Role of Medical Colleges in RNTCP

Special Report
Indian J Med Res , February 2013;137: 283-294

Contribution of medical colleges to tuberculosis control in India under the Revised National Tuberculosis Control Programme (RNTCP):Lessons learnt & challenges ahead

Surendra K. Sharma1,*, Alladi Mohan2,*, L.S. Chauhan3,*, J.P. Narain4,*, P. Kumar5,*, D. Behera6,*, K.S. Sachdeva7,*, Ashok Kumar7,*,for Task Force for Involvement of Medical Colleges in the Revised National Tuberculosis Control Programme

1Department of Medicine, All India Institute of Medical Sciences, New Delhi, 2Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, 3National Centre for Disease Control, New Delhi, 4Formerly Director, World Health Organization Regional Office for South-East Asia (WHO-SEARO) for Sustainable Development & Healthy Environments & for Communicable Disease Prevention & Control, WHO-SEARO, New Delhi, 5National Tuberculosis Institute, Bengaluru, 6Postgraduate Institute of Medical Education & Research, Chandigarh & 7Central Tuberculosis Division, Ministry of Health & Family Welfare, Government of India, New Delhi, India

Writing Committee

Other Contributors (names listed alphabetically):

Agarwal Priyanka, Awadh N.T., Bansal Avi, Baruah S, Baruwa Pranab, Balasangameshwara V.H., Balasubramanian Rani, Bhardwaj A.K., Bhargav Salil, Chadha Sarabjit, Chaddha V.K., Chhatwal Manpreet, Da Costa A.L., Dash D.P., Dep Jaydip, Dhingra Saroj, Dhooria Harmeet S., Frieden T.R., Garg Anil, Granich Reuben, Gulati Vinay, Gupta Deepak, Gupta Dheeraj, Gupta K.B., Gupta K.N., Jaikishan, Janmeja A.K., Jawahar M.S., Jethani S.L., Jindal S.K., John K.R., Kalra O.P., Kalra V.P., Kannan A.T., Kayshap S., Keshav Chander G., Khushwa S.S., Kushwaha R.S., Kumar Vinod, Laskar B., Leela Itty Amma K.R., Leuva A.T., Maitra Malay K., Mesquita A.M., Mathew Thomas, Mundade Yamuna, Munje Radha, Nagpal Somil, Nagaraja C., Nair Sanjeev, Narayanan P.R., Paramasivan C.N., Parmar Malik, Prasad Rajendra, Phukan A.C., Prasanna Raj, Purty Anil, Ramachandran Ranjani, Ramachandran Rajeswari, Ravindran C., Reddy Raveendra H.R., Sahu S., Santosha, Sarin Rohit, Sarkar Soumya, Sarma K.C., Saxena P., Sehgal Shruti, Sharath N., Sharma Geetanjali, Sharma Nandini, Shridhar P.K., Shukla R.S., Singh Om, Singh N. Tombi, Singh Varinder, Singla Rupak, Sinha Neena, Sinha Pranay, Sinha Sanjay, Solanki Rajesh, Sreenivas A., Srinath S., Subhakar Kandi, Suri J.C., Talukdar Palash, Tonsing Jamie, Tripathy S.P., Vaidyanathan Preetish, Vashist R.P., Venu K.

Abstract

Medical college faculty, who are academicians are seldom directly involved in the implementation of national

public health programmes. More than a decade ago for the first time in the global history of tuberculosis

(TB) control, medical colleges of India were involved in the Revised National TB Control Programme

(RNTCP) of Government of India (GOI). This report documents the unique and extraordinary course of

events that led to the involvement of medical colleges in the RNTCP of GOI. It also reports the contributions

made by the medical colleges to TB control in India. For more than a decade, medical colleges have been

providing diagnostic services (Designated Microscopy Centres), treatment [Directly Observed Treatment

(DOT) Centres] referral for treatment, recording and reporting data, carrying out advocacy for RNTCP

and conducting operational research relevant to RNTCP. Medical colleges are contributing to diagnosis

and treatment of human immunodeficiency virus (HIV)-TB co-infection and development of laboratory

infrastructure for early diagnosis of multidrug-resistant and/or extensively drug-resistant TB (M/XDRTB)

and DOTS-Plus sites for treatment of MDR-TB cases. Overall, at a national level, medical colleges

have contributed to 25 per cent of TB suspects referred for diagnosis; 23 per cent of ‘new smear-positives’

diagnosed; 7 per cent of DOT provision within medical college; and 86 per cent treatment success rate

among new smear-positive patients. As the Programme widens its scope, future challenges include

sustenance of this contribution and facilitating universal access to quality TB care; greater involvement

in operational research relevant to the Programme needs; and better co-ordination mechanisms between

district, state, zonal and national level to encourage their involvement.

Introduction

Tuberculosis (TB) is a dreadful infectious disease with devastating social and economic consequences.

India is one of the high TB burden countries. More adults die from TB than from any other infectious

disease in India1. With its commitment to reduce the morbidity, mortality and disability due to TB and

eliminate it as a public health problem, the Government of India (GOI), after piloting the DOTS strategy

successfully from 1993-1996, had initiated the Revised National Tuberculosis Control Programme (RNTCP) adopting the DOTS strategy in 1997. Subsequently, the Programme had expanded to cover the entire population of the country in March 20062. In India, TB patients are managed by several healthcare providers involving diverse sectors from the government, nongovernmental organizations (NGOs) and the private and corporate sectors. Effective control of TB will be possible if all these sectors join together and work towards a common goal.

A substantial proportion of patients with TB are managed at medical colleges across the country. From

the TB control point of view, medical colleges, in both the government and private sectors are recognized

to occupy a key position with a unique potential for involvement with the RNTCP. To widen access and

improving the quality of TB services, involvement of medical colleges and their hospitals is of paramount

importance. Being tertiary care medical centres, large numbers of patients seek care from the medical

colleges. In addition, the role of medical college faculty in TB control as key opinion leaders and role models

for practicing physicians and as teachers imparting knowledge, skills and shaping the attitude of medical

students cannot be underestimated. There is a pressing need for all medical colleges to advocate and practice

DOTS strategy which provides the best opportunity for cure of TB patients. In addition, medical colleges

have the diagnostic facilities for extra-pulmonary TB (EPTB), human immunodeficiency virus (HIV)-TB coinfection, multidrug-resistant TB and extensively drugresistant TB (M/XDR-TB). Recognizing the potential

of involving medical colleges in TB control a decade ago, the RNTCP of GOI, for the first time in the world

conceived and implemented the unique experiment of involving the academicians who constitute the faculty

in the public health programme for TB control. A mechanism of National, Zonal and State level Task

