Prevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural South African district hospitals: an epidemiological modelling study

doi:10.1016/S0140-6736(07)61636-5

The Lancet

Volume 370, Issue 9597, 27 October–2 November 2007, Pages 1500-1507

https://doi.org/10.1016/S0140-6736(07)61636-5 Get rights and content

Summary

Background

Extensively drug-resistant (XDR) tuberculosis has spread among hospitalised patients in South Africa, but the epidemic-level effect of hospital-based infection control strategies remains unknown. We modelled the plausible effect of rapidly available infection control strategies on the overall course of the XDR tuberculosis epidemic in a rural area of South Africa.

Methods

We investigated the effect of administrative, environmental, and personal infection control measures on the epidemic trajectory of XDR tuberculosis in the rural community of Tugela Ferry. Assessments were done with a mathematical model incorporating over 2 years of longitudinal inpatient and community-based data. The model simulated inpatient airborne tuberculosis transmission, community tuberculosis transmission, and the effect of HIV and antiretroviral therapy.

Findings

If no new interventions are introduced, about 1300 cases of XDR tuberculosis are predicted to occur in the area of Tugela Ferry by the end of 2012, more than half of which are likely to be nosocomially transmitted. Mask use alone would avert fewer than 10% of cases in the overall epidemic, but could prevent a large proportion of cases of XDR tuberculosis in hospital staff. The combination of mask use with reduced hospitalisation time and a shift to outpatient therapy could prevent nearly a third of XDR tuberculosis cases. Supplementing this approach with improved ventilation, rapid drug resistance testing, HIV treatment, and tuberculosis isolation facilities could avert 48% of XDR tuberculosis cases (range 34–50%) by the end of 2012. However, involuntary detention could result in an unexpected rise in incidence due to restricted isolation capacity.

Interpretation

A synergistic combination of available nosocomial infection control strategies could prevent nearly half of XDR tuberculosis cases, even in a resource-limited setting. XDR tuberculosis transmission will probably continue in the community, indicating the need to develop and implement parallel community-based programmes.

Introduction

Multidrug-resistant (MDR) tuberculosis—tuberculosis resistant to at least isoniazid and rifampicin—is an increasingly important public health and clinical issue, especially in countries with a high burden of HIV.¹ Reports of MDR tuberculosis isolates resistant to second-line drugs have amplified these concerns. In March, 2006, the first data were published on the worldwide occurrence of tuberculosis with resistance to second-line drugs, termed extensively drug-resistant (XDR) tuberculosis.² Of 17 690 isolates, 20% were MDR and 2% were XDR tuberculosis. XDR tuberculosis has since been redefined as resistance to isoniazid, rifampicin, any fluoroquinolone, and at least one of three injectable second-line drugs (ie, amikacin, kanamycin, or capreomycin).³ 37 countries have reported XDR tuberculosis cases as of May, 2007,⁴ and isolates have been identified from all regions of the world.⁵

South Africa, where the largest cluster of cases so far has been reported, has been a focus of attention.⁶ XDR tuberculosis has been diagnosed in every province of the country,⁷ with over 200 cases reported from 40 independent sites in the KwaZulu-Natal province alone as of November, 2006.⁸ The first 53 cases were reported from the rural town of Tugela Ferry, where infected patients had a median survival time of only 16 days from sputum collection, and had a 98% mortality rate.⁶ All of those tested were HIV positive. Most XDR tuberculosis patients had not been previously treated for tuberculosis, and none had been exposed to the second-line drugs to which they were resistant. However, 67% had been recently hospitalised, and two of the patients were healthcare workers, suggesting that nosocomial transmission of XDR tuberculosis might be a driver of this epidemic.

Outbreaks of nosocomial MDR tuberculosis have occurred in both poor and wealthy nations, typically in HIV-infected patients.9, 10, 11, 12 Transmission has been reduced in industrialised countries through a combination of infection control strategies, including comprehensive treatment protocols and staff training programmes (administrative measures); ventilation, isolation, air filtration, and ultraviolet germicidal irradiation (environmental controls); and the use of respiratory masks (personal protection).12, 13, 14 Similar strategies have been proposed to reduce nosocomial transmission of tuberculosis in low-income settings,14, 15, 16 but the optimum implementation of such measures in the context of resource-constrained facilities with crowded single-room wards, little or no isolation capacity, and restricted budgets for technological interventions is unknown. Thus, little data have been available to guide policymakers, clinicians, and administrators in selecting interventions to address the potential nosocomial transmission of XDR tuberculosis.

We estimated the epidemic trajectory of XDR tuberculosis in a rural South African setting, and examined the likely proportion of cases due to nosocomial transmission. We then modelled the effect of various hospital-based strategies for infection control on the future burden of XDR tuberculosis.

