Conceived and designed the experiments: JM QG. Performed the experiments: MZ PX XG LW. Analyzed the data: MZ XL XS KD JM QG. Contributed reagents/materials/analysis tools: XG LW. Wrote the paper: XL KD JM QG.
The authors have declared that no competing interests exist.
Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are global health problems. We sought to determine the characteristics, prevalence, and relative frequency of transmission of MDR and XDR TB in Shanghai, one of the largest cities in Asia.
TB is diagnosed in district TB hospitals in Shanghai, China. Drug susceptibility testing for first-line drugs was performed for all culture positive TB cases, and tests for second-line drugs were performed for MDR cases. VNTR-7 and VNTR-16 were used to genotype the strains, and prior treatment history and treatment outcomes were determined for each patient.
There were 4,379 culture positive TB cases diagnosed with drug susceptibility test results available during March 2004 through November 2007. 247 (5.6%) were infected with a MDR strain of
Transmission of MDR and XDR strains is a serious problem in Shanghai. While a history of prior anti-TB treatment indicates which individuals may have acquired MDR or XDR TB, it does not accurately predict which TB patients have disease caused by transmission of MDR and XDR strains. Therefore, universal drug susceptibility testing is recommended for new and retreatment TB cases.
Since 1994, nearly 90 countries and regions worldwide have reported one or more cases of multidrug-resistant (MDR) tuberculosis (TB)
In 2006, multiple cases of extensively drug-resistant (XDR) TB were reported in South Africa, raising concerns that XDR strains of
We performed a retrospective study to determine the number and percentage of TB patients in Shanghai with MDR and XDR TB, and to determine whether there is transmission of MDR and XDR strains of
We performed a retrospective cohort study using the existing data and specimens at the Shanghai Municipal Center for Disease Control and Prevention (Shanghai CDC), from TB patients who were diagnosed in Shanghai during March 2004 through November 2007. Since 1995 in Shanghai, all suspected pulmonary TB cases detected in general hospitals or community health centers were referred to a specialized TB hospital or TB clinic for further diagnostic tests, including sputum smear examinations, culture and chest radiography. There were 31 designated district TB hospitals in Shanghai; all of the pretreatment positive cultures from patients in each hospital were sent to the Tuberculosis Reference Laboratory (TRL) at Shanghai CDC for drug susceptibility testing and species identification. Shanghai CDC also collected data on the social and demographic characteristics, treatment history, clinical characteristics, drug-susceptibility test results, and clinical outcomes of each patient. All of the investigation protocols in this study were approved by ethics committee of Fudan University. Since this was a retrospective study and all patients' information was routinely collected by Shanghai CDC for analysis and reports to the government, consent was not obtained from the patients during 2004 through 2006. We started a research project in 2007, and informed consent has been obtained from all patients since then for the information to be used in scientific studies.
TRL at Shanghai CDC participated in the World Health Organization/International Union against Tuberculosis and Lung Disease Global Project on Anti-Tuberculosis Drug Resistance Surveillance
In the present study, we restricted our analysis to those patients whose first-line drug susceptibility tests were performed by the proportion method. The following drug concentrations were used: isoniazid (0.2 µg/ml), rifampin (40.0 µg/ml), streptomycin (4.0 µg/ml) and ethambutol (2.0 µg/ml). For any isolates that were MDR, we also used the WHO Guidelines for drug susceptibility testing for second-line anti-tuberculosis drugs for DOTS plus
MDR TB was defined as tuberculosis disease caused by a strain of
New cases were defined as TB patients who denied having had any prior anti-TB treatment or who received anti-TB treatment for <30 days. Previously treated cases were TB patients who reported having been treated for tuberculosis for at least 30 days or who had documented evidence of prior treatment in the case report form or surveillance database. Acquired drug resistance was defined as the isolation of drug-resistant
Migrants were defined as individuals from other areas of China who moved to Shanghai. Residents were defined as persons with a registered permanent residence in Shanghai.