Forces was conceived for the involvement of medical colleges, wherein the sole responsibility of participation

of medical colleges in DOTS strategy lies with the faculty of medical colleges, which perhaps made them

more responsive. Involvement of medical colleges in TB control: history and past activities Since 1997, concerted efforts have been made to involve medical colleges and their hospitals in the Programme when the first National Consensus Conference on TB was held in New Delhi3,4. This meeting was followed by two meetings in 2001 at the National Tuberculosis Institute (NTI), Bengaluru5 and the All India Institute of Medical Sciences (AIIMS) - World Health Organization, South-East Asia Regional Office (WHO, SEARO), New Delhi Meeting on the Involvement of Medical Colleges in TB and Sexually Transmitted Infections (STI) / HIV Control held at AIIMS, New Delhi6. Professors from over 35 prestigious medical colleges/institutes participated in these meetings and accepted RNTCP as a control programme with potential for a “remarkable success” in TB control in India and expressed their commitment to the Programme. In the meeting recommendations were made to consider medical colleges as an integral part of the RNTCP. As per these recommendations, it was envisaged that medical colleges will offer RNTCP diagnostic and treatment services, teach and carry out advocacy about RNTCP, and participate in implementation and monitoring of the Programme. The October 2002 National Level Workshop of Medical Colleges at AIIMS, New Delhi, was instrumental in developing the structure and processes required for the effective nation-wide participation of medical colleges in the Programme. Seven medical colleges located in the different zones of the country at New Delhi, Chandigarh (North), Jaipur, Mumbai (West), Kolkata (East), Vellore (South) and Guwahati (North-East) were identified as nodal centres and were requested to lead the initiative of participating in the Programme (Figs 1A and 1B). Nodal faculty members from these seven medical colleges, were trained at the national institutes [e.g., National Tuberculosis Institute (NTI), Bengaluru]. 

Structure of the National, Zonal and State Task Force

A Task Force mechanism at the National, Zonal and State level (Fig. 1A) was established. Subsequently,

there were consensus workshops in the States with medical colleges which further detailed the exact mechanisms for collaboration. This formed the basis for GOI’s policy of involving medical colleges in TB

control. The National Task Force (NTF) consisted of representatives from the zonal nodal centres, Zonal

Task Forces, central TB institutes, WHO-SEARO and the Central TB Division, Ministry of Health and Family Welfare (MoHFW), GOI was formed. The main role of the NTF was to guide, provide leadership and advocacy for the RNTCP, develop policies regarding medical colleges’ involvement in the RNTCP, coordinate between the Central TB Division, MoHFW, GOI, and monitor the activities of the Zonal Task Forces.The Zonal Task Forces (ZTF) facilitated the establishment of State Task Forces (STF), coordinated

between the national and State level Task Forces, as well as between medical colleges and the State/District

TB Centres, and monitored the activities of the STF. Zonal division of States for this activity comprised five

States in the East, eight each in the North-East, and the North, five in the South and five States in the West

zone. However, the real implementing unit was the STF, which undertook the necessary activities to facilitate

establishment of Directly Observed Treatment (DOT) centres, as well as other activities, in all the medical

colleges in the respective States. Over the subsequent years, wider interaction with medical colleges has

occurred through a series of sensitization seminars, training of medical college faculty staff at Central TB

institutes, national and zonal level workshops. Steps for involvement of individual medical colleges included sensitizing faculty members about RNTCP services, identifying a faculty member as a“Nodal Officer” for coordinating RNTCP activities and training of staff. Other steps included formation of a “Core Committee” consisting of the heads of various departments (Box 1). Core Committees, at the level of medical colleges facilitated inter-departmental coordination for implementation of DOTS strategy.Designated Microscopy Centres (DMC) and DOT Centres were established in all government and private medical colleges and these were equipped with suitably trained additional manpower in the form of laboratory technician (LT) and TB health visitor (TBHV). The RNTCP is one of the National Disease Control Programmes being implemented under National Rural Health Mission (NRHM) of GOI. NRHM is implemented through a mechanism of Health Societies established at State and District level. These Health Societies provide necessary administrative and financial support to medical colleges as per approved policy of RNTCP for implementation of Programme activities.

In 2003, action plans for the different levels of Task Forces were formulated and in 2004, the progress was reviewed and future course of action was planned. These annual meetings of the Task Forces also provided

an important forum for consultation with the medical fraternity on issues or new initiatives being considered

by the Programme such as external quality assurance of sputum microscopy, drug resistance surveillance,

TB/HIV management and coordination, management of M/XDR-TB and DOTS plus7-15.

Recording and reporting formats at the medical colleges 

Consequent to the decision in the NTF held in November 2004, NTF 2005 had recommended that the

existing recording formats of RNTCP would be used to document the processes in the medical college. Further, the medical colleges submitted the monthly peripheral health institution (PHI) report to the concerned Tuberculosis Unit (TU)/District (Fig. 2). In addition, it was recommended that the medical colleges, States and Zones shall submit reports to the next level on a quarterly basis on separate reporting formats. These were subsequently revised during the NTF workshops held in 2006 and 2007. The quarterly reporting formats have been implemented from the first quarter of 2006 onwards. Contributions made by medical colleges in RNTCP policy formulation In addition to the Core Committee meetings, recording and reporting of data, the medical college representatives had actively taken part in the STF meetings and the respective ZTF meetings that were held annually. Further, certain faculty members from medical colleges (e.g., Chairperson STF) also participated in the NTF meeting held annually. The action plans evolved in various ZTF meetings were deliberated upon in the NTF meeting and consensus action plan was evolved for guiding the RNTCP policy. This annual activity had been a key contributor to the RNTCP and responsible for many of the revisions and reforms that have constantly featured in the evolution of the RNTCP.The NTF has been the voice of the collective opinion of academicians in medical colleges and has contributed in shaping key policy issues, such as, ensuring that teaching and training regarding RNTCP and provision of infrastructural facilities like DMC and DOT Centre at medical colleges are made mandatory by Medical Council of India (MCI); rational use of fluoroquinolone antibiotics in the treatment of respiratory tract infections; airborne infection control policy, among others. 

Operational research

The RNTCP facilitated the conduct of operational research (OR) relevant to Programme needs by providing funds. To facilitate conduct of OR, State OR committees were formed in all the States with medical colleges and Zonal OR committees were formed in all the five zones. The OR Committees sanction funding for research projects ranging from up to `100,000 (State OR Committee), `500,000 to `1,500,000 (Zonal OR Committee) and above `1,500,000 (National OR Committee). The RNTCP also instituted a consolidated

grant amount of `20,000 for postgraduate thesis conducted on OR topics relevant to the Programme needs; at least one postgraduate thesis grant per medical college per year is awarded.

HIV-TB coordination and care

The RNTCP units (DMC and DOT Centre) and the Informed Counselling and Testing Centres (ICTC) in the medical colleges have been actively involved in the HIV-TB cross-referral mechanism (Fig. 3) of the RNTCP and the National AIDS Control Organization (NACO). The medical colleges, by their involvement

with NACO, provide facilities for CD4+/CD8+ count testing and provision of anti-retroviral therapy through

anti-retroviral treatment (ART) centres for HIV-TB coinfection. 

