- Email: [email protected]
Resistance to second-line drugs in multidrug-resistant tuberculosis
Correspondence
We declare that we have no conflicts of interest.
*Nicole M Ryan, Surinder S Birring, Peter G Gibson [email protected] Priority Centre for Asthma and Respiratory Diseases, School of Medicine and Public Health, University of Newcastle, Newcastle, NSW 2308, Australia (NMR, PGG); and Division of Asthma, Allergy and Lung Biology, King’s College London, London, UK (SSB) 1
2
3
4
5
6
7
8
9
10
Lee KK, Savani A, Matos S, Woods C, Pavord ID, Birring SS. 4 h cough frequency monitoring with the Leicester cough monitor. Thorax 2010; 65: A54. Ryan NM, Vertigan AE, Bone SL, Gibson PG. Cough reflex sensitivity improves with speech language pathology management of refractory chronic cough. Cough 2010; 6: 5. Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther 2003; 25: 81–104. Verne GN, Robinson ME, Vase L, Price DD. Reversal of visceral and cutaneous hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS) patients. Pain 2003; 105: 223–30. Van de Kerkhove C, Goeminne PC, Van Bleyenbergh P, Dupont LJ. A cohort description and analysis of the effect of gabapentin on idiopathic cough. Cough 2012; 8: 9. Sivenius J, Ylinen A, Kalviainen R, Riekkinen PJ Sr. Long-term study with gabapentin in patients with drug-resistant epileptic seizures. Arch Neurol 1994; 51: 1047–50. Moore R, Wiffen P, Derry S, McQuay H. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011; 3: CD007938. Mintz S, Lee JK. Gabapentin in the treatment of intractable idiopathic chronic cough: case reports. Am J Med 2006; 119: e13–15. Rowbottom M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998; 280: 1837–42. Yousaf N, Monteiro W, Parker D, Matos S, Birring S, Pavord ID. Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial. Thorax 2010; 65: 1107–10.
www.thelancet.com Vol 381 February 23, 2013
Resistance to secondline drugs in multidrugresistant tuberculosis The cohort study by Tracy Dalton and colleagues (Oct 20, p 1406),1 which finds that the prevalence of extensively drug-resistant (XDR) and second-line drug-resistant tuberculosis in nine countries is higher than current WHO estimates, confirms the alarming rates of resistance found by Medécins Sans Frontières (MSF). In our Uzbekistan tuberculosis programme,2 190 (27%) of 709 patients with MDR tuberculosis had pre-XDR disease (defined as resistance to any fluoroquinolone or injectable second-line drug). Dalton and colleagues1 found that previous treatment for MDR tuberculosis was the strongest risk factor for resistance. However, since they do not explain the indications for doing culture and drug-susceptibility testing in the study countries, these patients could be a select group with more previous exposure. Our Uzbekistan programme data are based on expanded access to culture and drug susceptibility testing to all patients suspected of having tuberculosis. With this approach we identified a higher than expected rate of MDR tuberculosis in new patients: 201 (38%) of the 529 patients started on MDR tuberculosis treatment in the first three quarters of 2012 had never been treated for tuberculosis before (Jane Greig, personal communication). This finding highlights the extent to which MDR tuberculosis has become an epidemic in its own right. It is important to ensure that new drug regimens are effective against Mycobacterium tuberculosis with extensive resistance to both first-line and second-line drugs. To ignore second-line resistance would be to repeat the error made when first-line resistance was ignored in the early implementation of DOTS programmes. We declare that we have no conflicts of interest.
Bern-Thomas Nyang’wa, Grania Brigden, *Philipp du Cros, Leslie Shanks [email protected]
James Cavallini/Science Photo Library
we did measure fractional exhaled nitric oxide for airway inflammation—a measurement that offers high sensitivity and specificity—and found that there was no difference between study groups at baseline or study entry. Nor did we screen for mycoplasma infection—a disorder that remains unclear in chronic cough, since treatment with low-dose erythromycin was found to have no effect on cough frequency or severity.10 A clinical history of refractory cough after an infection is quite common and gabapentin could have a treatment role since central sensitisation is a possible mechanism.