Section snippets

Methods

We constructed a mathematical model to simulate tuberculosis transmission in a rural area of South Africa with high HIV prevalence. Data for the construction, calibration, and validation of the model were derived from Tugela Ferry, in the province of KwaZulu-Natal, and the Church of Scotland Hospital, which serves a community of around 150 000 people of the Msinga subdistrict of Umzinyathi, a district of KwaZulu-Natal. Similar to other rural district hospitals in South Africa, this hospital has

Results

After calibration to longitudinal data describing the epidemic trajectory of drug-susceptible tuberculosis, non-XDR MDR tuberculosis, and XDR tuberculosis in both the inpatient community and the tuberculosis ward in Tugela Ferry (figures 1–4 in the webappendix), the model was tested against several subsequent studies to confirm its ability to reliably predict epidemic outcomes in this rural area (table 3 in the webappendix). The model predicted that in the absence of new interventions, the

Discussion

Without new interventions, about 1300 cases of XDR tuberculosis could arise in Tugela Ferry, KwaZulu-Natal by the end of 2012—most of which would be due to nosocomial transmission. Many individual measures for infection control would have limited epidemic-level effect if implemented alone. However, these strategies might exhibit synergy when combined. A combination of infection control strategies that can be rapidly implemented in South African district hospitals—improved natural ventilation,

References (44)

NR Gandhi et al.
Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa
Lancet
(2006)
PA da Silva et al.
Comparison of redox and D29 phage methods for detection of isoniazid and rifampicin resistance in Mycobacterium tuberculosis
Clin Microbiol Infect
(2006)
KP Fennelly
Personal respiratory protection against Mycobacterium tuberculosis
Clin Chest Med
(1997)
M Zignol et al.
Global incidence of multidrug-resistant tuberculosis
J Infect Dis
(2006)
Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs—worldwide, 2000–2004
MMWR Morb Mortal Wkly Rep
(2006)
Notice to Readers: Revised definition of extensively drug-resistant tuberculosis
MMWR
(2006)
Global map and information on XDR-TB
(2007)
NS Shah et al.
Worldwide emergence of extensively drug-resistant tuberculosis
XDR-TB found in all provinces
(2007)
C Makhaye
Deadly TB on upward spiral in KZN

BR Edlin et al.

An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome

N Engl J Med

(1992)

O Narvskaya et al.

Nosocomial outbreak of multidrug-resistant tuberculosis caused by a strain of Mycobacterium tuberculosis W-Beijing family in St. Petersburg, Russia

Eur J Clin Microbiol Infect Dis

(2002)

LV Sacks et al.

A comparison of outbreak- and nonoutbreak-related multidrug-resistant tuberculosis among human immunodeficiency virus-infected patients in a South African hospital

Clin Infect Dis

(1999)

TR Frieden et al.

Tuberculosis in New York City—turning the tide

N Engl J Med

(1995)

LA Stroud et al.

Evaluation of infection control measures in preventing the nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in a New York City hospital

Infect Control Hosp Epidemiol

(1995)

N Bock et al.

Tuberculosis infection control in resource-limited settings in the era of expanding HIV care and treatment

J Infect Dis

(2007)

PA Jensen et al.

Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005

MMWR Recomm Rep

(2005)

Guidelines for the prevention of tuberculosis in health care facilities in resource-limited settings

(1999)

N Gandhi et al.

Favorable outcomes of integration of TB and HIV treatment in a rural South Africa: The Sizonq'oba study

(2006)

J Andrews

Clinical predictors of multidrug resistance and mortality among tuberculosis patients in a rural South African Hospital: a case-control study

(2007)

K Weyer et al.

National survey of tuberculosis drug resistance in South Africa, 2001–2002. Pretoria: MRC

V Vella et al.

Surveillance of XDR and MDR at COSH, 2005–2006

KwaZulu-Natal Epidemiol Bull

(March 2007)

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ArticlesPrevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural South African district hospitals: an epidemiological modelling study

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Results

Discussion

Lancet

Clin Microbiol Infect

Clin Chest Med

Global incidence of multidrug-resistant tuberculosis

J Infect Dis

Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs—worldwide, 2000–2004

MMWR Morb Mortal Wkly Rep

Notice to Readers: Revised definition of extensively drug-resistant tuberculosis

MMWR

Global map and information on XDR-TB

Worldwide emergence of extensively drug-resistant tuberculosis

XDR-TB found in all provinces

Deadly TB on upward spiral in KZN

An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome

N Engl J Med

Nosocomial outbreak of multidrug-resistant tuberculosis caused by a strain of Mycobacterium tuberculosis W-Beijing family in St. Petersburg, Russia

Eur J Clin Microbiol Infect Dis

A comparison of outbreak- and nonoutbreak-related multidrug-resistant tuberculosis among human immunodeficiency virus-infected patients in a South African hospital

Clin Infect Dis

Tuberculosis in New York City—turning the tide

N Engl J Med

Evaluation of infection control measures in preventing the nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in a New York City hospital

Infect Control Hosp Epidemiol

Tuberculosis infection control in resource-limited settings in the era of expanding HIV care and treatment

J Infect Dis

Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005

MMWR Recomm Rep

Guidelines for the prevention of tuberculosis in health care facilities in resource-limited settings

Favorable outcomes of integration of TB and HIV treatment in a rural South Africa: The Sizonq'oba study

Clinical predictors of multidrug resistance and mortality among tuberculosis patients in a rural South African Hospital: a case-control study

National survey of tuberculosis drug resistance in South Africa, 2001–2002. Pretoria: MRC

Surveillance of XDR and MDR at COSH, 2005–2006

KwaZulu-Natal Epidemiol Bull

Articles
Prevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural South African district hospitals: an epidemiological modelling study