Management of M/XDR-TB

The diagnosis and treatment monitoring by sputum smear microscopy via quality assured laboratory services are key components of the RNTCP strategy. Keeping pace with its expansion and the increased demand for quality laboratory services, the RNTCP, by facilitating the establishment of accredited Intermediate Reference Laboratories (IRLs) and DOTS-Plus sites at certain medical colleges has also contributed to capacity building forsurveillance, diagnosis and treatment of MDR-TB. As a part of this exercise, the RNTCP has facilitated establishment of infrastructure for the diagnosis of MDR-TB by providing line-probe assay, liquid culture and GeneXpert MTB/RIF in future in the IRLs at the medical colleges. Several medical colleges in the country have already obtained accreditation for their laboratories for culture and drug-susceptibility testing under RNTCP; the processing of applications of several other medical colleges in underway.

Key contributions made by medical colleges in TB control in India

The key contributions made by medical colleges in RNTCP policy formulation and programme implementation during the last decade are shown in Box 2. Status of medical college involvement

By the end of December 2010, 282 of the 307 (92%) medical colleges were involved in the RNTCP

implementation. In these medical colleges, Core committees have been formed and DMC and DOT

centres have been established under the Programme (Table I)15. Out of the 282 medical colleges involved,

244 (87%) have submitted their reports for all the quarters during the period July 2009 to June 2010.

Supervision and monitoring by the STFs

During July 2009 to June 2010, all States organized at least one STF meeting; in total there were 55 STF

meetings. There were 77 medical college visits by the STF members and 19 visits by the ZTF members15.

RNTCP advocacy activities undertaken by medical college staff The medical colleges have reported 21 publications on RNTCP in peer reviewed journals during the period July 2009 to June 2010. All States have reported participation of the medical college faculty in Television/ Radio / Newspapers to disseminate information related to RNTCP. A total of 301 Workshops/Seminars/CMEs (continuing medical education) were conducted on RNTCP in the medical colleges. The medical college faculties have also reported conducting 31 State-level CMEs/workshops on RNTCP across the country during the period15. TB-HIV collaboration in medical colleges During July 2009 to June 2010, 216 medical college reported having both ICTC and DMCs in their premises; of these, 205 have established standard cross referrals between ICTC and DMCs. One hundred and forty two medical colleges also have ART centers and at all these centres, mechanisms to refer HIV co-infected patients to RNTCP for diagnosis and treatment of TB have been established15. Operational research activities undertaken by medical colleges

All the five zones have formed zonal OR Committees, and all the states with medical colleges have the state

OR Committees. In 2011, 72 thesis proposals and 14 OR proposals were approved by various Zonal OR

Committees1. All the State OR Committees have met atleast once during the period July 2009 to June 2010.

The State OR Committees have forwarded 41 OR proposals to the Zonal OR Committee for funding. Of

these, 31 proposals have been approved for funding by the Zonal OR Committee.The State OR Committees

approved 70 postgraduate thesis proposals for funding from RNTCP. Large multicentric OR studies on efficacy

Microscopy activities at the medical colleges

During the period July 2009 to June 2010, 92,071 of the 6,11,683 patients (15%) who had undergone

sputum smear examination for diagnosis at the DMCs in the medical colleges were diagnosed to have smear-positive pulmonary TB. Of these, 18,452 (20%) patients were started on DOTS from the DOT Centres in the medical colleges, while 65,563 (71%) were referred for treatment to the DOT centres at their place of domicile. During the same period, 45115 smear-negative patients and 81,615 patients with EP-TB were either started on DOTS from the DOT Centres in the medical colleges, or were referred for treatment to the DOT centres at their place of domicile. All the DMCs in the medical colleges have actively participated in the quality assurance protocol of the RNTCP which included on-site supervision, panel testing, and random blinded rechecking (RBRC) of routine slides. Overall, at a national level, medical colleges contributed to 25 per cent of the TB suspects referred for diagnosis, 23 per cent of new smear-positives diagnosed, 7 per cent DOT provision within medical colleges and 86 per cent treatment success rate for new smear-positive patients (Figs 4A and 4B)1,10-15.

Referral for treatment and feedback status

Of the sputum positive patients referred for treatment during the period April 2009 to March 2010 of RNTCP Category III treatment in EPTB, such as lymph node TB16, TB pleural effusions17 and Category

I treatment in abdominal TB (patient recruitment ongoing) are expected to provide valuable data on the

performance of the RNTCP DOTS regimens. 

Participation in the Joint Monitoring Mission

The RNTCP was started on a pilot basis in 1993 based on the recommendations of the first review held in 1992. The second joint programme review, conducted in February 2000, found the functioning of the Programme to be successful and had recommended rapid expansion of quality RNTCP services to cover

the entire country by 2005. The third review was conducted in September 2003 by a team of 20 national

(including faculty members from medical colleges) and 22 international TB experts. The team made field visits to five States, namely, Maharashtra, Orissa, Rajasthan, Tamil Nadu, and Uttar Pradesh18. The Joint Monitoring Mission (JMM) 2006 was jointly organized by the GOI

Early diagnosis of M/XDR-TB Early diagnosis of M/XDR-TB by facilitating establishment of infrastructure

for the diagnosis of MDR-TB by providing line-probe assay, liquid culture and GeneXpert MTB/RIF in future in the IRLs at the medical colleges. The related administrative, funding and human resource issues that are common constraints for implementing this need discussion and resolution. Institution of air-borne infection control measures Mandatory for upcoming medical colleges; modifications to be made in existing medical colleges.Fewer patients than the actual numbers diagnosed at DMC get treated under RNTCP In-depth study of referral feedback mechanism. Medical college faculty to conduct advocacy and sensitization more intensely to facilitate greater involvement of private practitioners.

Underutilization of RNTCP DOTS treatment of EPTB

For reviewing the preparatory activities for DOTSPlus, the State of Gujarat was selected. To observe TB/

HIV activities and to visit the NTI for human resource development (HRD) issues, the State of Karnataka was selected. Three other States were randomly selected from the north and east of the country (Madhya

Pradesh, West Bengal, Punjab and Haryana, being smaller States, were combined as one unit). The fourth

in the series of JMMs was organized in April 2009(20) and included representatives from all major national

(including faculty members from medical colleges)and international partners of RNTCP. The JMM team

had visited five states (Gujarat, Rajasthan, Tamil Nadu, Himachal Pradesh and Uttarakhand) and one

Union Territory (Puducherry). The fifth in the series of JMMs organized in August 2012 also included faculty members from medical colleges along with national and international partners of RNTCP. The JMM team

had visited 12 districts in six states, namely, Bihar, Maharashtra, Punjab, Karnataka, West Bengal and

Uttar Pradesh21. The key Challenges faced in the involvement of medical colleges in the RNTCP and suggested solutions are shown in Table II.

