Community-Based Surveillance for Drug Resistance of Mycobacterium tuberculosis in Selected Areas in the Philippines

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1 Community-Based Surveillance for Drug Resistance of Mycobacterium tuberculosis in Selected Areas in the Philippines Myrna T. Mendoza, M.D.,* Tessa Tan-Torres, M.D.,* Concepcion F. Ang, R.M.T.,* Rosemarie Arciaga, M.D.,** Flor Elona, M.D.,** Madelaine Retuta, M.D.,** Nora Cruz, M.D.*** and Mariquita Mantala, M.D.*** (*Infectious Disease Section, Department of Medicine, University of the Philippines, College of Medicine-Philippine General Hospital, Taft Avenue, Ermita, Manila, Philippines; **Regional TB Coordinators, Department of Health; and ***National TB Control Program, Department of Health; Please send correspondence to: Dr. Myrna T. Mendoza, Infectious Disease Section, Department of Medicine, UPCM - Philippine General Hospital, Taft Avenue, Ermita, Manila, Philippines; Telefax No. (6) 55--6; address: idsuppgh@pacific.net.ph) ABSTRACT Hospital based reports on multi-drug resistant tuberculosis (MDR-TB) in the Philippines are high. To determine the incidence of MDR-TB in the community, a surveillance was done in selected areas in the Philippines representing Luzon (La Union), National Capital Region (Metro Manila), Visayas (Leyte) and Mindanao (Zamboanga). Sputum specimens from newly registered TB symptomatics consulting at the community health centers were collected for mycobacterial smears and culture. Data on clinical signs and symptoms, history of previous anti-tb treatment, chest x-rays and AFB smear results were collected. Drug susceptibility tests for all isolates were done at the TB research laboratory in the University of the Philippines-Philippine General Hospital. The rate of MDR-TB in Metro Manila areas was 6.4% (95% CI.9, 9.9), in La Union, 9.6% (95% CI 4.6, 7.5), in Zamboanga, 4.4% (95% CI.4,7.6) and in Leyte 5.% (95% CI., 9.98). The findings indicate that MDR TB should be addressed to ensure the success of the TB control program in the areas studied. TB control efforts should be tailored according to the needs of the community. Community based surveillance should be continued and MDR-TB monitored in the areas where reports of TB is high. [Phil J Microbiol Infect Dis ; ():69-75] Keywords: MDR-TB, MDR-TB Philippines Surveillance, TB Drug Resistance, Drug Resistant TB, Drug Resistant PTB INTRODUCTION The state of tuberculosis (TB) problem in the Philippines has not significantly changed since 8 years ago. The Philippine Health Statistics of 99, reported a TB mortality rate of 5.9/, and a morbidity rate of /,. Based on the 997 National Prevalence Survey, with a population of 76M in 999, it is estimated that 75 Filipinos die of TB each day and approximately, new smear (+) Filipinos are spreading the disease and infecting other individuals annually, To address this problem the Philippine Department of Health (DOH) aims for the full implementation of directly observed therapy (DOTS) in the whole country by. The DOH treatment regimen is 4HRZ/HR for newly diagnosed PTB and 4HRZE or S/HR for patients with history of previous treatment. Inadequate case finding and high defaulter rates during treatment are reasons cited for the uncontrolled state of TB in the Philippines. Poor TB control can give rise to treatment failure, relapse and further transmission of tuberculosis. As a result of this, resistance to anti-tb drugs has become a potential problem. Studies have shown that there is an increased risk for patients with previous history of inadequate treatment for TB to develop multi-drug resistant-tuberculosis (MDR-TB). 4,5,6 MDR-TB is defined by the World Health Organization (WHO) as resistance to at least both isoniazid and rifampicin. MDR-TB if not prevented can be a major threat to the country's TB control program. Reports of drug resistant tuberculosis from hospitals in Metro Manila are alarming. Multi-drug resistant TB prevalence rates ranged from 4% to 45%. MDR rate was as high as 4% in the University of the Philippines-Philippine General Hospital (UP- PGH) report. 4 Since

