Sputum culture results to monitor MDR-TB patients during treatment: How many do we

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1 JCM Accepts, published online ahead of print on 5 December 2012 J. Clin. Microbiol. doi: /jcm Copyright 2012, American Society for Microbiology. All Rights Reserved Sputum culture results to monitor MDR-TB patients during treatment: How many do we need? Saskia Janssen 1,2, Xavier Padanilam 3, Rianna Louw 3, Russel Mahanyele 3, Gerrit Coetzee 4, Thomas Hänscheid 5, Tjalling Leenstra 1,6, Martin P. Grobusch 1,2,7# Study site: Sizwe Hospital for Tropical Diseases, Johannesburg, South Africa 1 Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands 2 Institute of Tropical Medicine, University of Tübingen, Germany 3 Sizwe Hospital for Tropical Diseases, Johannesburg, South Africa 4 National Reference Laboratory for Tuberculosis, National Health Laboratory Service, Johannesburg, South Africa 5 Instituto de Medicina Molecular, University of Lisbon, Portugal 6 Netherlands Ministry of Defence, The Hague, The Netherlands 7 Department of Infectious Diseases, Division of Internal Medicine, Faculty of Medicine, Johannesburg, South Africa # Correspondence: Prof. Martin Peter Grobusch; m.p.grobusch@amc.uva.nl Running title: Sputum culture for monitoring MDR TB patients

2 Abstract Discharge after a single negative sputum culture may be cost-saving when treating multidrugresistant tuberculosis. However, after initial sputum conversion in 336 South-Africans, 11.6% and 5.4% reconverted after 1 and 2 months, respectively. These findings endorse the WHO definitions of 2 negative cultures taken 30 days apart after sputum culture conversion Downloaded from on July 13, 2018 by guest 2

3 Multi drug-resistant tuberculosis (MDR-TB) is a global problem with an estimated 310,000 cases worldwide in 2011(12). South Africa with 10,085 notified cases ranks high on the global scale (12). Molecular epidemiologic data suggests that both, nosocomial and community transmission, plays an important role because a significant proportion of patients has primary infection with MDR-TB (5). The follow-up of MDR-TB cases for treatment efficacy and infectiousness includes monitoring sputum smear conversion and culture results. Expert opinion-based definitions suggest two consecutive negative smears or cultures, taken 30 days apart (8,11). Recent World Health Organization (WHO) recommendations for MDR-TB patients include the use of culture rather than microscopy alone, with a minimum of monthly sputum culture until culture conversion, followed by quarterly culture examination afterwards (11). However, this requires adequate quality of culture performance and limited resources are recognized as an important obstacle (11). While still infectious, MDR-TB patients need to be isolated, even in the more recently recommended ambulatory care models (11). In drug-susceptible TB, patients are considered infectious until the first two weeks of TB-treatment are completed and sputum smears are negative on three consecutive days (10). However, recent studies using culture conversion report that the time until conversion may be longer, implying prolonged infectiousness (3,4,6). The question arose whether substantial transmission may continue to occur during treatment of drugresistant TB in ambulatory settings (2). It may be tempting in resource-strapped settings to use the first negative culture result to reevaluate the need for respiratory isolation. Certainly, two consecutive negative samples are better than one, but do we really need them both? Or, notwithstanding limited resources, would three negative cultures not even be better for infection control? This study aimed at evaluating the 3

4 54 55 optimal number of consecutive sputum cultures after culture conversion for decisions on respiratory isolation of MDR-TB patients Clinical records were reviewed from a case-series of MDR-TB patients admitted to Sizwe Tropical Disease Hospital in Johannesburg, between and This hospital serves as a referral centre for all cases of MDR- and extensively drug-resistant (XDR)-TB for Gauteng province, South Africa. Treatment is initiated in-hospital; after sputum culture conversion patients are discharged and followed up by a health facility based ambulatory care model. Ethical approval was obtained from the Ethics Committee of the Faculty of Health Sciences of the University of the Witwatersrand. Demographic data, Mycobacterium tuberculosis resistance pattern, treatment regimes and parameters of treatment response (sputum culture, discharge date, adverse events, death, loss to follow-up) were extracted from patient files. Inclusion criteria for the current analysis were: having sputum smear-positive MDR-TB, resistant to at least isoniazid and rifampicin, possibly in addition to resistance to one or more of the following; ethambutol, ethionamide, pyrazinamide or streptomycin. Patients with mono-drug resistance, or resistance to ofloxacin and kanamycin (XDR-TB) were excluded. All patients were treated according to their susceptibility test results. For each patient in this case series, progression over consecutive sputum cultures was assessed. Only a single monthly culture following initial sputum culture conversion (from positive to negative) was counted; consecutive sputum cultures were labelled as month 1 if taken between day 7 and day 37, month 2 if taken between day 37 and day 67, etc. For patients with multiple sputum cultures within one month, the latest result was included. The Kaplan Meier method was used to calculate the cumulative proportion remaining sputum culture negative per month following initial conversion (positive-negative), and to calculate the cumulative proportion 4