Discussion

Till the time involvement of medical colleges in the RNTCP was conceived, the interaction between the

academicians in the medical colleges and the Programme managers was sparse and on many occasions discordant. The young doctors in training seldom got an opportunity to practice what was preached to them22. As a result, the facilities available under the RNTCP were seldom utilized to the full extent possible. Keeping in mind the needs of the country, a future “5-Star” doctor who would take up the responsibilities as a care provider, decision maker, communicator, community leader, and a manager was visualized and such a future doctor would not only serve the patients and the community but would also gain their respect3. The involvement of medical colleges in TB control envisaged and successfully implemented by the RNTCP for more than a decade in India is an extraordinary effort. The Task Force mechanism has entrusted the responsibility to medical colleges to ensure their effective contribution to the efforts of GOI in TB control. The successful amalgamation of the public health approach and the expertise of academicians has immensely benefited the RNTCP and TB control in India and facilitated the emergence of the “future doctor” from among the medical students3. A model DOT Centre was established at AIIMS, New Delhi, to serve as a role model for other medical colleges in the country with the help of WHO-SEARO in September 200123,24. The initial experience gained at this model DOT centre was subsequently adopted for evolving the modus operandi for involvement of medical colleges in the implementation of the RNTCP. During 2001-2005, 1490 patients were evaluated at the DOT Centre at the AIIMS hospital, New Delhi23. Of the 768 patients with cough, 27 per cent were found to be sputum positive for acid-fast bacilli (AFB). Among patients who were initiated on DOTS, cure was achieved in 92 per cent of new sputum smear positive patients; treatment completion was achieved in 91 per cent of EPTB and 75 per cent sputum-negative pulmonary TB patients. Overall treatment success was achieved in 86 per cent24. Further , this is also reflected by the fact that, over the last decade, medical colleges have consistently contributed to nearly 25 per centm of the chest symptomatic referred for sputum smear examination and nearly 20 per cent of new sputum smear-positive patients detected annually (Fig. 4A and 4B). This reflects a significant achievement because, this large proportion of patients would have otherwise been diagnosed to have TB on radiological or other grounds and not by the reliable sputum smear examination method. These patients would also have received suboptimal non-DOTS treatment if the medical colleges were not intensely involved in the RNTCP. The robust reporting system that has been developed has provided useful surveillance data and feedback on the functioning of the Programme. Irrespective of which medical college in the country the patient is diagnosed to have TB, the referral mechanisms for treatment have facilitated the delivery of DOTS at the patient’s place of domicile.

Medical colleges, by virtue of being referral centres with more facilities for invasive procedures and histo pathological and microbiological methods of diagnosis, have enhanced diagnostic yield of EPTB, such as, TB pleural effusion, lymph node TB, abdominal TB, neurological TB, among others. These have, thus, contributed to early diagnosis of EPTB cases and facilitated institution of the standard of care i.e., DOTS

for these patients. Medical college involvement has also facilitated more active involvement of paediatricians

in the RNTCP and effective utilization of RNTCP diagnostic and therapeutic services for paediatric TB.

Some problems have been identified in the implementation of RNTCP activities in medical colleges, especially in the new medical colleges set up in the private sector. These include delay in formation of Core Committees, establishment of DMCs in some of the medical colleges. Technical doubts about efficacy of DOTS regimens particularly in EPTB cases have lingered on. Consequently, many patients with EPTB, especially, orthopaedic and neurological TB are being treated with non-DOTS treatment resulting in

inadequate utilization of the RNTCP programme. 

Constraints and challenges ahead

The inadequacies in staff and human resources, shortage at all levels requires rectification. Issues, such as, staff vacancies in medical colleges not being filled up on time, and salaries to RNTCP contractual staff not being at par with payments in the sector also need to be addressed. In some states, delay/non-release of funds to STFs has resulted in non-performance of planned activities. There is a need to ensure financing

essential for sustenance of this model. In states with a large number of medical colleges, such as Karnataka, visit by the STF Chairperson has become a practical problem. Increasing the number of STF Chairpersons

could perhaps be a solution to this problem. Poor and inadequate airborne infection control practices in most

of the medical colleges, especially the overcrowded government medical colleges has been another issue of

concern. There is an urgent need for advocacy regarding education on cough hygiene and etiquette. Weaknesses that are evident in supervision capacity and quality as well as in planning, monitoring and evaluation need to be addressed. In medical colleges, there is a need for enhanced inter-departmental sensitization and better advocacy for RNTCP and need for more contribution in pulmonary TB (smear-positive and smear-negative cases) and EPTB cases. There is also a need for strengthening the feedback for transferred out cases. This can be facilitated by holding regular core committee meetings, more intense and sustained sensitization regarding the Programme and enhanced inter-departmental cooperation. Establishment of IRLs and DOTS-Plus sites for M/XDR-TB in medical colleges would contribute to capacity building and strengthening of mycobacteriology laboratory services in the department of microbiology in medical colleges. Availability of quality assured accredited laboratories in medical colleges would facilitate better management

of drug-resistant TB and HIV-TB co-infection. Active medical college involvement in prior planning and efficient management of drug logistics cycle will avoid shortages and will ensure timely supply of drugs. However, in spite of all these deterrents and shortcomings, the landmark decision taken more than a decade ago to involve medical colleges in TB control appears to have extraordinary foresight. This has resulted in the establishment of DOTS as the standard of care for TB patients in all medical colleges and their hospitals. It is expected that through their own practice, senior faculty (professor) in medical colleges will influence the practice in the private sector as well as the future generation of physicians thus making DOTS the standard of care for TB patients in the country. This will ensure that all TB patients, irrespective of where they

seek care, receive the best available care, free of cost. Several issues need to be streamlined and improved

upon in the coming years to make this partnership between the RNTCP and the medical colleges a truly

effective collaboration. As the Programme widens the scope of services that it provides, medical colleges will have an increasingly important role to play in areas such as TB/HIV coinfection, external quality assurance of the sputum microscopy network, drug-resistance surveillance and management of multidrug-resistant TB patients. The RNTCP needs active support of medical colleges in carrying out OR in these areas to guide the development of the Programme’s future policies. Recently, medical colleges have also begun participation in airborne infection control policy implementation25. This will involve engineering works, renovation of existing

infrastructure by involving medical college authorities. Medical colleges also have the potential for evaluating the efficacy of isoniazid preventive treatment (IPT) in the field setting. Thus, by their active involvement in the “3Is”, namely, intensified case finding, (airborne) infection control policy, and IPT medical colleges are active partners in the implementation of the RNTCP. The beginning and the progress made so far seem promising. But, the need of the hour is to sustain the momentum gained and push medical college involvement forward by continuing coordination and communication. The OR relevant to the Programme needs can be further facilitated by providing attractive funding and a clear-cut modus operandi with a specified time-line so as to attract interested faculty members from medical colleges to take up research studies. Identifying thrust areas relevant to current needs of the Programme, and making available quality generic protocols can facilitate OR studies to be carried out in medical colleges in multicentre mode. There is also a need for visible networking to facilitate the widespread dissemination of the outcomes and results documented in the OR studies so that this will also enthuse and inspire more research relevant to the Programme needs. The experience from India in involving medical colleges in national Programme shows that tangible additional benefits can be obtained in TB control, especially by improving case detection. In view of this, involvement of medical colleges should be promoted widely and the experience replicated not only in theregion but also globally.

