Situation of multidrug-resistant pulmonary tuberculosis in Alexandria governorate from July 2008 to December 2012

Aim The aim of this study was to estimate the prevalence, possible risk factors, patterns of resistance, and fate of multidrug-resistant pulmonary tuberculosis (MDR-TB) in Alexandria governorate as a representative part of Egypt during the period between July 2008 and December 2012. Patients and methods This retrospective study included all patients with pulmonary TB that was recorded in Alexandria governorate during the period between July 2008 (the time that MDR ward was held in Alexandria) and December 2012. They were divided into two groups: group I included patients with pulmonary TB that was recorded in Alexandria governorate (1893 cases), and group II included patients with pulmonary TB who were admitted in El-Maamoura Chest Hospital (509 cases). They were subdivided into two subgroups: group IIa included patients with MDR pulmonary TB (82 cases), and group IIb included patients with pulmonary TB not categorized as MDR-TB (427 cases). Results All patients with MDR-TB had acquired resistance. MDR-TB was more common in the male population, diabetic patients, and those with chronic chest disease. The effect of treatment of MDR-TB cases was as follows: cured patients, 49 (59.8%); patients under treatment, 10 (12.2%); treatment failure, four cases (4.9%); deceased patients, 10 (12.2%); and defaulters, nine (10.9%). The overall total prevalence rate of MDR-TB in Alexandria governorate from 2008 to 2012 was 4.3%. Conclusion There was a decreasing trend of MDR-TB cases. History of anti-TB treatment is the strongest independent predictor of MDR-TB. The highest figures of resistance in the MDR group besides isoniazide and rifampicin were for streptomycin, whereas the lowest resistance was for ethambutol.


Introduction
Strains of Mycobacterium tuberculosis that are resistant to both isoniazid and rifampicin with or without resistance to other drugs have been termed multidrug-resistant (MDR) strains. Isoniazid and rifampicin are keystone drugs in the management of tuberculosis (TB). However, resistance to either isoniazid or rifampicin may be managed with other first-line drugs [1].
Multidrug-resistant tuberculosis (MDR-TB) is caused by the transmission of MDR M. tuberculosis strains in new cases, or by the selection of single-drug-resistant strains induced by previous treatments [2].
The incidence of drug resistance has increased since the first drug treatment for TB was introduced in 1943. The emergence of MDR-TB followed the widespread use of rifampicin since the 1970s [3]. The spectrum of this form of TB now ranges from 'basic' MDR-TB, with resistance only to rifampicin and isoniazid, to XDR-TB, which has additional extensive drug resistance to at least three of the six main classes of second-line anti-TB drugs [4]. Alexandria governorate is one of the governorates of Egypt. It is located in the northern part of the country, directly on the Mediterranean Sea, making it one of the most important harbors in Egypt.
governorate. The exclusion criteria included patients with extrapulmonary TB.
The patients were divided into two groups: Group I included patients with pulmonary TB that was recorded in Alexandria governorate (1893 cases).
Group II included patients with pulmonary TB who were admitted in El-Maamoura Chest Hospital (509 cases).
Group II was subdivided into two groups: Group IIa included patients with MDR pulmonary TB (82 cases).
Group IIb included patients with pulmonary TB that was not categorized as MDR-TB (427 cases).
Files of group II were analyzed and the following data were collected: (1) Medical history and physical examination.
(2) Laboratory investigations, including direct sputum smear examined using the Ziehl-Neelsen method for 3 successive days, sputum culture for M. tuberculosis with traditional culture on Lowenstein-Jensen medium, and drug susceptibility tests for firstline and some of the second-line anti-TB drugs (kanamycin and ofloxacin).

Data management and analysis
The collected data were revised, coded, tabulated, and introduced to a PC using Statistical Package for Social Science (SPSS 15.0.1 for Windows, 2001; SPSS Inc., Chicago, Illinois, USA).