We used the VNTR-7 and VNTR-16 methods to genotype the 189 clinical isolates of
There is presently no standard treatment strategy, such as DOTS-Plus, to guide the therapy of MDR-TB patients in Shanghai. Individualized therapies were given to MDR TB patients based on the patient's physical and financial situation, the strains' drug-susceptibility patterns and the clinicians' experience. The following drugs were used, in different combinations: two injectable second-line drugs, including capreomycin and amikacin; fluoroquinolones, including ofloxacin, levofloxacin, gatifloxacin, moxifloxacin and ciprofloxacin; a modified form of isoniazid, called prothionamide; two modified forms of rifampicin, called rifapentine and rifabutin; and 4-aminosalicylic acid.
We used the chi-square test of proportions to identify significant differences between two or more groups of patients. A
From March 2004 through November 2007, there were 19,722 newly registered pulmonary tuberculosis patients in 31 designated district tuberculosis hospitals in Shanghai. Of these, 6,200 (31.4%) patients were culture positive for
TB = tuberculosis. MDR = multidrug-resistant. MOTT = Mycobacteria other than tuberculosis.
To determine the number and percentage of the MDR TB patients that were infected with an XDR strain of
We compared the patient characteristics associated with MDR, pre-XDR and XDR TB, such as age, sex, treatment history and status (resident versus migrant) (
Characteristic | All MDR | Simple MDR | Pre-XDR | XDR | χ2 | P |
n = 175 (%) | n = 109 (%) | n = 55 (%) | n = 11 (%) | |||
Age (years) | 16.182 | 0.040 | ||||
15–29 | 35 (20.0) | 24 (22.0) | 11 (20.0) | 0 (0.0) | ||
30–44 | 53 (30.3) | 37 (33.9) | 13 (23.6) | 3 (27.3) | ||
45–59 | 57 (32.6) | 26 (23.9) | 23 (41.8) | 8 (72.7) | ||
60–74 | 20 (11.4) | 14 (12.8) | 6 (10.9) | 0 (0) | ||
≥75 | 10 (5.7) | 8 (7.4) | 2 (3.6) | 0 (0) | ||
Sex | 2.772 | 0.250 | ||||
Male | 132 (75.4) | 84 (77.1) | 38 (69.1) | 10 (90.9) | ||
Female | 43 (24.6) | 25 (22.9) | 17 (30.9) | 1 (9.1) | ||
Treatment history | 1.314 | 0.519 | ||||
New | 105 (60.0) | 69 (63.3) | 30 (54.5) | 6 (54.5) | ||
Retreatment | 70 (40.0) | 40 (36.7) | 25 (45.5) | 5 (45.5) | ||
Status | 0.480 | 0.787 | ||||
Resident | 112 (64.0) | 70 (64.2) | 34 (61.8) | 8 (72.7) | ||
Migrant | 63 (36.0) | 39 (35.8) | 21 (38.2) | 3 (27.3) |
MDR = resistance to at least isoniazid and rifampin.
Simple MDR = resistance to only isoniazid and rifampin.
Pre-XDR = Pre-extensively drug resistant; the strain is resistant to isoniazid, rifampin, and a fluoroquinolone or three of the second-line drugs (capreomycin, amikacin, kanamycin).
XDR = extensively drug resistant; the strain is resistant to isoniazid, rifampin and a fluoroquinolone and any of three of the second-line drugs (capreomycin, amikacin, kanamycin).
Fifty-six percent of the patients with MDR TB and 9.1% of the patients with XDR TB were successfully treated. The cure rate in simple MDR TB, pre-XDR TB and XDR TB patients decreased and the mortality increased as the drug resistance increased (
Simple MDR | Pre-XDR | XDR | Total | |
n = 109 (%) | n = 55 (%) | n = 11 (%) | n = 175 (%) | |
Cured, bacteriological confirmed | 62 (56.9) | 29 (52.7) | 1 (9.1) | 92 (52.6) |
Completed treatment regimen | 3 (2.8) | 2 (3.6) | 0 (0.0) | 6 (3.4) |
Died during TB treatment | 6 (5.5) | 5 (9.1) | 1 (9.1) | 12 (6.9) |
Still on treatment | 30 (27.5) | 14 (25.5) | 8 (72.7) | 51 (29.1) |
Lost to follow up | 1 (0.9) | 1 (1.8) | 1 (9.1) | 3 (1.7) |
Moved/transferred | 7 (6.4) | 4 (7.3) | 0 (0) | 11 (6.3) |
MDR = resistance to at least isoniazid and rifampin.