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Attain Multicentric Study Report

Telavancin versus Vancomycin in Hospital-acquired pneumonia due to gram positive pathogens

Clin Infect Dis. 2011 January 1; 52(1): 31–40.

doi:  10.1093/cid/ciq031

PMCID: PMC3060890

Telavancin versus Vancomycin for Hospital-Acquired Pneumonia due to Gram-positive Pathogens

Ethan Rubinstein,¹ Tahaniyat Lalani,^2,3 G. Ralph Corey,^2,3 Zeina A. Kanafani,¹¹ Esteban C. Nannini,¹² Marcelo G. Rocha,¹⁵ Galia Rahav,¹⁶ Michael S. Niederman,^4,5 Marin H. Kollef,⁶ Andrew F. Shorr,⁷ Patrick C. Lee,⁸ Arnold L. Lentnek,⁹ Carlos M. Luna,¹³ Jean-Yves Fagon,¹⁷ Antoni Torres,¹⁸ Michael M. Kitt,^a Fredric C. Genter,¹⁰ Steven L. Barriere,¹⁰ H. David Friedland,^a Martin E. Stryjewski,^2,14 and for the ATTAIN Study Group^b

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Abstract

Background.Telavancin is a lipoglycopeptide bactericidal against gram-positive pathogens. 

Methods.Two methodologically identical, double-blind studies (0015 and 0019) were conducted involving patients with hospital-acquired pneumonia (HAP) due to gram-positive pathogens, particularly methicillin-resistant  Staphylococcus aureus (MRSA). Patients were randomized 1:1 to telavancin (10 mg/kg every 24 h) or vancomycin (1 g every 12 h) for 7–21 days. The primary end point was clinical response at follow-up/test-of-cure visit.

Results.A total of 1503 patients were randomized and received study medication (the all-treated population). In the pooled all-treated population, cure rates with telavancin versus vancomycin were 58.9% versus 59.5% (95% confidence interval [CI] for the difference, –5.6% to 4.3%). In the pooled clinically evaluable population ( n = 654), cure rates were 82.4% with telavancin and 80.7% with vancomycin (95% CI for the difference, –4.3% to 7.7%). Treatment with telavancin achieved higher cure rates in patients with monomicrobial S. aureus infection and comparable cure rates in patients with MRSA infection; in patients with mixed gram-positive/gram-negative infections, cure rates were higher in the vancomycin group. Incidence and types of adverse events were comparable between the treatment groups. Mortality rates for telavancin-treated versus vancomycin-treated patients were 21.5% versus 16.6% (95% CI for the difference, –0.7% to 10.6%) for study 0015 and 18.5% versus 20.6% (95% CI for the difference, –7.8% to 3.5%) for study 0019. Increases in serum creatinine level were more common in the telavancin group (16% vs 10%).

Conclusions.The primary end point of the studies was met, indicating that telavancin is noninferior to vancomycin on the basis of clinical response in the treatment of HAP due to gram-positive pathogens. 

Hospital-acquired pneumonia (HAP) is the second most common nosocomial infection and the leading cause of mortality attributable to these critical infections [ 1– 3]. Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), is now a major cause of HAP [ 4– 6]. Rates of clinical failure in patients with HAP due to MRSA are high [ 7, 8]. Currently, only vancomycin and linezolid are recommended for treatment of HAP due to MRSA [ 9]. Results from recent pneumonia trials with new antibiotics active against MRSA have not been encouraging [ 10– 12]. Therefore, additional antistaphylococcal agents for treatment of HAP are urgently needed.

Telavancin is a lipoglycopeptide antibacterial agent exhibiting potent, concentration-dependent bactericidal effects via a dual mechanism of action that combines inhibition of cell wall synthesis and disruption of membrane barrier function [ 13– 15]. In vitro, telavancin is rapidly bactericidal against clinically important gram-positive bacteria, including MRSA, vancomycin-intermediate S. aureus, and penicillin-resistant S. pneumoniae [ 13, 16, 17].

Telavancin penetrates well into the epithelial lining fluid and alveolar macrophages of healthy subjects, achieving concentrations up to 8-fold and 85-fold, respectively, above telavancin's minimum inhibitory concentration (MIC) for 90% (MIC₉₀) of MRSA strains (.5 μg/mL) [ 16, 18]. Unlike daptomycin (a cyclic lipopeptide), telavancin remains active in vitro in the presence of pulmonary surfactant [ 16]. Telavancin is approved in the United States and Canada for the treatment of adult patients with complicated skin and skin-structure infections due to susceptible gram-positive pathogens.

The current studies were designed to assess the clinical efficacy and safety of telavancin compared with vancomycin in the treatment of HAP due to gram-positive organisms, with a focus on infections due to MRSA. Partial results of these studies have been previously reported.

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METHODS

The Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia (ATTAIN) studies were 2 identical randomized, double-blind, comparator-controlled, parallel-group phase III trials, 0015 and 0019 (NCT00107952 and NCT00124020), with patients enrolled between January 2005 and June 2007. The institutional review board at each site approved the protocol, and all patients or their authorized representatives provided written informed consent.

Patient selection.

Male and nonpregnant female patients aged ≥18 years were eligible for enrollment if they had pneumonia acquired after 48 h in an inpatient acute or chronic care facility or that developed within 7 days after being discharged. Patients were required to have ≥2 of the following: cough, purulent sputum, auscultatory findings, dyspnea, tachypnea, or hypoxemia; or identification of an organism consistent with a respiratory pathogen isolated from respiratory tract or blood. In addition, patients were also required to have ≥2 of the following: fever (temperature >38°C) or hypothermia (rectal/core temperature <35°C); respiratory rate >30 breaths/min; pulse rate ≥120 beats/min; altered mental status; need for mechanical ventilation; and white blood cell count >10,000 cells/mm³, <4500 cells/mm³, or >15% immature neutrophils (band forms). All patients were required to have new or progressive infiltrates, consolidation, with or without pleural effusion on chest radiograph (or computed tomography), and an adequate respiratory specimen for Gram stain and culture.

Patients were excluded if they had any of the following: receipt of potentially effective systemic antibiotic therapy for gram-positive pneumonia for >24 h immediately prior to randomization (unless there was documented clinical failure after 3 days of therapy or if the pathogen was resistant in vitro to previous treatment); only gram-negative bacteria seen on Gram stain or culture; baseline QTc interval >500 msec, uncompensated heart failure; absolute neutrophil count <500 cells/mm³; or pulmonary disease that precludes evaluation of therapeutic response (eg, lung cancer, active tuberculosis, cystic fibrosis, or granulomatous disease).

Randomization and treatment regimens.

The ATTAIN trials were double-blinded studies in which patients were randomized (1:1) to receive either intravenous (IV) telavancin at a dosage of 10 mg/kg every 24 h or vancomycin at a dosage of 1 g IV every 12 h for 7–21 days. Randomization was conducted through an interactive voice response system using permuted block algorithm and stratifying by country group, presence of diabetes, and ventilatory status. The vancomycin regimen could be monitored and adjusted according to the institutional policy at each site but had to be performed such that blinding was not compromised. The dose of telavancin was adjusted in patients with creatinine clearance ≤50 mL/min. For patients with pneumonia due to suspected or proven methicillin-susceptible S. aureus (MSSA), a switch to antistaphylococcal penicillin from vancomycin was permitted. In patients with polymicrobial (mixed gram-positive/gram-negative) infection, concomitant therapy with aztreonam or piperacillin-tazobactam was allowed.

