From multidrug- to extensively drug-resistant tuberculosis: upward trends as seen from a 15-year nationwide study

Abstract

Background: Emergence of extensively drug-resistant tuberculosis (XDR-TB) represents an enormous challenge to Public Health globally.

Methods: Progression towards XDR-TB was investigated in Belgium, a country with a typically low TB incidence, by analyzing the magnitude, characteristics, and treatment success of multidrug-resistant tuberculosis (MDR-TB) through a population-based study from 1994 to 2008.

Results: Among the 174 MDR-TB patients, 81% were foreign-born, 48% of these being asylum seekers. Although the number of MDR-TB patients remained stable through the study period at around 15 new cases annually, frequencies of resistance of the patients' first MDR-TB isolate to second-line drugs increased, as well as the total number of antibiotics it was resistant to (p<0.001). XDR-TB cases were detected from 2002 onwards. For 24 patients, additional resistance to several second-line drugs was acquired during treatment. Molecular-guided investigations indicated little to no contribution of in-country clonal spread or exogenous re-infection. The increase of pre-XDR and XDR cases could be attributed to rising proportions of patients from Asia and Central and Eastern Europe (p<0.001) and an increase in the isolation of Beijing strains in these groups (p<0.001). Despite augmented resistance, the treatment success rate improved from 63.0% to 75.8% (p = 0.080) after implementation in 2005 of improved surveillance measures and therapeutic access.

Conclusions: Increasing severity in drug resistance patterns leading to more XDR- and "panresistant" TB cases in a country with a low TB incidence like Belgium represents a strong alert on worsening situations in other world regions and requires intense public health measures.

Figure 1. Number of MDR with first-line drug resistance only, pre-XDR and XDR isolates in the study cohort.

Figure 2. Evolution of the resistance profile of serial isolates obtained from 24 patients.

For these 24 MDR-TB patients out of 37 with multiple isolates, resistance to additional drugs was observed during treatment. Legend: ▪ = Susceptible, ▪ = Resistant, −Test not performed, I: Isoniazid, R: Rifampicin, E: Ethambutol, Z: Pyrazinamid, Rb: Rifabutin, Ofl: Ofloxacin, Amk: Amikacin, Thio: Thioamide, Cap: Capreomycin NA = Not Applicable as less than 2 isolates were FLP profiled, so no conclusion possible.

Figure 3. Characteristics of the 58 MDR-TB patients in strain-clusters and results of epidemiological investigation.

Legend: Y = yes; N = no, U = unknown; − = not applicable.

Figure 4. Treatment outcome of MDR (first-line drug resistance only), pre-XDR and XDR-TB patients.

Legend: ^astart of BELTA-TBnet in 2005 ^bincluding 3 isolates with unknown amikacin susceptibility ^cincluding 1 isolate with unknown amikacin susceptibility MDR: first-line drug resistance only Pre-XDR: MDR with additional resistance to either a fluoroquinolone or amikacin XDR: MDR with additional resistance to a fluoroquinolone and amikacin.

Figure 5. Patients with XDR-TB in their first isolate examined in Belgium, 1994–2008.

Part I: patient characteristics and DST results. Part II: second-line therapy with treatment outcome. Legend: *New treatment regimen initiated after 19 months without anti-TB treatment **Retreatment after interruption of 5 months ^#Stop after 8 months ^##Stop after 7 months Antibiotics: R = Rifampicin, I = Isoniazid, E = Ethambutol, Z = Pyrazinamid, Rb = Rifabutin, SM = Streptomycin, Amk = Amikacin, Ofl = Ofloxacin, Cip = Ciprofloxacin, Mox = Moxifloxacin, Cap = Capreomycin, Thio = Thioamides, Clf = Clofazimin, Clr = Clarithromycin, PAS = para-aminosalycilic acid, Lzd = Linezolid, A-Cl = amoxicillin–clavulanate, Mrp = Meropenem, Trz = Thioridazine. The first treatment failure (XDR03) was simultaneously infected by two genetically different Beijing XDR strains, as detected by double alleles in 5 MIRU-VNTR loci. The second strain, not included in this study because not isolated from the patient’s first specimen, had additional resistance to capreomycin and clofazimine compared to the first one. After 31 months of unsuccessful hospital-supervised therapy, treatment was stopped. Nineteen months later, a new 9-drug regimen (including thioridazine) was prescribed but the patient died 4 months later. The second failure case (XDR04, the “panresistant” patient MDR169 mentioned in the text) returned to his home country after 18 months therapy, and subsequently died.