2 these reports emanate from tertiary care referral hospitals, the high resistance rates are to be expected because most physicians request for culture and sensitivity testing only for patients who fail treatment. One community-based study also reported high rates of drug resistance but since it was a drug trial, there may have been a referral bias. 7 Factors favoring the development of drug resistance are also present in the community. Anti-TB drugs can be obtained over the counter even without a prescription. Isoniazid has a reputation for being a vitamin and is taken as self-medication for "weak lungs," a local euphemism for tuberculosis. Less than 85% of PTB patients do not get cured because of noncompliance in completing the 6 months treatment regimen. Resistance to anti TB drugs is the inevitable result of incomplete and repeated treatment. This leads to patients acquiring drug resistant tuberculosis i.e. acquired drug resistance. They can transmit the resistant organisms to their contacts that may subsequently develop drug resistant tuberculosis. These contacts that develop the disease are now said to have primary resistance or initial drug resistance. Treatment failure is also likely to occur if drug resistance is present. If the organism is resistant to or more of the primary drugs and most especially to both isoniazid and rifampicin, the chance of cure is poor because only amikacin and the expensive fluoroquinolones are available as second line drugs in the Philippines. MDR strains that are resistant to isoniazid and rifampicin are often resistant to other drugs as well. The occurrence of widespread MDR-TB can do considerable harm to the TB control program of the country. The more important task of the TB Control Service of the Department of Health (DOH) therefore is to ensure that country-wide spread of MDR-TB does not happen. This can be done by an effective surveillance system so that control measures can readily be done in areas proven to have high MDR rates. Drug resistant TB is not included in the antimicrobial resistance surveillance system of DOH. Surveillance for MDR TB is essential to determine the current scale and nature of drug resistance problem in the country and to define the correct solution. This study was undertaken with the following objectives: set up a community-based, sentinel site surveillance system for drug resistance of Mycobacterium tuberculosis (M. Tb) in selected areas in the country; determine resistance rates of M. tuberculosis to the 4 first line anti- TB drugs; determine history of previous anti-tb therapy among patients surveyed and provide recommendations to the tuberculosis control program on the standard treatment of sputum positive patients. MATERIALS AND METHODS The Philippines is composed of 7, islands. It is divided into major groups of islands namely Luzon, Visayas and Mindanao. Surveillance areas were selected to represent these major groups of islands. The capital city of Manila is in the National Capital Region of the country, which is located in Luzon. The major steps taken to set up the surveillance were setting up of laboratories and surveillance sites. Selection of sites for surveillance was done in coordination with the National TB Control Program and the Field Epidemiology Training Program of the DOH. The selection of sites was based on geographical representation of the major groups of islands and availability of regional laboratory equipment for level mycobacteriology. The following were chosen: Ilocos Regional Training and Medical Center in La Union (North Luzon), Zamboanga City Medical Center in Zamboanga (Mindanao), Leyte province (Visayas) and Metro Manila (Manila and surrounding cities and municipalities in the National Capital Region). The existing TB research laboratory of the University of the Philippines-Philippine General Hospital (UP-PGH) in Manila served as the coordinating laboratory.