Assessments.

Clinical assessments were performed at baseline and daily throughout study treatment, at the end of therapy (EOT), and at follow-up/test of cure visit (FU/TOC). Laboratory assessments were performed every 3 days up to the EOT. FU/TOC assessment was conducted 7–14 days after EOT.

Respiratory samples (invasive or noninvasive) and 2 blood culture specimens were obtained at baseline for Gram stain and culture [ 9]. Isolated pathogens were submitted to a central laboratory for confirmation of identity and susceptibility testing [ 19].

Telavancin plasma samples for pharmacokinetic analyses were obtained at some centers, as were vancomycin trough levels, in accordance with site-specific procedures.

Efficacy and safety variables.

Clinical responses at FU/TOC were defined as follows. Cure was defined as improvement or lack of progression of baseline radiographic findings at EOT and resolution of signs and symptoms of pneumonia at FU/TOC. Failure was defined as persistence or progression of signs and symptoms or progression of radiological signs of pneumonia at EOT; termination of study medications due to “lack of efficacy” and initiation within 2 calendar days of a different potentially effective antistaphylococcal medication; death on or after day 3 attributable to primary infection; or relapsed infection at TOC after termination of study medications. Indeterminate response was defined as the inability to determine outcome. Adverse events (AEs), vital signs, electrocardiograms, and laboratory parameters were also evaluated.

Analysis populations.

The all-treated (AT) population included all randomized patients who received ≥1 dose of study medication. The modified all-treated (MAT) population consisted of patients in the AT population who had a respiratory pathogen identified from baseline samples (or from blood cultures if no respiratory sample was positive). The clinically evaluable (CE) population consisted of patients in the AT population who were protocol-adherent or who died on or after study day 3, if death was attributable to the HAP episode under study. The microbiologically evaluable (ME) population consisted of CE patients who had a gram-positive respiratory pathogen recovered from baseline respiratory specimens or blood cultures. The safety population included patients who received ≥1 dose of study medication.

Statistical analyses.

The primary efficacy end point of each study was clinical response at FU/TOC in the AT and CE populations. Failure at EOT was carried forward to FU/TOC. Two-sided 95% confidence intervals (CIs) were calculated on the difference in response rate; pooled-study CIs were stratified on study. The primary efficacy end point was tested for the noninferiority of telavancin compared with vancomycin in both the AT and CE populations in each study, using a prespecified non-inferiority margin of 20% and a 1-sided significance level of .025. Assuming that 35% of enrolled patients would be in the CE group and that cure rates would be 60% in both treatment groups, 312 enrolled patients per treatment arm would provide 109 CE patients and statistical power of 86% to achieve noninferiority. A key prespecified secondary objective was to perform a 2-study pooled analysis of telavancin superiority compared with vancomycin treatment in patients with pneumonia due to MRSA. Post hoc analyses of cure rates at FU/TOC visit by baseline pathogen characteristics (methicillin resistance status, vancomycin MIC, and evidence for mixed gram-negative/gram-positive infection) were also performed; statistical inferential statements are not adjusted for multiple comparisons.

Deaths through FU/TOC were summarized. If there was no FU/TOC visit, any death reported to have occurred within 28 days after end of treatment was included in the analysis. Within this article, results are presented from analysis of the pooled datasets from the 2 studies. Primary efficacy results are also presented for each study separately.

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RESULTS

Disposition of patients.

A total of 1532 patients from 274 study sites in 38 countries were randomized (Figure 1). In all, 1503 patients received ≥1 dose of study medication (telavancin, n = 749; vancomycin,n = 754; AT population). The most common reasons for exclusion from the CE population were indeterminate or missing responses at FU/TOC, receipt of potentially effective nonstudy systemic antibiotics, and isolation of only gram-negative bacteria ( Figure 1). The most common reasons for missing or indeterminate responses at FU/TOC were patient death due to causes other than HAP and presence of gram-negative pathogen only, respectively.

Figure 1.

Patient disposition for studies 0015 and 0019. Patients could have >1 reason for exclusion from either the clinically evaluable (CE) or microbiologically evaluable (ME) populations. *Among those randomized to receive vancomycin, 20 patients had ...

Baseline and demographic characteristics.

Baseline and demographic variables were comparable between treatment groups ( Table 1). Patients aged ≥65 years accounted for more than one-half of those enrolled and treated in both treatment groups. More than one-half of the patients were in intensive care units at baseline. Common co-morbidities included diabetes mellitus, chronic obstructive pulmonary disease, and acute and/or chronic renal failure. Almost two-thirds of patients had multilobar infiltrates, and nearly one-third had pleural effusions. Bacteremia was present in ∼6% of patients. More than one-half of the patients received antibiotic therapy for ≥24 h prior to enrollment. Among these patients, the most common reasons allowing enrollment were clinical failure despite prior antibiotic therapy and development of pneumonia while receiving antibacterials for other indications.

Table 1.

Baseline and Demographic Characteristics for the Pooled Studies All-Treated Population

Most of the respiratory sampling was via expectorated sputum or endotracheal aspirates (particularly in intubated patients), with <20% of patients undergoing more-invasive procedures ( Table 2). S. aureuswas the most common gram-positive pathogen isolated from the respiratory tract; the majority (60%) of S. aureus isolates were MRSA ( Table 2). Mixed infections (ie, infections due to gram-positive and gram-negative pathogens) were present in 27% of patients. The most common gram-negative pathogens were Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter species.

Table 2.

Microbiological Characteristics at Study Entry for the Pooled Studies Microbiologically Evaluable Population

The MIC₉₀ for both MRSA and MSSA was .5 μg/mL for telavancin and 1 μg/mL for vancomycin. The mean (± standard deviation [SD]) predose plasma concentration (C_trough) of telavancin for patients in the 2 studies were 10–12 μg/mL. Telavancin mean peak plasma concentration was ∼70 μg/mL. In those patients for whom >1 vancomycin serum trough level was obtained (n = 226), mean trough levels were ≥5 μg/mL in 94% (n = 212) and ≥10 μg/mL in 66% (n = 149) of patients.

Primary outcome measures.

Cure rates at FU/TOC in the 2 treatment groups were similar in each study (Table 3). Results from studies 0015 and 0019 each met the criterion for noninferiority of telavancin compared with vancomycin. The 95% CI for the treatment difference between the 2 regimens from each study overlapped, supporting pooling of the data. Thus, cure rates in the pooled AT population were 58.9% for telavancin and 59.5% for vancomycin (95% CI for the difference, –5.6% to 4.3%), whereas in the pooled CE patients, cure rates were 82.4% for telavancin and 80.7% for vancomycin (95% CI for the difference, –4.3% to 7.7%). The most commonly listed reason for failure at FU/TOC in AT and CE patients in both treatment groups was treatment failure at EOT ( Table 4).

Table 3.

