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Letter
Mycobacterium tuberculosis
Complex Drug Resistance in Italy
Giovanni B. Migliori,*† Rosella Centis,* Lanfranco Fattorini,* Giorgio
Besozzi,* Cesare Saltini,* Claudio Scarparo,* Daniela Cirillo,* Andrea
Gori,* Antonio Cassone,* and Claudio Piersimoni*
*SMIRA (Italian Multicentre Study on Resistance to Antituberculosis Drugs)
Coordinating Committee; and †S. Maugeri Foundation, Tradate, Italy
Suggested citation
for this article:
Migliori GB, Centis R, Fattorini L, Besozzi G, Saltini C, Scarparo C.
Mycobacterium tuberculosis complex drug resistance in Italy.
Emerg Infect Dis [serial online] 2004 Apr [date cited]. Available
from: http://www.cdc.gov/ncidod/EID/vol10no4/03-0667.htm
To the Editor: The reemergence of tuberculosis (TB) as a global
health problem over the past 2 decades, accompanied by increased drug
resistance, which represents a serious problem both in terms of TB control
and clinical management (1), prompted Western European
countries to develop comprehensive national surveillance systems to monitor
trends in TB drug resistance. Moreover, the World Health Organization
(WHO) and the International Union Against Tuberculosis and Lung Disease
(IUATLD) launched the Global Project on Anti-Tuberculosis Drug Resistance
Surveillance to measure the prevalence of drug resistance by using standardized
methods and assess its correlation with indicators of TB control (2,3).
Since comprehensive data on resistance to firstline drugs were not available
in Italy, a network of 20 regional laboratories was established to participate
in this project. The Department of Bacteriology and Medical Mycology of
Istituto Superiore di Sanità in Rome and the Mycobacteriology Unit of
Istituto Villa Marelli in Milan (appointed respectively as Supranational
Reference Laboratory and National Reference Laboratory) supervised and
controlled the network of regional laboratories. The combination of reference
laboratories in the network and associated clinical units, which covered
30% of definite cases reported each year (4), was known
as SMIRA (Italian Multicentre Study on Resistance to Anti-Tuberculosis
Drugs). The WHO/IUATLD coordinating center in Ottawa, Canada, provided
a batch of 20 Mycobacterium tuberculosis strains to set up proficiency
testing to check drug susceptibility procedures in all SMIRA laboratories
(5). We summarize the nature and extent of TB drug resistance
in Italy between 1998 and 2001.
Isolates from all consecutive, definite cases diagnosed in TB units during
1998 through 2001 were included. When a patient’s previous treatment status
was unknown or dubious, the case was excluded. Resistant cases from patients
with and without history of previous treatment were stratified by the
following categories: any resistance, monoresistance, resistance to both
isoniazid and rifampicin (known as rifampin in the United States), or
resistance to three or more drugs. Confidence intervals were also calculated.
Participating laboratories were allowed to use the WHO-recommended drug
susceptibility method with which they were most familiar: absolute concentration
method, resistance ratio method, proportion method and its variants, or
BACTEC 460 radiometric method (Becton Dickinson, Towson, MD) (6,7).
Among the laboratories reporting results by the proportion method, the
majority used Löwenstein-Jensen medium while others used liquid nonradiometric
media (8). Each of the 20 M. tuberculosis strains
was tested against firstline drugs by the Italian Reference Laboratories
in Rome and Milan and classified as resistant or susceptible. Results
were compared to the standard criterion, represented by the judicial results
of the WHO/IUATLD Global Network of Supranational Laboratories (9).
Each network laboratory was validated for each firstline drug when no
more than two results were different from the standard criterion.
The prevalence of drug resistance detected during the period 1998–2001
is summarized in the Table. Among previously untreated
cases, the prevalence of resistance to isoniazid, rifampicin, ethambutol,
and streptomycin was 3.5%, 0.8%, 0.5%, and 4.3%, respectively, while prevalence
of multidrug resistance (resistance to at least isoniazid and rifampicin)
and polyresistance (resistance to two or more drugs, but not both isoniazid
and rifampicin) was 1.1% and 2.4%, respectively. No difference was found
by stratifying prevalence data by age, sex, or HIV status. In isolates
from patients with previous treatment, drug resistance was found to be
almost four times higher than in those from patients with no history of
treatment. However, the prevalence of monoresistant strains was low (5.3%,
4.3%, 0.3%, and 4.3% for isoniazid, rifampicin, ethambutol, and streptomycin,
respectively) compared with the prevalence of multidrug-resistant strains
whose rate reached a peak of 30.4%.
Drug-resistant TB in countries with good national control programs, such
as in Western Europe, is not commonly a major health problem, although
increasing immigration prompts public health authorities to maintain vigilant
surveillance systems. The results of our study indicate that throughout
Italy, prevalence of resistance to firstline drugs and multidrug resistance
among isolates from new cases was consistently low over the 4-year survey
period. Prevalence of multidrug resistance among isolates from previously
treated patients was high, although a downward trend could be demonstrated
during the last 2 years. Since almost 2 out of 10 isolates resistant to
rifampicin were multidrug resistant, using rapid molecular methods to
identify rifampicin resistance in questionable cases appears cost-effective
to facilitate early detection and control of multidrug-resistant TB (10).