Médecins Sans Frontières (MSF) UK, London, UK (B-TN, PdC); MSF Access Campaign, Geneva, Switzerland (GB); and MSF, Amsterdam, Netherlands (LS) 1
2
Dalton T, Cegielski P, Akkslip S, et al. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet 2012; 380: 1406–17. Lalor MK, Allamuratova S, Tiegay Z, et al. Treatment outcomes in multidrug resistant tuberculosis patients in Uzbekistan. Poster presentation, 42nd Union World Conference on Lung Health; Lille, France; Oct 26–30, 2011.
The lack of participation of India and China, who between them share 50% of the world’s burden of multidrugresistant (MDR) tuberculosis, is a major limitation of the Preserving Effective TB Treatment (PETTS) study.1 Despite this limitation, the findings of the PETTS investigators find great and ominous resonance in India. Second-line drugs are prescribed with brazen impunity by a range of private practitioners in India, many of them not even allopaths. A study from Dharavi,2 Asia’s largest slum, located in the heart of Mumbai, showed that, of the 106 practitioners prescribing second-line drugs to a hypothetical patient with MDR tuberculosis, 60% were trained in one of the alternative systems of medicine (homoeopathy, ayurveda, or unani) that flourish in India. Only five of these 106 physicians could write an appropriate prescription with a minimum of three new secondline drugs in the right doses for a minimum recommended duration of 18 months. Most respondents added a single second-line drug, which 70% of the time was a fluoroquinolone. More tragically, these inappropriate prescriptions would be dispensed without any checks or safeguards in place, since tuberculosis prescriptions are not controlled in India and even the most inexperienced doctor can prescribe second-line drugs with impunity. India has 1 million chemists policed by just 4000 drug inspectors, and even if laws 625
Correspondence
were enacted they would be difficult to enforce. Considering the large and diverse pool of private physicians in India, regulatory approaches and legislation are urgently needed to ensure that MDR tuberculosis care is accessible only through outlets approved by the Revised National TB Program. Failing this, the slide into the kind of virtually untreatable cases of totally drug-resistant tuberculosis recently described in Mumbai3 seems inevitable. I declare that I have no conflicts of interest.
Zarir Udwadia [email protected] Hinduja Hospital and Research Center, Veer Savarkar Marg, Mahim, Mumbai 400030, India 1
2
3
Dalton T, Cegielski P, Akkslip S, et al. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet 2012; 380: 1406–17. Udwadia ZF, Pinto LM, Uplekar MW. Tuberculosis control by private practitioners in Mumbai, India: has anything changed in two decades? PLoS One 2010; 5: e1203. Udwadia ZF, Amale RA, Ajbani KK, Rodriguez C. Totally drug-resistant tuberculosis in India. Clin Infect Dis 2012; 54: 579–81.
Authors’ reply Bern-Thomas Nyang’wa and colleagues provide relevant data regarding drug resistance in Médecins Sans Frontières project areas. In clarification, the Preserving Effective Tuberculosis Treatment Study (PETTS)1 showed higher levels of extensively drugresistant (XDR) tuberculosis than WHO’s estimates for 2005–08, the time period when PETTS was enrolling patients; however, newer WHO estimates show an even higher prevalence of XDR tuberculosis than we saw in PETTS.2,3 This is a worrisome trend. Nyang’wa and colleagues also raise the question as to whether the PETTS enrolment protocol could have led to selection of patients with previous treatment simply because culture and drug susceptibility testing were not universally available to patients with suspected tuberculosis. In our study, culture and drug susceptibility testing were done routinely for all such 626
patients from Latvia, Estonia, Russia, and South Korea. In the Philippines, Thailand, South Africa, and Peru, drug susceptibility testing was routine only for patients who had risk factors for drug-resistant tuberculosis, including no improvement with standardised first-line treatment. Zarir Udwadia describes the inappropriate use and lack of regulation of second-line antituberculosis drugs in India’s private sector. The described overuse and misuse of second-line drugs are widespread global problems. However, restriction of the use of fluoroquinolones or aminoglycosides to tuberculosis treatment is impractical since they are essential antibiotics used to treat many other bacterial infections. Perhaps as new drugs specifically for tuberculosis emerge from the development pipeline, restriction of access to these drugs could prove effective in preventing acquired resistance. However, combating the already high levels of drug-resistant tuberculosis in the world will require active involvement from both private and public entities. Both of these letters, in combination with the data in our paper, illustrate the urgent need for accelerated progress to prevent the further spread of drug-resistant tuberculosis and the acquisition of additional resistance. To do this, we must continue drug development efforts, build capacity of frontline providers for improved diagnosis, develop international standards for phenotypic as well as genetic approaches to drug susceptibility testing for both existing and new drugs, develop optimised treatment procedures, and ensure treatment adherence. We declare that we have no conflicts of interest.