3 Selection of Patients Identification of health centers per site was chosen to represent urban and rural areas. Prior to actual surveillance, orientation of municipal health officers, health center physicians, nurses and medical technologists/microscopists were oriented about the mechanics of the surveillance. Due to limited funds, the patient sample size was targeted to be at least % of the estimated smear (+) in the site population based on the 994 DOH census report. Patients for surveillance were taken from all newly registered TB symptomatics in the community health centers. TB symptomatics was defined by DOH as patients with chronic cough of more than two weeks duration, with fever, and either weight loss, back pain or hemoptysis. Re-treatment cases were excluded from the study. The first surveillance site developed was Metro Manila (population = 5M). The sputum specimens of new TB symptomatics consulting at the health centers were smeared and read at the centers. If found (+) for AFB, to specimens of sputum were collected per patient and were processed for culture isolation for M. tuberculosis at the PGH TB research laboratory. Chemotherapy was started in the health centers if the sputum smear was read as AFB positive. A case form was filled up to include signs and symptoms and data on previous intake of anti-tb medications for at least one month and chest x-ray results if available were collected. The same procedures were done in the provinces of La Union (population =.8M) and Zamboanga (population =.7M), where the regional TB laboratories were set up. If positive, sputum specimens were sent for culture to the provincial regional and UP-PGH TB laboratories. If M. tuberculosis was grown and isolated, the isolates from the provinces were sent via courier to the UP-PGH TB research laboratory in Manila for drug susceptibility testing (DST). Results were sent back to the health centers upon completion of all studies. The last surveillance area was Leyte province (population =.M). Since the province has no regional TB laboratory all smear (+) sputum specimens were sent via courier to the PGH TB Research Laboratory in Manila for processing. Laboratory Procedures Medical technologists from La Union and Zamboanga were trained on culture isolation and drug susceptibility testing of M.TB at PGH. The training manuals were based on the standards set by 996 National Committee of Clinical Laboratory Standards (NCCLS) and the standard manual of laboratory procedures on TB Bacteriology by Kubica et al. 8 The drug susceptibility testing (DST) method adopted was the indirect test by proportion method utilizing disc diffusion in 7H media. The 4 first line drugs e.g. INH, ethambutol, rifampicin and streptomycin were included in the DST. Briefly, for culture isolation, sputum specimens per patient were pooled for initial processing of digestion and decontamination with 4% NaOH. 9 After 5 minutes of decontamination, specimens were centrifuged and. ml of the sediment was inoculated onto two Lowenstein-Jensen (LJ) egg medium tubes. These were incubated for 8 weeks or until growth was detected. When pure colonies of mycobacteria (without contamination) were observed, biochemical identification was performed using the nitrate and niacin tests to identify Mycobacterium tuberculosis. Drug susceptibility testing (DST) was performed when colonies were at least weeks old with more than colonies per LJ tube. For DST, 7H (DIFCO) culture media plates were prepared 4 hours prior to actual tests. Standard sensitivity discs (BBL) of isoniazid, rifampicin, ethambutol and streptomycin were placed on quadrant plates of 7H media inoculated with standard amount of Mycobacterium tuberculosis isolate equivalent to 7 CFU. The standard discs potency used was equivalent to the recommended critical concentrations. These were INH. ug/ml and. ug/ml,

4 streptomycin. ug/ml, ethambutol 5. ug/ml and. ug/ml and rifampicin. ug/ml. Drug susceptibility was determined by (+) or (-) growth or the presence or absence of colonies in quadrants with antimicrobial discs. The number of colonies in quadrants with (+) growth was compared with the number of colonies in the control quadrant without antimicrobial discs. A proportion of % was considered resistant. Readings of DST plates were done after weeks of incubation. Total turn around times from receipt of specimen to reporting of results was 4-8 weeks for culture isolation and another weeks for DST. Statistical Analysis Descriptive statistics inclu ding means and proportions were reported for continuous and categorical data respectively. Epi-info version 6 software was used to calculate confidence intervals. RESULTS Metro Manila Results Actual collection of sputum specimens from surveillance patients was started in Metro Manila in September 995 and ended June 996. Sixty-four barangay health centers (BHC) from within Manila and nearby cities and municipalities participated. There were a total of,4 TB symptomatics who submitted their sputum, 65 were found to be smear and culture positive. Their mean age was 4.4 years and 54% were males. In the past, 6.7% took anti-tb medications for at least one month (Table ). The drug