Simple MDR = resistance to only isoniazid and rifampin.
Pre-XDR = Pre-extensively drug resistant; the strain is resistant to isoniazid, rifampin, and a fluoroquinolone or any one of three second-line drugs (capreomycin, amikacin, kanamycin).
XDR = extensively drug resistant; the strain is resistant to isoniazid, rifampin and a fluoroquinolone and any one of three second-line drugs (capreomycin, amikacin, kanamycin).
Treatment success | No treatment success | Odds ratio (OR) | 95% CI | P | |
N = 96 (54.9%) | N = 79 (45.1%) | ||||
XDR | |||||
New | 0 (0.0) | 6 (3.4) | |||
Retreatment | 1 (0.6) | 4 (2.3) | - | - | 0.2506 |
Pre-XDR | |||||
New | 23 (13.1) | 9 (5.1) | 1.00 | ||
Retreatment | 8 (4.6) | 15 (8.6) | 4.79 | (1.32, 17.85) | 0.0062 |
Simple MDR | |||||
New | 47 (26.9) | 19 (10.9) | 1.00 | ||
Retreatment | 17 (9.7) | 26 (14.9) | 3.78 | (1.56, 9.24) | 0.0010 |
Total | |||||
New | 70 (40.0) | 34 (19.4) | 1.00 | ||
Retreatment | 26 (14.9) | 45 (25.7) | 3.56 | (1.80, 7.06) | 0.0001 |
OR = odds ratio.
CI = confidence interval.
MDR = resistance to at least isoniazid and rifampin.
Simple MDR = resistance to only isoniazid and rifampin.
Pre-XDR = Pre-extensively drug resistant; the strain is resistant to isoniazid, rifampin, and a fluoroquinolone or any one of three second-line drugs (capreomycin, amikacin, kanamycin).
XDR = extensively drug resistant; the strain is resistant to isoniazid, rifampin and a fluoroquinolone and any one of three second-line drugs (capreomycin, amikacin, kanamycin).
We genotyped one isolate from each of 175 MDR TB patients. 87.3% (165/189) of the MDR isolates and 90.9% (10/11) of the XDR isolates were Beijing genotype strains. Patients infected with
The present study showed that 5.6% of the tuberculosis patients in Shanghai were infected with a strain of
Since second-line drugs have been used in Shanghai for several decades and there is no standard treatment strategy for patients with MDR and pre-XDR strains, there was concern that the prevalence of XDR TB in Shanghai would be higher. Based on our study using specimens from the 31 designated district tuberculosis hospitals, we report that XDR TB occurs in Shanghai, albeit currently with a relatively low prevalence during the study period.
After XDR TB became a public concern during 2006, many countries retested their stored isolates and XDR strains were reported in 41 countries
More than half of the infections with MDR and XDR strains of
To identify chains of transmission of
Overall, the treatment outcomes of MDR TB patients have been less favorable than the treatment outcomes of TB patients whose disease is caused by a pan-susceptible strain, a mono-resistant, or a poly-resistant strain of
Our study showed that the cure rate is higher among new TB cases than among previously treated TB cases, whether they were MDR or pre-XDR patients. A previous study reported that TB patients with primary drug resistant tuberculosis had better treatment outcomes than TB patients with acquired drug resistant TB
In summary, 5.6% of the TB cases in Shanghai were infected with a MDR strain of
We thank Dr. Peter Small for his valuable review of the manuscript.