Results
Tables 1-9. There was significant association between MDR-TB and male sex, age group 25-44 and unemployment (Table 1). There was statistically significant association between group IIa and group IIb as regards smoking, addiction, and alcoholism ( Table 2). There was statistically significant association between group IIa and group IIb as regards DM, liver cirrhosis, and chronic chest disease (Table 3). There was statistically significant association between previous TB treatment and group IIa as all of them had acquired resistance (Table 4). Resistance to antituberculous drugs was as follows: 100% to INH, 100% to rifampicin, 93.9% to streptomycin, 30.1% to ethambutol, and no resistance to ofloxacin and kanamycin ( Table 5). The cure rate was 59.8%, dead cases were 12.2% (two of the dead cases were diabetic, three cases were with IHD and one case had depression), under treatment was 12.2%, defaulter rate was 10.9%, and treatment failure was 4.9% (Table 8). A rising trend of MDR-TB cases from 2008 to 2009, and then a decreasing trend from 2009 to 2012 is shown. The overall total prevalence rate of MDR-TB in Alexandria governorate from 2008 to 2012 was 4.3% (Table 9).

Discussion
In this study, the mean age of group IIa was 37.1 ± 13.02 years. This mean age represents the period of physical, mental, and occupational stress. The current study coincides with the study by Abdel Fatah [6], which included patients admitted in Abassia Chest Hospital during the period between July 2006 and June 2008 in the MDR ward. There were 116 MDR-TB patients. He reported that the mean age was 36.7 years. In the current study, there were 65 male (79.3%) and 17 female cases (20.7%) in group IIa. The current study coincides with the study by Abdel-Aim (2003), who investigated the identification of gene mutation in M. tuberculosis isolated from patients resistant to rifampicin and isoniazid treatment. He reported that, of the MDR-TB patients, 82% were male and 18% were female [7]. Male predominance may be attributed to the greater exposure of the male population to infection in the community compared with the female population because of occupational and mental stress or other social factors, which prevent women from seeking medical advice early [8]. In group IIa in this study, there were 32 (39%) employed patients, whereas there were 50 (61%) unemployed patients. The current study is in agreement with the study by Safwat et al. (2011), who stated that the highest incidence of TB infection was found among unemployed patients, because they were mostly ignorant and illiterate and thus had an increased risk for TB [9]. The current study is not in agreement with the study by Hamdy and Wagdan (1991) [10], who studied the role of patient compliance during the treatment of TB and stated that the highest incidences of TB infection    were found among employed patients, as employed patients had a greater exposure to the environment and patients as a source of infection. It was noticed that in group IIa the most frequent habit was tobacco smoking: 59 patients (72%) were smokers, and 23 patients (28%) were nonsmokers. The current study coincides with the study by Kamal (2006) [11], who revealed that the incidence of MDR-TB smokers was 61.53% and that of nonsmokers was 38.47%, and he stated that smoking represents a source of infection and a risk factor for TB. The current study is not in accordance with the study by Fawzy (2005), who evaluated the resistance to INH isoniazid and rifampicin in pulmonary TB patients in Abassia Chest Hospital as well as in Chest Clinics in Cairo in 2004. He reported that there was no statistically significant difference as regards smoking among TB patients [12]. This may be explained by the small number of MDR cases (21 cases) included in his study, which is nonrepresentative. In our study, the most common comorbidity associated with MDR-TB in group IIa was diabetes (62 cases; 75.6%), followed by chronic chest diseases (53 cases; 64.6%). No reported cases of MDR-TB were HIV positive. The current study coincides with the study by Safwat et al. (2011), who reported that the most common comorbidity associated with MDR-TB was diabetes (33 cases; 18.3%), followed by chronic chest diseases (16 cases; 8.9%). No reported cases of MDR-TB were HIV positive. He stated that diabetes mellitus leads to decreased immunity of the patients, which results in reactivation of the primary TB infection and the occurrence of the resistance to the anti-TB drugs [9]. In the current study, in group IIa, all patients had acquired resistance: acquired resistance, 82 cases (100%), and primary resistance, 0 cases (0%). The current study coincides with the surveillance carried out in Egypt in 2012, which showed that the incidence of acquired resistance was higher compared with the incidence of primary resistance [13]. The present study coincides with the study by Safwat et al. (2011), who reported that the incidence of acquired resistance was greater than that of primary resistance; the incidence of acquired resistance was 69.4% and that of primary resistance was 30.6% [9]. In the present study, the resistance of anti-TB drugs in group IIa was as follows: resistance to isoniazid was 100%, resistance to rifampicin was 100%, resistance to streptomycin was 93.9%, resistance to ethambutol was 30.1%, resistance to ofloxacin was 0%, and resistance to kanamycin was 0%.
The results of the current study coincide with the study by Safwat et al. (2011), who revealed that the resistance to isoniazid was 100%, resistance to rifampicin was 100%, resistance to streptomycin was 81.1%, and resistance to ethambutol was 75.6% [9]. In group IIa in this study, the most common complications of secondline anti-TB drugs were gastritis and gastrointestinal   tract (GIT) disturbance: 36.6% of patients had gastritis, 28% had GIT disturbance, 11% had hypokalemia, 8.5% had hypothyroidism, 7.3% had hyponatremia, 6% had hyperuricemia, 3.7% had psychological disturbance, 3.7% had hepatotoxicity, 1.2% had renal toxicity, and 1.2% had peripheral neuritis. These results coincide with those of Safwat et al., who stated that gastritis was the most common complication (88.3%), followed by peripheral polyneuritis (76.7%), hypothyroidism (44.4%), hepatitis (8.3%), central nervous system complication (16.1%), hypokalemia (23.3%), and irritable bowel syndrome (46.7%) [9]. This coincides with the study by Abdel Fatah (2009) [6] as well, who stated that GIT disturbance was the most common complication (84%), followed by peripheral polyneuritis (58.4%), hypothyroidism (57.5%), skin manifestations, arthralagia, and psychosis (29.2%), depression (26.5%) and electrolyte disturbance (17.7%). In this study, effect of treatment of the MDR-TB cases was as follows: cured patients, 49 (59.8%); patients under treatment, 10 (12.2%); treatment failure, four cases (4.9%), deceased patients, 10 (12.2%); and defaulters, nine cases (10.9%). This study coincides with the study by Safwat et al. (2011), who stated that, of the 180 cases, 117 (65.0%) patients were cured, 38 (21.1%) were under treatment, three cases (1.7%) had treatment failure, 17 patients (9.4%) died, four cases (2.2%) were defaulters, and surgical interference was applied in one case (0.6%) [9]. This study coincides with the study by Abdel Fatah (2009) [6], who stated that, of the 113 cases, 72 patients (63.8%) were cured, 18 (15.9%) patients were under treatment, 10 cases (8.8%) had treatment failure, eight patients (7.1%) died, and five patients (4.4%) were defaulters. In the current study, the overall total prevalence rate of MDR-TB in Alexandria governorate from 2008 to 2012 was 4.3%. This result is in disagreement with the study by Safwat et al. (2011), who stated that the prevalence rate of MDR-TB in Egypt was 0.45% from 2006 to 2009 [9]. Abdel Fatah (2009) [6] stated that the prevalence rate of MDR-TB in Egypt was 0.37% from 2006 to 2008. Nada (2009) [14] stated that the prevalence rate of MDR-TB in Egypt was 0.45% from 2006 to 2009. This difference may be due to fact that the prevalence rate in these studies was for the total number of TB cases in Egypt and not for Alexandria governorate as shown in the current study, and this may be explained by the better case finding in Alexandria governorate due to the presence of MDR ward.

Conclusion
The overall total prevalence rate of MDR-TB in Alexandria governorate from 2008 to 2012 was 4.3%. There was a decreasing trend of MDR-TB cases. History of anti-TB treatment is the strongest independent predictor of MDR-TB. Other risk factors for MDR-TB were being middle aged, unemployment and illiteracy, presence of comorbidities such as diabetes mellitus and chronic chest disease, and smoking habit. The highest figures of resistance in the MDR group besides isoniazid and rifampicin were for streptomycin, whereas the lowest resistance was for ethambutol, the most common complications of the second-line anti-TB drugs were gastritis, followed by GIT disturbance. The effect of treatment of the MDR-TB cases was as follows: cured patients, 59.8%; patients under treatment, 12.2%; treatment failure, 4.9%; deceased patients, 12.2%; and defaulters, 10.9%.

Financial support and sponsorship
Nil.

Conflicts of interest
There are no conflicts of interest.