Cure Rates for Hospital-Acquired Pneumonia at Follow-up/Test-of-Cure Visit

Table 4.

Reasons for Treatment Failure at Follow-up/Test-of-Cure Visit for Pooled Studies

Secondary outcome measures.

In patients with pneumonia due to MRSA with or without other pathogens, the clinical response at FU/TOC between the treatment groups was similar ( Table 5). Cure rates were higher in the telavancin group in patients with monomicrobial infection due to S. aureus, and this was consistent for both patients with MRSA and those with MSSA. Telavancin cure rates were also higher in patients infected with S. aureus that demonstrated a vancomycin MIC ≥1 μg/mL ( Table 5). Lower cure rates in patients with mixed infections were observed in the telavancin group. In patients with mixed infections who received adequate gram-negative coverage, cure rates were similar between the 2 groups ( Table 5).

Table 5.

Cure Rates at Follow-up/Test-of-Cure Visit by Baseline Pathogen for the Pooled Microbiologically Evaluable Population

Safety analysis.

The overall incidence of AE was comparable in the 2 groups ( Table 6). For study 0015, 80 (21.5%) of 372 telavancin-treated patients died, and 62 (16.6%) of 374 vancomycin-treated patients died (95% CI for the difference, –0.7% to 10.6%). For study 0019, 70 (18.5%) of 379 telavancin-treated patients died, and 78 (20.6%) of 378 vancomycin-treated patients died (95% CI for the difference, –7.8% to 3.5%).

Table 6.

Safety parameters for the Pooled Studies Safety Population

Most common treatment-emergent AEs (TEAEs) in both treatment groups were diarrhea, anemia, hypokalemia, constipation, and renal impairment ( Table 6). The incidences of serious AEs (SAEs) and TEAEs leading to discontinuation of study medication were higher in the telavancin group (31% vs 26% and 8% vs 5%, respectively). The most common SAEs in patients receiving telavancin and those receiving vancomycin were septic shock (4% vs 4%), respiratory failure (3% vs 3%), and multiorgan failure (3% vs 2%). The most frequently reported AE leading to study medication discontinuation was acute renal failure (1.2%) in telavancin-treated patients and septic shock (0.7%) in vancomycin-treated patients.

Potentially clinically significant increases in serum creatinine levels (>50% increase from baseline and a maximum value >1.5 mg/dL) were more common in the telavancin group than in the vancomycin group (16% vs 10%). Other than creatinine level increases, the most common abnormalities in both treatment groups were anemia, abnormal serum potassium levels, and hepatic enzyme abnormalities (Table 7). All of these abnormalities occurred with similar frequencies in the 2 treatment groups.

Table 7.

Laboratory Abnormalities in Patients with Normal Values at Baseline for the Pooled Studies Safety Population

Prolongation of Fridericia-corrected QT interval (QTcF) by >60 msec occurred in 8% and 7% of the telavancin-treated and vancomycin-treated patients, respectively. A maximum QTcF interval value >500 msec occurred in a similar proportion of patients (2%) in the 2 groups. None of the patients experienced arrhythmias attributable to a prolonged QTcF interval.

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DISCUSSION

The results of the ATTAIN trials reported herein demonstrate that telavancin has clinical response outcomes that are noninferior to those of vancomycin in the treatment of patients with HAP due to the gram-positive bacteria, such as S. aureus (MRSA and MSSA) and S. pneumoniae. Importantly, these findings, which incorporate data for more than 1500 patients from >250 sites around the world, are robust and consistent across all efficacy populations.

The ATTAIN trials, which enrolled almost 300 ME patients with monomicrobial S. aureus pneumonia, demonstrated that telavancin therapy achieved higher cure rates than did vancomycin therapy in the group of patients with pneumonia due to S. aureus. Higher cure rates were also observed in the telavancin group among patients infected with S. aureus that had a vancomycin MIC ≥1 mg/L.

Importantly, telavancin was effective in the treatment of patients with pneumonia due to MRSA, as well as in the treatment of those patients with pneumonia due to MSSA. The high cure rates obtained in the telavancin group support the use of telavancin as empirical therapy for suspected S. aureus pneumonia as well as its use as targeted therapy for both MRSA and MSSA infections.

A lower cure rate was associated with telavancin therapy in the subgroup of patients with mixed infections, although the difference was not statistically significant. Because telavancin has no activity against gram-negative pathogens, these findings could be a result of inadequate gram-negative therapy. This is supported by the finding that, in the subset of patients with mixed infections who received adequate gram-negative coverage, cure rates were similar in the 2 treatment groups.

Although more patients in the telavancin group experienced SAEs or had treatment discontinued due to an AE, compared with patients in the vancomycin group, the incidences of most common AEs were similar in the 2 treatment groups. Clinically significant increases in serum creatinine level were more frequent among telavancin-treated patients. In the majority of patients in both groups with significant creatinine increases, the impairment in renal function had resolved or was resolving at the last follow-up visit. The numbers of patients with QTcF interval prolongation >60 msec or those with absolute QTcF interval >500 msec were comparable between the treatment groups. Death rates were higher for telavancin-treated patients than they were for vancomycin-treated patients in study 0015, whereas the opposite trend was seen in study 0019. Although the ATTAIN trials were not optimally designed for a mortality end point, the differences observed in these studies were not statistically significant.

The strengths of the ATTAIN trials should be underscored. First, when the ATTAIN trials were conducted, the combined populations of these identically designed trials provided, to our knowledge, the largest cohort of patients studied to date for HAP. Similarly, to date, the S. aureus and MRSA subgroups are the largest such subgroups available of patients with HAP. Third, the breadth and diversity of the patient population make the results generalizable to many settings. Lastly, a significant proportion of patients enrolled in these studies were critically ill.

These studies also have limitations. First, the standard of care in much of the world for diagnosis of HAP does not include semi-invasive diagnostic procedures (eg, bronchoalveolar lavage), and the limited number of patients who underwent these procedures makes determination of the exact etiology of HAP potentially less reliable than would otherwise be the case. However, the noninvasive diagnostic techniques used in these studies followed the guidelines of the American Thoracic Society and the Infectious Diseases Society of America [ 9] and are supported by a large ventilator-associated pneumonia study that demonstrated similar outcomes for patients undergoing invasive or noninvasive diagnostic approaches [ 22]. Second, our comparator antibiotic (vancomycin) has been cited as potentially inferior to linezolid for patients with MRSA pneumonia. However, the results of the post hoc analysis of 2 previous studies of linezolid versus vancomycin are controversial [ 23]. As a result, vancomycin continues to be commonly used to treat patients with HAP in whom MRSA infection is suspected or identified [ 24]. Third, the vancomycin dosage was adjusted in accordance with institutional policies. Although such policies differed between sites, they reflect the real use of vancomycin during the time period in which these studies were conducted. Despite the unresolved controversy regarding the clinical value of determining serum levels of vancomycin, the large majority of patients for whom vancomycin levels were obtained had mean trough levels that were considered “adequate” (ie, 5–15 μg/mL) at the time the studies were conducted. Baseline renal status, as well as co-morbidities known to predispose patients to renal dysfunction, should be taken into consideration before treatment is initiated. Renal function should be monitored in all patients receiving telavancin.