*Tracy Dalton, Peter Cegielski, Ekaterina Kurbatova, Julia Ershova, Janice Campos Caoili [email protected] Division of TB Elimination, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA (TD, PC, EK, JE); and Tropical Disease Foundation, Manila, Philippines (JCC)
1
2
3
Dalton T, Cegielski P, Akkslip S, et al. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet 2012; 380: 1406–17. WHO. Multidrug and extensively drugresistant TB (M/XDR-TB): 2010 global report on surveillance and response. Geneva: World Health Organization, 2010. http://www.who. int/tb/publications/2010/978924599191/en/ index.html (accessed Feb 6, 2013). Zignol M, van Gemert W, Falzon D, et al. Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007–2010. Bull World Health Organ 2012; 90: 111–119D.
Maternal underweight and child growth and development In an analysis of data pooled across 27 countries from sub-Saharan Africa, Jenny Cresswell and colleagues (Oct 13, p 1325)1 report that maternal obesity is associated with an increased risk of neonatal mortality, especially in the first 2 days after birth. We are puzzled that Cresswell and colleagues did not find an association between maternal underweight and neonatal mortality. Maternal underweight before pregnancy is a well established risk factor for adverse neonatal outcomes, especially low birthweight.2 In a randomised trial from Bangladesh,3 provision of micronutrient and caloric supplementation to women with a low body-mass index resulted in a lower offspring mortality rate at birth and at 5 years.3 More broadly, the agenda of child survival has to be considered alongside the agenda of child growth. We reanalysed the same data with the same adjustments as Cresswell and colleagues using offspring underweight at 0–3 months and 4–6 months (defined as Z-score <–2 relative to children of the same sex and age in the reference WHO population) as an outcome. Underweight mothers were more likely to have underweight children at 0–3 months (odds ratio 1·6, 95% CI 1·3–2·0) and 4–6 months (2·1, www.thelancet.com Vol 381 February 23, 2013
We declare that we have no conflicts of interest.
*Nicole M Ryan, Surinder S Birring, Peter G Gibson [email protected] Priority Centre for Asthma and Respiratory Diseases, School of Medicine and Public Health, University of Newcastle, Newcastle, NSW 2308, Australia (NMR, PGG); and Division of Asthma, Allergy and Lung Biology, King’s College London, London, UK (SSB) 1
2
3
4
5
6
7
8
9
10
Lee KK, Savani A, Matos S, Woods C, Pavord ID, Birring SS. 4 h cough frequency monitoring with the Leicester cough monitor. Thorax 2010; 65: A54. Ryan NM, Vertigan AE, Bone SL, Gibson PG. Cough reflex sensitivity improves with speech language pathology management of refractory chronic cough. Cough 2010; 6: 5. Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther 2003; 25: 81–104. Verne GN, Robinson ME, Vase L, Price DD. Reversal of visceral and cutaneous hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS) patients. Pain 2003; 105: 223–30. Van de Kerkhove C, Goeminne PC, Van Bleyenbergh P, Dupont LJ. A cohort description and analysis of the effect of gabapentin on idiopathic cough. Cough 2012; 8: 9. Sivenius J, Ylinen A, Kalviainen R, Riekkinen PJ Sr. Long-term study with gabapentin in patients with drug-resistant epileptic seizures. Arch Neurol 1994; 51: 1047–50. Moore R, Wiffen P, Derry S, McQuay H. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011; 3: CD007938. Mintz S, Lee JK. Gabapentin in the treatment of intractable idiopathic chronic cough: case reports. Am J Med 2006; 119: e13–15. Rowbottom M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998; 280: 1837–42. Yousaf N, Monteiro W, Parker D, Matos S, Birring S, Pavord ID. Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial. Thorax 2010; 65: 1107–10.