sensitivity results of the 65 isolates from Metro Manila are presented in Tables and. Multi-drug resistant rate, defined as resistance to INHrifampicin was 6.4% (95% CI.9, 9.9) overall. Table. Summary of the patient profile and their MDR rates in the different surveillance sites ( ) Metro Manila La Union Zamboanga Leyte Barangay Health Centers 64 4 Total (+) patients Mean Age (Years) M:F :.9.6:.5:.5: History of Previous anti-tb Tx (%) Total MDR (%) Table. Community-based surveillance for MDRTB ( ) Fully Susceptible (%) Single Drug Resistance (%) Resistant to > Drugs (%) MDR % (WHO definition) Total Isolates (95% Confidence Interval) La Union (4.5, 7.5) Metro Manila (.9, 9.9) Leyte (., 9.98) Zamboanga (.4, 7.) Provincial Results Collection of sputum specimens started at different periods in 996 in the provincial sites. In the La Union surveillance, barangay health centers from 5 municipalities participated. However, surveillance was interrupted for almost a year because of the hospital construction, which disrupted the laboratory work. One hundred sixteen patients were screened and 8 patients

5 had (+) sputum smears and culture. In the past, 8.5% of them took anti TB medications. The MDR rate was 9.6% (95% CI 4.6, 7.5). Zamboanga City and 7 other municipalities including Basilan and Jolo participated in the Zamboanga surveillance. Data collection from 4 BHCs was from January 996 to October 998. In the Zamboanga site, 4 were screened and 74 were smear and culture (+). The population studied was younger (mean age 9.6 years), and they had a lower proportion of patients with a history of previous treatment (.7%), Table. The cumulative MDR rate in Zamboanga was 4.4% (95% CI.4, 7.). Tables and show the detailed DST results from these provinces. The province of Leyte was surveyed in 999 and out of 84 patients surveyed, 65 were sputum smear (+) and 5 culture (+). Their mean age was 4. years and M:F ratio was.5:. Only 5% of them gave a history of previous anti TB treatment. The pattern of resistance in Leyte is shown in Tables and. Almost 8% of the isolates tested were susceptible to the first line anti-tb drugs tested. MDR rate was 5.% (95%CI., 9.98). Table. Detailed drug susceptibility results of M. Tb isolates from Community-based surveillance for MDRTB, all sites Sites Metro Manila La Union Leyte Zamboanga Pattern No. % No. % No. % No. % Fully susceptible One Drug Resistance INH RIF EMB STREP Two Drug Resistance INH-RIF INH-EMB INH-STREP RIF-EMB RIF-STREP EMB-STREP Three Drug Resistance INH-RIF-EMB INH-RIF-STREP INH-EMB-STREP RIF-EMB-STREP Four Drug Resistance INH-RIF-EMB-STREP 4 Total Isolates According to number of drug resistance* drug resistance At least drug resistance At least drug resistance At least drug resistance At least 4 drug resistance According to type of drug resistance* drug resistance Isoniazid Rifampicin Ethambutol Streptomycin % INH-RIF resistance (MDR- TB) 6.4% (95% CI =.9, 9.9) 9.6% (95% CI = 4.6, 7.5) *note that categories are not mutually exclusive and therefore, total exceeds % % (95% CI =., 9.98) % (95% CI =.4, 7.6)

6 Table shows the detailed DST of M.TB isolates from all sites. Resistance to rifampicin was found in various combinations with other first line drugs when the isolate is MDR. Total INH resistance was higher in the provinces than Metro Manila. Total ethambutol resistance was highest in Metro Manila (8.8%) and total streptomycin resistance was highest in La Union (4.4%). The table also tends to show that in any chemotherapeutic combination regimen, there is a -7% chance that the infection will be resistant to at least one of the drugs in the regimen. DISCUSSION Multi-drug Resistant Tuberculosis The development of multi-drug resistance in tuberculosis is a feared development because of its implication on treatment. MDR-TB is notoriously difficult to treat with few second line drugs available that are effective and, at the same time, safe and relatively inexpensive. The reported rate of 6.4% in Metro Manila in 996 is not as high as those reported from tertiary care hospitals, as hypothesized. It is also within the range of MDR-TB rates reported in systematic review of reports in the literature. In 99, the First National TB consensus reported a noncompliance rate of % which was believed to be the major factor in treatment failure. The MDR rate reported in the National Capital Region means that greater than % of patients being treated at the health centers will not get cured, primarily not because of non-compliance, but also now additionally because of MDR. The candidate drugs of ethambutol and streptomycin to be added, in the four-drug regimen for re-treatment of PTB, also have worrying rates of resistance (Table ). Ethambutol is more convenient to administer than streptomycin. However, the advantage of streptomycin is that it needs to be given by a health worker and could be used as 'conditioning' for the introduction of DOTS. The MDR rates were relatively low in Leyte and Zamboanga. This just means that the triple drug regimen of 4HRZ/HR previously recommended by DOH for all PTB cases may still work in both areas. It is however different in La Union where the MDR rate is even higher than