Evolution of XDR-TB in KwaZulu-Natal A. Willem Sturm Interim Director K-RITH Nelson R Mandela School of Medicine University of KwaZulu-Natal
Drug resistance among culture positive TB cases by South African Province (2001-2002) Any Drug Resistance (%) MDR (%) Province No History of Prior History of Prior TB No History of Prior History of Prior TB TB Treatment** Treatment** TB Treatment** Treatment** Eastern Cape 11.3 17.7 1.0 7.4 Free State*** 8.6 9.2 1.8 1.7 Gauteng 6.6 12.7 1.4 5.5 KwaZulu-Natal 6.6 18.4 1.7 7.7 Limpopo 7.1 17 2.4 6.8 Mpumalanga 9.4 23.4 2.6 13.7 North West 8.1 19.1 2.2 6.9 Western Cape 5.6 7.9 0.9 3.9 South Africa 7.7 15.5 1.6 6.6 (Weyer et al, 2004)
53 cases of XDR-TB diagnosed in CoSH in Tugela Ferry 1.1 1.0.9.8 (early 2005) Proportion Surviving.7.6.5.4.3.2.1 0.0 -.1 0 30 60 90 120 150 180 210 240 Days since Sputum Collected (Gandhi et al, 2006)
Questions What happened between 2002 and 2005? Where did these 53 XDR cases come from? Was (is) this a hospital outbreak at CoSH or a more wide spread problem? Are the 2001-2002 data an underrepresenting the MDR situation?
1396 cases suspected of PTB attending CoSH out-patient department 475 culture positive (2005)? infected in hospital 185 MDR 30 XDR 14 history of prior hospitalisation? infected in community 16 never hospitalised community transmission (Gandhi et al, 2006)
Questions What happened between 2002 and 2005? Where did these 53 XDR cases come from? Was (is) this a hospital outbreak at CoSH or a more wide spread problem? Are the 2001-2002 data an underrepresenting the MDR situation?
Proportion of F15/LAM4/KZN strains amongst genotyped isolates Year Total no. genotyped No. (%) KZN strains Total no. (%) MDR No. (%) MDR KZN strains 1994 322 6 (2) 9 (3) 4 (44) 1995 104 20 (19) 27 (26) 12 (44) 1996 140 21 (15) 56 (40) 15 (27) 1997 32 10 (31) 24 (75) 8 (33) 1998 23 2 (9) 8 (35) 1 (13) 1999 47 8 (17) 15 (32) 4 (27) 2000 45 14 (31) 28 (62) 8 (29) 2001 88 15 (17) 64 (73) 13 (20) 2002 165 13 (8) 38 (23) 10 (26) Total 966 109 (11) 269 (31) 75 (28) p < 0.0001 (Pillay and Sturm, 2007)
Fig 1. Resistance development in the KZN family of strains of Mycobacterium tuberculosis from 1994 till 2006 Resistance found for the first time in: Resistance to: 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 none IE IS ISE IR IRE IRET IREEtT IRS IRSE IRSEEtT IRSETCa IRSEEtTK IRSEEtFq IRSEEtKFq IRSEKFq I isoniazid; S streptomycin; E ethambutol; Et ethionamide; R rifampicin; T thiacetazone Ca capreomycin; K kanamycin/amikacin; Fq fluoroquinolones (Pillay and Sturm, CID, Dec. 2007)
Situation in KZN in 2006/07 Culture and DST results of all patients in KZN on sputum specimens received between 1 Jan. 2006 and 30 June 2007 Susceptibility testing done routinely for: isoniazide rifampicine ethambutol streptomycin kanamycine ofloxacin
KwaZulu-Natal Province Population size: 9,616,009 11 health districts divided in subdistricts
Differences in number of TB cases in districts of KZN District Population New TB cases MDR Cases XDR Cases Amajuba 477,472 150 47 2 ethekwini 3,152,405 11250 1526 90 ilembe 571,686 898 168 8 Sisonke 304,409 463 83 9 Ugu 718,221 788 265 15 Umgungundlovu 946,545 2833 418 53 Umkhanyakude 584,898 1016 45 4 Umzinyathi 465,660 1463 509 247 Uthukela 670,226 383 74 9 Uthungulu 903,822 1018 274 11 Zululand 820,661 466 211 4 Total 9,616,005 20728 3620 452
Differences in incidence of TB cases in districts of KZN Incidence of new TB Incidence of MDR Incidence of XDR District (per 100.000/yr) (per 100.000/yr) (per 100.000/yr) Amajuba 20.9 6.6 3.0 ethekwini 237.9 32.3 1.9 ilembe 104.7 19.6 0.9 Sisonke 101.4 18.2 2.0 Ugu 73.1 24.6 1.4 Umgungundlovu 199.5 29.4 3.7 Umkhanyakude 115.8 5.1 0.5 Umzinyathi 209.5 72.9 35.4 Uthukela 38.1 7.4 0.9 Uthungulu 75.1 20.2 0.8 Zululand 37.9 17.1 0.3 Total 143.7 25.1 3.1
Association between no. of new cases of TB diagnosed by culture and percentage MDR
Differences in rates of MDR and XDR cases in districts of KZN No. of MDR per No. of XDR per District 100 new TB cases 100 new TB cases Amajuba 31.3 1.3 ethekwini 13.6 0.8 ilembe 18.7 0.9 Sisonke 17.9 1.9 Ugu 33.6 1.9 Umgungundlovu 14.8 1.9 Umkhanyakude 4.4 0.4 Umzinyathi 34.8 16.9 Uthukela 19.3 2.3 Uthungulu 26.9 1.1 Zululand 45.3 0.9 Total 17.5 2.2
From 2005, CoSH is the only health care facility with culture diagnostics performed on all possible TB cases Includes Msinga (CoSH)
How resistant is our XDR TB?
