Tuberculosis due to resistant Haarlem strain, Tunisia.Multidrug-resistant tuberculosis was diagnosed in 21 HIV-negative, nonhospitalized male patients residing in northern Tunisia. A detailed investigation showed accelerated transmission of a Mycobacterium tuberculosis Mycobacterium tuberculosis n. Tubercic bacillus. Mycobacterium tuberculosis clone of the Haarlem type in 90% of all patients. This finding highlights the epidemic potential of this prevalent genotype genotype (jēn`ətīp'): see genetics. genotype Genetic makeup of an organism. The genotype determines the hereditary potentials and limitations of an individual. . ********** The ability of multidrug-resistant (MDR MDR, n See multidrug resistance. MDR, n the abbreviation for minimum daily requirement, specifically the Minimum Daily Requirements for Specific Nutrients compiled by the United States Food and Drug Administration. ) strains of Mycobacterium tuberculosis to cause epidemics and spread globally contrasts with the initial perception that MDR tuberculosis (MDR-TB MDR-TB Multi-Drug Resistant Tuberculosis ) has a reduced potential for transmission (1,2). In this respect, the W/Beijing type appears to be most common in humans and accounts for most reported MDR-TB outbreaks (3). In this report, we provide evidence for the epidemic potential of another worldwide prevalent M. tuberculosis M. tuberculosis, n the bacterium responsible for tuberculosis, generally a respiratory infection in man; nonrespiratory tuberculosis is considered an indicator disease for AIDS. See also tuberculosis. genotype, namely, the Haarlem family (4,5). The identified strain is MDR and has rapidly expanded within immunocompetent im·mu·no·com·pe·tent adj. Having the normal bodily capacity to develop an immune response following exposure to an antigen. im and nonhospitalized patients. The Study M. tuberculosis isolates were obtained from the Laboratory of Mycobacteriology of the Institut Pasteur de Tunis as part of the National Tuberculosis Surveillance Program. All samples (884 specimens) from patients with suspected TB residing in northern Tunisia (Bizerte) from August 2001 to October 2003 were forwarded to us by the referral regional hospital. This hospital serves a region with 483,086 people and an area of 3,501 [km.sup.2]. The incidence of TB in this area from 2001 to 2002 was 29/100,000 male patients and 11/100,000 female patients. All patients received the standard chemotherapy regimen of the Tunisian National Tuberculosis Program, i.e., 2 months of rifampicin rifampicin /rif·am·pi·cin/ (rif´am-pi-sin) rifampin. rifampin, rifampicin a derivative of rifamycin; an antibacterial and antifungal agent used in the treatment of mycobacterial infections, actinomycosis and histoplasmosis. , isoniazid isoniazid (ī'sōnī`əzĭd), drug used to treat tuberculosis. Also known as isonicotinic acid hydrazide, isoniazid is the most effective antituberculosis drug currently available. , pyrazinamide, and streptomycin streptomycin (strĕp'tōmī`sĭn), antibiotic produced by soil bacteria of the genus Streptomyces and active against both gram-positive and gram-negative bacteria (see Gram's stain), including species resistant to other , followed by 4 months of rifampicin and isoniazid (2RHZS/4RH). This regimen was introduced into the region in 1995. Of the 193 M. tuberculosis isolates recovered, 20 were MDR. The corresponding patients were interviewed, and detailed epidemiologic investigations were conducted according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. described protocols (6). In April 2004, while the study was in progress, a new MDR case was diagnosed. Analyses by IS6110 restriction fragment length polymorphism restriction fragment length polymorphism n. Abbr. RFLP Intraspecies variations in the length of DNA fragments generated by the action of restriction enzymes and caused by mutations that alter the sites at which these enzymes act, changing (IS6110 RFLP RFLP abbr. restriction fragment length polymorphism RFLP restriction fragment length polymorphism. RFLP ), ligation-mediated polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is (PCR PCR polymerase chain reaction. PCR abbr. polymerase chain reaction Polymerase chain reaction (PCR) ), and spoligotyping were carried out by using standard protocols (7-9). Typing of the polymorphic polymorphic - polymorphism GC-rich repetitive sequence (PGRS PGRS Postal Grievance Research System (software) ) with probe MTB MTB Mountain Bike MTB Mycobacterium Tuberculosis MTB Marshall Tucker Band MTB Motor Torpedo Boat MTB Making The Band (TV show) MTB Minus The Bear (band) MTB Mozilla Thunderbird 484 (1) was conducted according to a previously reported protocol (10), with the exception that DNA DNA: see nucleic acid. DNA or deoxyribonucleic acid One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. was digested with AluI. Isolates were assigned to principal genetic groups according to the polymorphisms in the katG and gyrA genes (11). The