Metro Manila. This rate maybe unstable because of the small sample size. But a MDR rate of 9.6% is worrisome. The surveillance data collected may have been infused with patients who actually had histories of previous treatment. More attention to the implementation of TB control efforts should be given to this place. Continuing surveillance must be done to see if there is really a trend. Active case finding and treatment in the form of DOTS should be applied in this province. In comparison to the WHO/IUATLD global surveillance for anti-tb drug resistance, our data is within the range of MDR prevalence rates reported from 5 countries surveyed e.g. primary MDR of.4% minimum and 4.4% maximum. The overall prevalence for single drug resistance was.6% in the global surveillance against our average rate of.7%. Compared to Thai-land and Vietnam, our MDR rate is higher. Based on patients, MDR in Thailand was.8% (95% CI.4-9.) and in Vietnam, based on 64 patients, MDR was only.% (95% CI.4 -.9). The response of the World Health Organization (WHO) to this global threat of MDR TB is directly observed treatment with short course chemotherapy (DOTS). The directly observed therapy has been reported to be successful in other developing countries also with the problem of drug resistant tuber-culosis. 4,5 The DOTS program has been established in some areas in the country. It is hoped that the same success as in other countries will be observed.

7 Sentinel Site Surveillance System for MDR-TB The surveillance identified multi-drug resistant cases. However, for the patient and the health personnel treating the patient, the information on DST would not be very helpful. By the time the sensitivity results come in, the health personnel would most probably have already identified the patient as potential 'treatment failure' because of persistently positive AFB smears. In a country with limited resources, the only recourse is early identification of MDR-TB patients especially among those with previous history of treatment and refers them to specialists who are MDR-TB experts for proper treatment and management. The surveillance system in areas with laboratory capability should be standardized and continued. Periodic prevalence surveys on the other hand can be done in areas where a TB laboratory is not available. During transport of specimens however; fewer positive results is obtained due to contamination. Future surveillance should target for more than % of the estimated smear (+) cases to offset this problem. Depending on the amount of resources available, one can also further tailor the sampling by recommending that culture and DST be performed for all patients with a previous history of anti-tb drug intake. CONCLUSIONS Recommendations The Philippines being an archipelago may have different rates of MDR TB. As noted in the study, the 4 sites studied did not give similar results. Combining data for a national prevalence rate will only mask the problem in areas with high rates. Community based sentinel site surveillance should be adopted in other strategic regions of the country where TB pre-valence is high. The control efforts should "tailored" according to the needs of the regions. Eventually this will prove to be cost effective especially where the regional laboratories are in place. A central national reference laboratory should continue monitoring quality control of the laboratory results. A sustainable national surveillance system is most important. This will be useful to accurately assess the outcome of the control programs of DOH in these sentinel sites. The WHO recommended the DOTS strategy for effective TB control. Short Course Chemotherapy (SCC) with or 4 drug regimens should be accessible to the health center level only through a DOTS program. In areas with potential high MDR rates such as La Union and NCR, case detection and susceptibility testing should be done on site for accurate diagnosis and guidance of treatment. Referral centers for the treatment of patients with MDR-TB should be established in these "hot spot" areas. The 'DOTS plus' program of the WHO should be adopted in these centers where patients are given fully supervised DOT that are individualized according to the patient's drug resistance pattern. Finally, the surveillance only monitors the development of MDR-TB and may be the basis for recommending the addition of new drugs. However, if nothing definitive is done to prevent the development of MDR-TB, the surveillance will just document increasing rates. There is a need to improve case-holding in the health centers to prevent the development of MDR TB, define the contribution of private practitioners in TB control and improve their participation in the control program, define the contribution of self-medication in TB control and increase the opportunities for patients to be under medical supervision. At the least, a unified effort is needed to improve the control of tuberculosis in the country. Acknowledgements The study would not have been carried out without the funding from the Philippine Council for Health Research and Development and the Essential National Health Research Program of the Department of Health.