Fig 1. Resistance development in the KZN family of strains of Mycobacterium tuberculosis from 1994 till 2006 Resistance found for the first time in: Resistance to: 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 none IE IS ISE IR IRE IRET IREEtT IRS IRSE IRSEEtT IRSETCa IRSEEtTK IRSEEtFq IRSEEtKFq IRSEKFq I isoniazid; S streptomycin; E ethambutol; Et ethionamide; R rifampicin; T thiacetazone Ca capreomycin; K kanamycin/amikacin; Fq fluoroquinolones (Pillay and Sturm, CID, Dec. 2007)
Genotypic resistance in F15/LAM4/KZN XDR isolates (n=52) Mutations in rss gene: 100 % resistance to streptomycin, kanamycine, amikacin and capreomycin Mutations in pcn A gene: 69 % resistance to pyrazinamide
MICs of M. tuberculosis isolates Table 2b: MICs of 11 M. tuberculosis isolates in Middlebrook 7H9 broth Median (range) MIC (mg/l) Susc. MDR XDR PAS 0.25 0.25 0.25 (0.12-0.25) Capreomycin 4 4 8 (4-16) Linezolid 2 (0.5-2) 0.5 (0.25-0.5) 1 (0.5-4) Merepenem 16 16 16 (8-32) Meropenem-clavulanic acid 1 1 (1-2) 1 (0.5-4)
How resistant is XDR M.tuberculosis in KZN? Most isolates are resistant to: 1. isoniazid 2. rifampicin 3. ethambutol 4. pyrazinamide 5. streptomycin 6. kanamycin 7. amikacin 8. capreomycin 9. ofloxacin 10.ethionamide
Tuberculosis in the Msinga sub-district compared with other parts of KwaZulu- Natal no. (%*) no. of MDR per no. of XDR per population new TB cases 100 new TB cases 100 new TB cases Msinga sub-district 160,000 1091 (0.68) 36.7 20 Umzinyathi without Msinga 305,660 372 (0.12) 29.3 7.8 districts with academic centre** (n=3) 4,683,848 15099 (0.32) 11 1 other districts ** (n=9) 4,466,497 4166 (0.09) 28 2 * percentage of the population ** MDR and XDR: average of the districts How does Msinga (CoSH) differ from the rest of the province?
Differences between Msinga subdistrict and the rest of the province Msinga sub-district Culture and DST on all on first contact No delay in DST results Rest of province Culture and DST on indication Delay in DST results No delay in appropriate treatment Delay in appropriate treatment
53 cases of XDR-TB diagnosed in CoSH in Tugela Ferry 1.1 1.0.9.8 Proportion Surviving.7.6.5.4.3.2.1 0.0 -.1 0 30 60 90 120 150 180 210 240 Days since Sputum Collected (Gandhi et al, 2006)
Referral for treatment of MDR/XDR cases Total number of MDR/XDR diagnosed between 1 Jan 2006 and 30 June 2007 3620 Total number referred for treatment to MDR/XDR referral hospital 1439 (40%) Waiting list for admission
Is Msinga (CoSH) different from the rest of the province? May be not! Many patients in the rest of the province die: before a specimen is taken or before the DST results become available
Clonal spread? If so, did it start in Msinga /Tugela Ferry/CoSH?
Whole genome sequencing F15/LAM4/KZN XDR isolates 8 sequences completed all same mutations in resistance genes
Geographical distribution of sequenced XDR isolates 8 isolates 7 locations 4 districts Tugela Ferry
Whole genome sequencing F15/LAM4/KZN XDR isolates 8 sequences completed All same mutations in resistance genes Isolates from 7 different geographical locations 4 districts Suggests clonal spread number needs to be extended
Clonal spread? If so, did it start in Msinga /Tugela Ferry/CoSH?
Tuberculosis in the Msinga sub-district compared with other parts of KwaZulu- Natal no. (%*) no. of MDR per no. of XDR per population new TB cases 100 new TB cases 100 new TB cases Msinga sub-district 160,000 1091 (0.68) 36.7 20 Umzinyathi without Msinga 305,660 372 (0.12) 29.3 7.8 districts with academic centre** (n=3) 4,683,848 15099 (0.32) 11 1 other districts ** (n=9) 4,466,497 4166 (0.09) 28 2 * percentage of the population ** MDR and XDR: average of the districts
Origin of XDR isolates in 1 st half of 2005 (laboratory database) Tugela Ferry Other locations January - March 15 6 April - June 17 11 Did it start in Tugela Ferry? We will never know!
Conclusions KwaZulu-Natal has an enormous TB burden MDR and XDR strains are present throughout the province F15/LAM4/KZN isolates from 2005 were already TDR Sequence data suggest clonal spread of the XDR phenotype of F15/LAM4/KZN Prevalence data and time-of-first appearance data suggest that it may have started in Msinga district/tugela Ferry/CoSH
The team Durban Prashini Moodley Manormoney Pillay Staff and students of the TB research laboratory in at NRMSM Tugela Ferry Tony Moll Staff at Church of Scotland Hospital Albert Einstein/Yale Sarita Shah Neel Gandhi Gerald Friedland Bill Jacobs and his team