In summary, the 2 large identically designed, double-blinded, randomized ATTAIN trials demonstrate that telavancin is effective in the treatment of patients with HAP caused by gram-positive pathogens. In the overall population, telavancin has an acceptable risk profile for the treatment of patients with HAP.

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Members of the ATTAIN Study Group

C-S. Abboud, N. Abdullah, A. Allworth, J. Altclas, T. Amgott, A. D. Aquila, K. Ashutosh, J.W. Baddley, C.X. Bai, A. Bajpai, I. Balik, M.I.C. Barker, M.G. Bayasi, C. Beltrán, A.K. Bhattacharya, P. K. Bhattacharya, D. L. Bowton, J. Brodnan, U. Bucksteg, J. Cardoso, Y. Castaing, C. Chahin, K. Chang, C. Charters, Y.H. Chen, J. Cheníček, R. Chetambath, H.J. Choi, J.Y. Choi, N. Chowta, Y.C. Chuang, M. Clavel, M. Confalonieri, G. Criner, D. Curcio, F. De Rozario, F. Della Corte, G. Deng, S. Dhalla, A. Dhar, F. M. Díaz, R. H. Dretler, O. Dziublyk, J. Edington, A. El Sohl, W. Flynn Jr., P. Fogarty, F. Fôret, J. Fratzia, C. Freuler, C. Galletti, J.B. Garcia-Diaz, V. Gasparovic, M. J. Gehman, A. Germar, A. Gerogianni, M. Gerson, D. Ghelani, M. Giannokou-Peftoulidou, M. Giladi, V. Golin, R. Grinbaum, I. Gudelj, I. Gugila, J.B. Gupta, O. Hadjiiski, G.L. Hara, M. Heiner, K. Holn, M. Hojman, C. H. Huang, S.C. Hwang, K. H. In, A. Itzhaki, T. Janasková, M. Kaaki, T. Kavardzhiklieva, S. Keenan, G. Kekstas, A. Khoja, W.J. Kim, Y.K. Kim, U. Kivistik, S.K. Kochar, J. Koirala, I. Koksal, A. Komnos, F. Koura, J. Kraatz, L. Kucharski, I. Kuzman, J. LaForge, D. Lakey, Z. Lazic, A. Leditschke, J-Y. Lefrant, F. Lewis, J. Lipman, S. Liu, H. Lopes, T. Louie, C. Lovesio, J. Mador, M. Magaña, A.A. Mahayiddin, M. Makhviladze, I. Maia, J. Malone-Lee, E. Martinez, H. Metev, H. Minkowitz, M. Mitic-Miliki, N. Monogarova, B.C. Montaldo, M. C. Montalban, P. Montravers, E. Moore, P. Mootsikapun, R.A. Mori, G. Nackaerts, V. Nayyar, R. Norviliene, P. O'Neill, I. Oren, W. O'Riordan, A. Ortiz, A.H.D. Pacheco, H.K. Park, Y.S. Park, M.J. Park, S. Peake, T. Pejcic, Y. Pesant, G. Philteos, G. Pittoni, V. Platikanov, J. Plutinsky, I. Potasman, J.P. Pretorius, D. Pryluka, J. Pullman, R. Raz, N.M. Razali, M. Riachy, C. Rodriguez, Y. Roldan, E. Romero, C. Rondina, R. Salazar, J. Santiagual, M.K. Sarna, F.A. Sarubbi, P. Sepulveda, T. Sheftel, Y. Shehabi, P. Shitrit, E. Shmelev, J. Showalter, R. Siebert, V. Simanenkov, G. Simmons, J. Sirotiakova, V. Skerk, S. Song, H. Standiford, C. Stefanov, R. Stienecker, K. Stock, M. Street, R. Tabukashvili, D. Talwar, A. Tamariz, C. Tanaseanu, A. Timerman, T. Todisco, S. Towfigh, V. Tsvetkov, N. Tudoric, A. Valavicius, R. Valentini, C. Van Dyk, H. Van Rensburg, G. Villamizar, J-L. Vincent, C. Walker, G.F. Wang, J.H. Wang, L.S. Wang, K. Weiss, J. Welker, Z. Wen, L.A. Witty, C. Wu, P. Wu, C.T. Yang, K-Y. Yang, L. Yashyna, S. Yi, S.J. Yong, V. Yovtchev, M. M. Yusoff, T. Zhang, X. Zhou, R. Zimlichman, E. Zonova, and F. Zveibil.

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Acknowledgments

Financial support.The research and publication process was supported jointly by Theravance, Inc. and Astellas Pharma Global Development, Inc. 

Manuscript preparation.Theravance, Inc. (South San Francisco) provided assistance with statistical analyses. Medical writing and editorial support was provided by Ivo Stoilov and Zeena Nackerdien, Envision Scientific Solutions, funded by Astellas Pharma Global Development, Inc. 

Potential conflicts of interest.E.R. has served as a consultant for Theravance, Inc., Astellas, Pfizer, Bayer, Wyeth, Merck, Atox, Ortho-McNeill, and sanofi-aventis. G.R.C. has served as a consultant for Theravance, Inc.; has received support from Cubist Pharmaceuticals and Theravance, Inc.; and serves as a consultant for Cerexa, Merck, Pfizer, Cempra, and Astellas. E.C.N. received honoraria from Theravance, Inc. and research support from Astellas and Johnson  & Johnson. M.G.R. has received research support from Theravance, Inc., Hospira, Novartis, and Chiron for conducting clinical trials. G.R. has received a research grant from Pfizer. M.S.N. has served as a consultant and received honoraria from Pfizer, Merck, Astra-Zeneca, Johnson & Johnson, Theravance, Inc., Schering-Plough, and Nektar and had received research support from Nektar and Pfizer. M.H.K. has received research support from Merck, Pfizer, and Astellas. A.F.S. has either served as a consultant or investigator or has delivered promotional lectures for Astellas, Theravance, Inc., Pfizer, Merck, Johnson & Johnson, Boehringer Ingelheim, GSK, sanofi-aventis, Canyon and Medicine Comp. P.L. has served as a consultant for Smiths Medical and received honoraria from Wyeth, King Pharmaceutical, and Adolor Corporation. A.L.L. has received research support from Ortho-McNeill, Cerexa, Targanta, Optimer, and Theravance, Inc. and has received honoraria from Cubist Pharmaceuticals. C.M.L. has served as a consultant and received honoraria from Pfizer, Merck, Astra-Zeneca, and Bayer and has received independent research support from Pfizer. A.T. has served as a speaker for Astellas, Novartis, and Bayer and has research support from Pfizer. M.M.K. is a former employee of Theravance, Inc. F.C.G. is an employee of Theravance, Inc. S.L.B. is an employee of Theravance, Inc. H.D.F. is a former employee of Theravance, Inc. M.E.S. has served as a consultant for Theravance, Inc. and Trius Therapeutics, has received honoraria from Astellas, and received research support from Theravance, Inc.

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