8 We thank the participation of the different barangay health centers of NCR, La Union, Zamboanga and Leyte for making this surveillance possible. Finally, the authors would like to acknowledge the technical support of Ms. Carmela Enrile, Wilma Casaclang, Marc Agnew Cajucom of the TB Research Laboratory, UP-PGH and the typing expertise of Ms. Richell Jeciel Mojica. REFERENCES. Philippine Health Statistics, Health Intelligence Service 99.. Task Force on Tuberculosis. Philippine Practice Guidelines Group in Infectious Diseases. Diagnosis, Treatment and Control of Tuberculosis, Clinical Practice Guideline Number. Quezon City, Philippines,.. Tupasi TE, Radhakrishna S, Rivera AB, et al. The 997 Nationwide Tuberculosis Prevalence Survey in the Philippines. Int J Tuberc Lung Dis 999; (6): Mendoza MT, Gonzaga AJ, Roa C, Velmonte MA, et al. Nature of drug resistance and predictors of multi-drug resistant tuberculosis among patients seen at the Philippine General Hospital, Manila, Philippines. Int J Tuberc Lung Dis 997; (): Jacobs R. Multi-drug Resistant Tuberculosis. Clin Infect Dis 994; 9: Kent JH. The epidemiology of multi-drug resistant tuberculosis in the United States. Med Clin North Am 99; 77(6): Manalo F, Tan F, Sbarbaro JA, Iseman MD. Community-based treatment: short course treatment of pulmonary tuberculosis in a developing nation: Initial report of an eight month, largely intermittent regimen in a population with a high prevalence of drug resistance. Am Rev Respir Dis 99; 4: Kent PT, Kubica GP. Public Health Mycobacteriology: A guide for the Level III Laboratory. US Dept of Health and Human Services, Public Health Service. Centers for Disease Control, Atlanta Georgia, Araneta UV, Roa C, Dantes R, Jorge M. Single early morning sputum and -day pooled early morning sputum in the diagnosis of PTB. Phil J Chest Dis 995; Iseman MD. Treatment of multi-drug resistant tuberculosis. N Engl J Med 99; 9: Cohn D, Bustreo F, Raviglione M. Drug resistant tuberculosis: Review of the worldwide situation and the WHO/IUATLD Global Surveillance Project. Clin Infect Dis 997; 4(suppl ):S-S.. Tri-Chest Organization. Committee Reports. The First National Consensus in Tuberculosis, Part I Pablos Mendez A, Laszlo A, Bustreo F, et al. Anti-tuberculosis drug resistance in the world. WHO/TB/97.9, Geneva; WHO Global Tuberculosis Programme Abderrahim K, Chaulet P, Oussedik N, Amrane R, Hassen CS, Mercer N. Practical results of standard first -line treatment in pulmonary tuberculosis: influence of primary resistance. Bulletin of the International Union Against Tuberculosis 976; 5: Zhang IX, Kan GQ, Tu DH, Li JS, Liu XX. Trend of initial drug resistance of tubercle bacilli isolated from new patients with pulmonary tuberculosis and its correlation with the tuberculosis programme in Beijing. Tubercle Lung Disease 995; 76:-.