www.thelancet.com Vol 381 February 23, 2013
Resistance to secondline drugs in multidrugresistant tuberculosis The cohort study by Tracy Dalton and colleagues (Oct 20, p 1406),1 which finds that the prevalence of extensively drug-resistant (XDR) and second-line drug-resistant tuberculosis in nine countries is higher than current WHO estimates, confirms the alarming rates of resistance found by Medécins Sans Frontières (MSF). In our Uzbekistan tuberculosis programme,2 190 (27%) of 709 patients with MDR tuberculosis had pre-XDR disease (defined as resistance to any fluoroquinolone or injectable second-line drug). Dalton and colleagues1 found that previous treatment for MDR tuberculosis was the strongest risk factor for resistance. However, since they do not explain the indications for doing culture and drug-susceptibility testing in the study countries, these patients could be a select group with more previous exposure. Our Uzbekistan programme data are based on expanded access to culture and drug susceptibility testing to all patients suspected of having tuberculosis. With this approach we identified a higher than expected rate of MDR tuberculosis in new patients: 201 (38%) of the 529 patients started on MDR tuberculosis treatment in the first three quarters of 2012 had never been treated for tuberculosis before (Jane Greig, personal communication). This finding highlights the extent to which MDR tuberculosis has become an epidemic in its own right. It is important to ensure that new drug regimens are effective against Mycobacterium tuberculosis with extensive resistance to both first-line and second-line drugs. To ignore second-line resistance would be to repeat the error made when first-line resistance was ignored in the early implementation of DOTS programmes. We declare that we have no conflicts of interest.
Bern-Thomas Nyang’wa, Grania Brigden, *Philipp du Cros, Leslie Shanks [email protected]
James Cavallini/Science Photo Library
we did measure fractional exhaled nitric oxide for airway inflammation—a measurement that offers high sensitivity and specificity—and found that there was no difference between study groups at baseline or study entry. Nor did we screen for mycoplasma infection—a disorder that remains unclear in chronic cough, since treatment with low-dose erythromycin was found to have no effect on cough frequency or severity.10 A clinical history of refractory cough after an infection is quite common and gabapentin could have a treatment role since central sensitisation is a possible mechanism.
Médecins Sans Frontières (MSF) UK, London, UK (B-TN, PdC); MSF Access Campaign, Geneva, Switzerland (GB); and MSF, Amsterdam, Netherlands (LS) 1
2
Dalton T, Cegielski P, Akkslip S, et al. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet 2012; 380: 1406–17. Lalor MK, Allamuratova S, Tiegay Z, et al. Treatment outcomes in multidrug resistant tuberculosis patients in Uzbekistan. Poster presentation, 42nd Union World Conference on Lung Health; Lille, France; Oct 26–30, 2011.
The lack of participation of India and China, who between them share 50% of the world’s burden of multidrugresistant (MDR) tuberculosis, is a major limitation of the Preserving Effective TB Treatment (PETTS) study.1 Despite this limitation, the findings of the PETTS investigators find great and ominous resonance in India. Second-line drugs are prescribed with brazen impunity by a range of private practitioners in India, many of them not even allopaths. A study from Dharavi,2 Asia’s largest slum, located in the heart of Mumbai, showed that, of the 106 practitioners prescribing second-line drugs to a hypothetical patient with MDR tuberculosis, 60% were trained in one of the alternative systems of medicine (homoeopathy, ayurveda, or unani) that flourish in India. Only five of these 106 physicians could write an appropriate prescription with a minimum of three new secondline drugs in the right doses for a minimum recommended duration of 18 months. Most respondents added a single second-line drug, which 70% of the time was a fluoroquinolone. More tragically, these inappropriate prescriptions would be dispensed without any checks or safeguards in place, since tuberculosis prescriptions are not controlled in India and even the most inexperienced doctor can prescribe second-line drugs with impunity. India has 1 million chemists policed by just 4000 drug inspectors, and even if laws 625
Correspondence
were enacted they would be difficult to enforce. Considering the large and diverse pool of private physicians in India, regulatory approaches and legislation are urgently needed to ensure that MDR tuberculosis care is accessible only through outlets approved by the Revised National TB Program. Failing this, the slide into the kind of virtually untreatable cases of totally drug-resistant tuberculosis recently described in Mumbai3 seems inevitable. I declare that I have no conflicts of interest.