5 remaining sputum culture positive following re-conversion (positive-negative-positive). Patients were censored if deceased, discharged or lost to follow-up; which entails that these patients were excluded from the denominator of cumulative proportion calculation at all time-points following their censoring event Three hundred-and-seventy-one sputum culture positive MDR-TB patients were included; 199 (53.6%) were male, the median age was 36 (interquartile (IQ) range 29-45). On admission, 272 (73.3%) were HIV positive, of whom 158 (58.1%) were already receiving antiretroviral treatment; the median CD4 cell count was 157 (IQ range ). Of these patients, 26 patients died and 9 were lost to follow up before a 1 st negative culture, leaving 336 patients who had a first sputum culture conversion after variable intervals. Results of progression over consecutive sputum cultures are shown in the table. Sputum cultures of 11.6% (95%CI: ) of patients reconverted to positive within one month following the initial negative culture result. An additional 5.4% (95%CI: ) reconverted after two consecutive negative cultures (the formal culture conversion definition) (Table). Importantly, in 60.9% (95%CI: ) of patients with a reconversion, the sputum culture returned negative within 1 month. In all of these patients the sputum culture returned negative within 4 months (Table). Limited data on follow-up cultures was available for discharged patients. Follow-up cultures were available for only 100 out of 249 patients discharged after at least one negative culture (40.2%). Sixteen of these 100 patients (16.0%) had a positive sputum culture post-discharge (reconversion), which is comparable to the proportion observed during inpatient follow-up. 5

6 Culture-based monitoring of MDR-TB patients is used to evaluate treatment efficacy and helps to identify those who remain infectious. The internationally agreed-upon definition of culture conversion is two consecutive negative cultures 30 days apart (8) which. certainly reduces falsenegative results when compared to a single negative culture. In fact, in this study 37 (11.6%) inpatients had a positive culture after a first negative culture result which supports the definitions for sputum culture conversion used for the current WHO Guidelines on the management of MDR-TB(8,11). In another setting, namely New York City, NY in the USA in the mid-nineties, the yield of continued monthly cultures after culture conversion showed a small percentage (1.3%) of reconversions in drug-susceptible TB, leading the authors to conclude that culture after conversion was unnecessary(9). Culture reconversion has been described in MDR-TB(6) and a recent study, looking into the optimal frequency and type of microbiological monitoring for MDR-TB treatment, reported a culture reconversion rate of 23.7% (7). Our results imply that three consecutive negative cultures would offer a minimal improvement before re-evaluating the need for respiratory isolation. Yet, this would dramatically increase the isolation period and this would probably not be feasible in highly endemic, non-affluent settings. In this study, a considerable amount of patients were lost to follow up. This might have lead to a selection of clinically worse patients staying in hospital, the better ones having been discharged or lost to follow-up. Because of this limitation generalization of our results to the ambulatory setting must be done with caution. Less close supervision and structure, compared to the hospital setting, might lead to a deterioration of adherence and compliance, leading to a less favourable picture for the ambulatory setting. Recommending the management of MDR-TB patients in an ambulatory care model can only be justified when quality of ambulatory care with regards to close supervision on medication adherence and adequate respiratory isolation can be guaranteed. 6

7 In fact, a study from Peru, where an ambulatory system of care is used for several years, showed that there is a high risk of disease recorded in household contacts of patients with MDR and XDR-TB(1). The fact that only 40.2% of discharged patients in our study provided a follow-up sputum sample further illustrates the challenges encountered in an ambulatory care model Acknowledgments We thank Sympathy Nseula for data entry and Mischa Huson for thoughtful comments. Downloaded from on July 13, 2018 by guest 7