Resistance to isoniazid is associated with immigration from countries
where isoniazid was used extensively in the past. This information is
a useful tool for clinicians, as isoniazid resistance may be suspected
early in the disease and properly treated. Finally, the finding of substantial
multidrug resistance among isolates from previously treated patients,
combined with the evidence that immigrants from areas where isoniazid
resistance is endemic contribute substantially to the number of new TB
cases in Italy every year, strongly suggests that public health action
is needed to improve treatment outcomes.
This work was funded
independently by the Istituto Superiore di Sanità-Rome (National TB
Project) and the World Health Organization. It was also supported by
a grant (TBC1) from the Associazione Italiana Pneumologi Ospedalieri
(AIPO).
References
- Kochi A, Vareldzis B, Styblo K. Multidrug-resistant
tuberculosis and its control. Res Microbiol 1993;144:104–10.
- Anti-tuberculosis drug resistance in the world. The WHO/IUATLD Global
Project on anti-tuberculosis drug resistance surveillance. World Health
Organization, Geneva, 1997. WHO/TB/97.229:1–227.
- WHO/IUATLD Global Working Group on antituberculosis drug resistant
surveillance. Guidelines for surveillance of drug resistance in tuberculosis.
World Health Organization, Geneva, 1997. WHO/TB/96.216:1–36.
- Centis R, Ianni A, Migliori GB, on behalf of the Tuberculosis section
of the National AIPO Study Group and the SMIRA Group. Evaluation
of tuberculosis treatment results in Italy, report 1998. Monaldi
Arch Chest Dis 2000;55:293–8.
- Migliori GB, Ambrosetti M, Fattorini L, Penati V, Vaccarino P, Besozzi
G, et al. Surveillance
of anti-tuberculosis drug resistance: results of the 1998/1999 proficiency
testing in Italy. Int J Tuberc Lung Dis 2000;4: 940–6.
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pour la détermination de l’isoniazido-résistance du bacille tuberculeux,
leur ampleur et leur inconvénients. Bull Int Union Tuberc 1955;25:157–78.
- Roberts GD, Goodman NL, Heifets L, Larsh HW, Lindner TH, McClatchy
JK, et al. Evaluation
of the BACTEC radiometric method for recovery of mycobacteria and drug
susceptibility testing of Mycobacterium tuberculosis from acid-fast
smear-positive specimens. J Clinic Microbiol 1983;18:689–96.
- Rusch-Gerdes S, Domehl C, Nardi G, Gismondo MR, Welscher HM, Pfyffer
GE. Multicenter
evaluation of the mycobacteria growth indicator tube for testing susceptibility
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Microbiol 1999;37:45–8.
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detection of resistance in Mycobacterium tuberculosis: a review
discussing molecular approach. Clin Microbiol Infect 2003;9:349–59.
| Table.
Pattern of drug resistance among strains from tuberculosis patients
with and without a history of treatment, Italy 1998–2001a |
|
|
Tested MTB strains
|
No history of previous treatment
|
History of previous treatment
|
|
|
|
No.
|
%
|
95% CI
|
No.
|
%
|
95% CI
|
|
|
Total tested
|
2,117
|
100
|
–
|
322
|
100
|
–
|
|
Fully sensitive
|
1,847
|
87.2
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85.8 to 88.6
|
155
|
48.1
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42.7 to 53.6
|
|
Any drug
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270
|
12.7
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11.4 to 14.2
|
167
|
51.8
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46.4 to 57.3
|
|
INH
|
75
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3.5
|
2.8 to 4.4
|
17
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5.3
|
3.2 to 8.2
|
|
RMP
|
17
|
0.8
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0.5 to 1.3
|
14
|
4.3
|
2.5 to 7.0
|
|
EMB
|
10
|
0.5
|
0.2 to 0.8
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1
|
0.3
|
0.02 to 1.5
|
|
SM
|
93
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4.3
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3.6 to 5.3
|
14
|
4.3
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2.5 to 7.0
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|
Resistant to both INH and RMP
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8
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0.40
|
0.8 to 0.7
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24
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7.5
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4.9 to 10.7
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Resistant to INH, RMP, EMB
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2
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0.10
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0.01 to 0.3
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19
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6.0
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3.7 to 8.9
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Resistant to INH, RMP, SM
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6
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0.30
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0.1 to 0.6
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23
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7.1
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4.7 to 10.4
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Resistant to INH, RMP, EMB, SM
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7
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0.30
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0.1 to 0.6
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32
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9.9
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7.0 to 13.5
|
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| aMTB, Mycobacterium
tuberculosis complex; CI, confidence interval; INH, isoniazid;
RMP, rifampicin; EMB, ethambutol; SM, streptomycin. |
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