Zarir Udwadia [email protected] Hinduja Hospital and Research Center, Veer Savarkar Marg, Mahim, Mumbai 400030, India 1
2
3
Dalton T, Cegielski P, Akkslip S, et al. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet 2012; 380: 1406–17. Udwadia ZF, Pinto LM, Uplekar MW. Tuberculosis control by private practitioners in Mumbai, India: has anything changed in two decades? PLoS One 2010; 5: e1203. Udwadia ZF, Amale RA, Ajbani KK, Rodriguez C. Totally drug-resistant tuberculosis in India. Clin Infect Dis 2012; 54: 579–81.
Authors’ reply Bern-Thomas Nyang’wa and colleagues provide relevant data regarding drug resistance in Médecins Sans Frontières project areas. In clarification, the Preserving Effective Tuberculosis Treatment Study (PETTS)1 showed higher levels of extensively drugresistant (XDR) tuberculosis than WHO’s estimates for 2005–08, the time period when PETTS was enrolling patients; however, newer WHO estimates show an even higher prevalence of XDR tuberculosis than we saw in PETTS.2,3 This is a worrisome trend. Nyang’wa and colleagues also raise the question as to whether the PETTS enrolment protocol could have led to selection of patients with previous treatment simply because culture and drug susceptibility testing were not universally available to patients with suspected tuberculosis. In our study, culture and drug susceptibility testing were done routinely for all such 626
patients from Latvia, Estonia, Russia, and South Korea. In the Philippines, Thailand, South Africa, and Peru, drug susceptibility testing was routine only for patients who had risk factors for drug-resistant tuberculosis, including no improvement with standardised first-line treatment. Zarir Udwadia describes the inappropriate use and lack of regulation of second-line antituberculosis drugs in India’s private sector. The described overuse and misuse of second-line drugs are widespread global problems. However, restriction of the use of fluoroquinolones or aminoglycosides to tuberculosis treatment is impractical since they are essential antibiotics used to treat many other bacterial infections. Perhaps as new drugs specifically for tuberculosis emerge from the development pipeline, restriction of access to these drugs could prove effective in preventing acquired resistance. However, combating the already high levels of drug-resistant tuberculosis in the world will require active involvement from both private and public entities. Both of these letters, in combination with the data in our paper, illustrate the urgent need for accelerated progress to prevent the further spread of drug-resistant tuberculosis and the acquisition of additional resistance. To do this, we must continue drug development efforts, build capacity of frontline providers for improved diagnosis, develop international standards for phenotypic as well as genetic approaches to drug susceptibility testing for both existing and new drugs, develop optimised treatment procedures, and ensure treatment adherence. We declare that we have no conflicts of interest.
*Tracy Dalton, Peter Cegielski, Ekaterina Kurbatova, Julia Ershova, Janice Campos Caoili [email protected] Division of TB Elimination, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA (TD, PC, EK, JE); and Tropical Disease Foundation, Manila, Philippines (JCC)
1
2
3
Dalton T, Cegielski P, Akkslip S, et al. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet 2012; 380: 1406–17. WHO. Multidrug and extensively drugresistant TB (M/XDR-TB): 2010 global report on surveillance and response. Geneva: World Health Organization, 2010. http://www.who. int/tb/publications/2010/978924599191/en/ index.html (accessed Feb 6, 2013). Zignol M, van Gemert W, Falzon D, et al. Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007–2010. Bull World Health Organ 2012; 90: 111–119D.
Maternal underweight and child growth and development In an analysis of data pooled across 27 countries from sub-Saharan Africa, Jenny Cresswell and colleagues (Oct 13, p 1325)1 report that maternal obesity is associated with an increased risk of neonatal mortality, especially in the first 2 days after birth. We are puzzled that Cresswell and colleagues did not find an association between maternal underweight and neonatal mortality. Maternal underweight before pregnancy is a well established risk factor for adverse neonatal outcomes, especially low birthweight.2 In a randomised trial from Bangladesh,3 provision of micronutrient and caloric supplementation to women with a low body-mass index resulted in a lower offspring mortality rate at birth and at 5 years.3 More broadly, the agenda of child survival has to be considered alongside the agenda of child growth. We reanalysed the same data with the same adjustments as Cresswell and colleagues using offspring underweight at 0–3 months and 4–6 months (defined as Z-score <–2 relative to children of the same sex and age in the reference WHO population) as an outcome. Underweight mothers were more likely to have underweight children at 0–3 months (odds ratio 1·6, 95% CI 1·3–2·0) and 4–6 months (2·1, www.thelancet.com Vol 381 February 23, 2013