8 135 References Becerra, M. C., S. C. Appleton, M. F. Franke, K. Chalco, F. Arteaga, J. Bayona, M. Murray, S. S. Atwood, and C. D. Mitnick Tuberculosis burden in households of patients with multidrug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort study. Lancet 377: Cox, H. and C. G. van Household screening and multidrug-resistant tuberculosis. Lancet 377: Fitzwater, S. P., L. Caviedes, R. H. Gilman, J. Coronel, D. LaChira, C. Salazar, J. C. Saravia, K. Reddy, J. S. Friedland, and D. A. Moore Prolonged infectiousness of tuberculosis patients in a directly observed therapy short-course program with standardized therapy. Clin.Infect.Dis. 51: Fortun, J., P. Martin-Davila, A. Molina, E. Navas, J. M. Hermida, J. Cobo, E. Gomez- Mampaso, and S. Moreno Sputum conversion among patients with pulmonary tuberculosis: are there implications for removal of respiratory isolation? J.Antimicrob.Chemother. 59: Grobusch, M. P Drug-resistant and extensively drug-resistant tuberculosis in southern Africa. Curr.Opin.Pulm.Med. 16: Holtz, T. H., M. Sternberg, S. Kammerer, K. F. Laserson, V. Riekstina, E. Zarovska, V. Skripconoka, C. D. Wells, and V. Leimane Time to sputum culture conversion 8

9 in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome. Ann.Intern.Med. 144: Kurbatova, E. V., V. M. Gammino, J. Bayona, M. Becerra, M. Danilovitz, D. Falzon, I. Gelmanova, S. Keshavjee, V. Leimane, C. D. Mitnick, M. I. Quelapio, V. Riekstina, A. Taylor, P. Viiklepp, M. Zignol, and J. P. Cegielski Frequency and type of microbiological monitoring of multidrug-resistant tuberculosis treatment. Int.J.Tuberc.Lung Dis. 15: Laserson, K. F., L. E. Thorpe, V. Leimane, K. Weyer, C. D. Mitnick, V. Riekstina, E. Zarovska, M. L. Rich, H. S. Fraser, E. Alarcon, J. P. Cegielski, M. Grzemska, R. Gupta, and M. Espinal Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis. Int.J.Tuberc.Lung Dis. 9: Sundaram, V., P. I. Fujiwara, C. R. Driver, S. S. Osahan, and S. S. Munsiff Yield of continued monthly sputum evaluation among tuberculosis patients after culture conversion. Int.J.Tuberc.Lung Dis. 6: World Health Organization Tuberculosis infection control in the era of expanding HIV care and treatment. Addendum to the WHO Guidelines for the Prevention of Tuberculosis in Health Care Facilities in Resource-Limited Settings World Health Organization Guidelines for the programmatic management of drug- resistant Tuberculosis update World Health Organization Global Tuberculosis Report

10 Table 1 Monthly sputum cultures following initial conversion (p-n) Time point Population at risk Re-conversion events (p-n-p) Cumulative proportion remaining negative (95% Confidence Interval) % Re-converted to positive Censored* Reason for censoring Deceased LTFU & discharged Month ( ) ** 10 7 Month ( ) Month ( ) Month ( ) Monthly sputum cultures following re-conversion after initial conversion (p-n-p) Time Population point at risk Conversion events (p-n-p-n) Cumulative proportion remaining positive (95% Confidence Interval) % Converted to negative Censored * Reason for censoring Deceased Month ( ) Month ( ) Month ( ) Month ( ) LTFU & discharged Table Kaplan Meier survival table presenting the cumulative proportion remaining sputum culture negative per month following the initial sputum culture conversion in 336 South African MDR-TB patients (upper table) and the cumulative proportion remaining sputum culture positive per month in the 54 patients with a re-conversion after initial conversion (lower table). The population at risk was calculated based on the previous month s re-conversion events and the current month s censored events. Of the 44 patients with a

11 p-n-p-n conversion event, three reconverted a second time (p-n-p-n-p) and one reconverted a third time (p-n-p-n-p-n-p) before being discharged with a negative culture result. * Censored entails that patients were excluded from the denominator of cumulative proportion calculation at time-points following the censoring event (being deceased, discharged or lost to follow-up [LTFU]). ** One patient was censored because of toxic hepatitis. Downloaded from on July 13, 2018 by guest 11