detection of remote infection, its specificity is not so high and PCR amplification testing for leishmania DNA is not practical on the field. The proposed method, if widely proved effective along with high specificity and positive only in acute phases, will be practically ideal to use as an excellent test in fields. This method will be helpful in preventing long distance travels of patients which is also accompanied by economic benefits.

Abdolvahab Alborzi, M.D., Shiraz, Iran

Source: Sundar S, Reed SG, Singh VP, et al. Lancet 1998 Feb 21; 351:563-5.

ADEQUACY OF INTERVIEWS VS CHECKLISTS FOR CLASSIFYING CHILDHOOD PSYCHIATRIC DISORDERS BASED ON PARENT REPORTS

Summary: Background The advantages and disadvantages of lay-administered structured Interviews and self-administered problem checklists for estimating prevalence and associated features of childhood psychiatric disorder have attracted little comment. This article compares the scientific adequacy of these? Instruments for classifying DSM-III-R categories of childhood psychiatric disorder in general population samples. Methods Study data are from parental assessments of 251 children aged 6 to 16 years participating in a 2-stage measurement evaluation study. Reliability and validity were compared between the Diagnostic Inter view for Children and Adolescents (The structured interview used in the study) and the revised Ontario Child Health Study Scale (the self-administered problem checklist used in the study). Results Reliability estimates based on the k statistic were comparable for the 2 instruments and ranged from 0.21 (conduct disorder) to 0.70 (depression) on the lay interview and from 0.27 (depression) to 0.61 (oppositional defiant disorder) on the self-administered checklist. Validity coefficients tended to favor the checklist categories, but only marginally. Conclusions On balance, differences in reliability and validity were small between the 2 instruments. These differences would appear to have no discernible impact on the knowledge about prevalence and associated features of disorder generated by use of such instruments in general population surveys.

Comment: During recent decade there has been a spectacular burgeoning of research into chid psychiatric disorders. The results have changed clinical practice in child psychiatry and have done much to aid understanding the childhood roots of some adult psychiatric disorders¹. However, psychiatric research continues to be troubled by difficulties in measurement ² At one time, many investigators thought that the use of standardized interviews and operationalized criteria for diagnosis would solve the problems, but it is evident that they have not. The study by Boyle et al³ is helpful infusing on the relative merits and demerits of structured respondent-based interviews and checklists. They conclude that there is not much to choose between the 2 methods for reliability and validity, note that checklist take much less time to complete, and point out that the approach of the 2 methods is basically similar.

Having said that given situations in countries like Iran with shortage of qualified interviewers, the presented results are quite interesting. In recent years concern about psychiatry especially child psychiatry has surged in Iran. Meanwhile mental health institutions are reclining toward research in these issues.

Results of Boyle et al study would probably favor allocating more to devising check-lists rather than the more time consuming structured interview. These results should be considered before launching large scale national surveys.

Alagheband J, M.D., Tehran, Iran.

Source: Boyle MH, Offord DR, Raoine YA, et al. Arch Gen Psychiatry 1997; 54:793-9.

USEFULNESS OF VENOUS LACTATE LEVELS FOR THE DIAGNOSIS OF SEIZURE IN UNCONSCIOUS PATIENTS

Summary: Objectives This prospective study was conducted to evaluate the usefulness of venous lactate assay in the diagnosis of generalized seizures. Patients and Methods Over a three month period, 78 consecutive adults admitted to the emergency unit for unconsciousness were included in the study. Three study groups were defined; patients with generalized seizures (n=22), unconscious patients without seizure (n=34) and known epileptic patients with unexplained malaise (n=22). Patients with a disease susceptible of increasing lactate levels were excluded. Peripheral venous blood was drawn to determine lactates, bicarbonates and pH on a blood gas analyzer. All determinations were performed within 5 minutes of blood withdrawal. CPK levels was also determined with an enzymatic method. Results In patients who had seizures, venous lactate levels were higher than those in patients who had no seizures; 4.3±0.5 mmol/l in generalized seizure patients versus 1.04±0.1 and 2.2±1.39 in unconscious patients without seizure and known epileptic patients with unexplained malaise respectively. The lactate level of 2.5 mmol/l given by ROC curves gave a 0.97 specificity and a 0.73 sensitivity. Discussion The acidosis observed in patients with generalized seizures results from the combined effects of respiratory and metabolic acidosis. High lactate level would be a consequence of hypoxemia, per seizure rise in catecholamine and aerobic and anaerobic metabolism in muscles during the tonic- clonic phase. In patients presenting in an unconscious state increased lactate levels, even when determined up to 2 hours after venous blood withdrawal, could be a useful parameter for the diagnosis of epileptic seizure.

Comment: As the authors have acknowledged; arterial lactic acid concentrations has been proposed as a diagnostic aid for discriminating tonic-clonic seizures from other causes of unconsciousness since almost 20 years ago. But measuring venous lactate levels seems quite innovative. Hazouard et al acclaim that venous lactate levels above 2.5 mmol/l center a 0.97 specificity and 0.73 sensitivity in differentiating patients with generalized seizures from unconscious patients without seizures. The latter group was comprised of vasovagal attack, hypoglycemia and even panic attack patients.

Staff of medical emergency units usually face difficulties in assessing whether a patient presenting with a history of unconsciousness has suffered a tonic-clonic seizure. The available methods such as measuring serum prolactin, ACTH, cortisol and even CPK are not always promising and EEG is not available in all services especially in developing countries.

Special cultural concerns in Iran and some other developing countries about seizures and unconsciousness (e.g. negative attitude toward epilepsy, equating different kinds of unconsciousness) usually tarnish Layman eye witness description of attacks and further complicate diagnosis.

Thus measuring venous lactate seem a simple, non-invasive, inexpensive but very valuable method especially in developing countries where access to more sophisticated procedures are limited. The main drawback is the need for immediate analysis (within 5 minutes) of blood samples which mandates special equipment.

References:

Mokri A, M.D., Tehran, Iran.

Source: Hazouard F, Deguin PF, Lanatte R, et al. Presse Med 1998; 27: 604-7.

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