following primer pairs were used to sequence rpoB, katG, and pncA gene mutations Noun 1. gene mutation - (genetics) a mutation due to an intramolecular reorganization of a gene point mutation genetic science, genetics - the branch of biology that studies heredity and variation in organisms that confer resistance to rifampicin, isoniazid, and pyrazinamide, respectively: rpoB (5'-ATCACACCGCAGACGTTG-3', 5'-TGCATCACAGTGATGTAGTCG-3'); katG (5'-CGTCGAAACAGCGGCGCTGA-3', 5'-CAAGCGCCAGCAGGGCTCTT-3'); and pncA (5'-GGCGCACACAATGATCGGTG-3', 5'-GCTTTGCGGCGAGCGCTCCA3'). The recently described single nucleotide polymorphisms Noun 1. single nucleotide polymorphism - (genetics) genetic variation in a DNA sequence that occurs when a single nucleotide in a genome is altered; SNPs are usually considered to be point mutations that have been evolutionarily successful enough to recur in a in putative M. tuberculosis mutator A mutator may refer to:
The determination of the sequence of nucleotides in a sample of DNA. was conducted directly on the purified PCR products by using the Prism Ready Reaction Dye Deoxy Terminator (1) A character that ends a string of alphanumeric characters. (2) A hardware component that is connected to the last peripheral device in a series or the last node in a network. Cycle sequencing kit on an ABI Abi (ā`bī) [short for Abijah], in the Bible, King Hezekiah's mother. (Application Binary Interface) A specification for a specific hardware platform combined with the operating system. Prism 377 DNA sequencer A DNA sequencer is an instrument used to automate the DNA sequencing process. DNA sequencers have become more important due to large genomics projects and the need to increase productivity. (Applied Biosystems Applied Biosystems, Inc. (formerly NASDAQ: ABIO) is the original name of a pioneer biotechnology company founded in 1981 in Foster City, California, among the Silicon Valley cities of the southern San Francisco Bay Area. , Foster City, CA, USA). Epidemiologic and clinical data indicated that all patients with MDR-TB were male with a mean age of 31 years at diagnosis (Table 1). All were Tunisians and permanently resided in the northern part of the country (Bizerte). All patients were seronegative seronegative /se·ro·neg·a·tive/ (-neg´ah-tiv) showing negative results on serological examination; showing a lack of antibody. se·ro·neg·a·tive adj. for HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. with no documented history of travel abroad, and none had a history of immunosuppression immunosuppression Suppression of immunity with drugs, usually to prevent rejection of an organ transplant. Its aim is to allow the recipient to accept the organ permanently with no unpleasant side effects. , diabetes, or respiratory diseases Noun 1. respiratory disease - a disease affecting the respiratory system respiratory disorder, respiratory illness adult respiratory distress syndrome, ARDS, wet lung, white lung - acute lung injury characterized by coughing and rales; inflammation of the other than TB. Mapping of the 21 patients with MDR-TB according to their residence sites showed that they were mostly scattered over the northeastern part of the region (surface area [approximately equal to] 1,000 [km.sup.2]) with no concentration in a particular locality (data not shown). Resistance to 5 first-line drugs was observed for most isolates (Table 2). As indicated in Table 1, with the exception of patient P20, the DNA samples subjected to molecular typing were obtained from the initial isolate of all new patients. RFLP showed that 18 patients had nearly identical IS6110 profiles (Figures 1 and 2). The predominant profile (occurring in 13 patients) showed 11 bands, while the remaining 5 patients had an additional IS6110 band. The presence or absence of the additional IS6110 band was not restricted to new or previously treated patients. The RFLP pattern of patient P11, a new patient, clearly showed a mixture of the 12-band profile and some additional IS6110 bands (Figure 2A). Typing of his follow-up culture, which was obtained after 6 months of directly observed short-course therapy, as recommended by the World Health Organization, yielded only the 12-band profile (Figure 2A). Laboratory records and epidemiologic data indicate that this patient likely had a dual infection. [FIGURES 1-2 OMITTED] The isolate from patient P13 was typed by ligation-mediated PCR. Its profile was identical to the 18 other MDR isolates. Thus 19 patients with MDR-TB could be clustered according to IS6110-based typing. Effective epidemiologic links were identified for 9 (47%) patients (Table 1). Another similar RFLP pattern was observed for patient P20. It shows 10 IS6110 bands (Figure 2B), 9 of which are common to the 12-band RFLP pattern described for the other isolates. The isolate from patient P19 displayed a 9-band IS6110 profile that was clearly distinct from all the other patients with MDR-TB (data not shown). With the exception of patient P19, the MDR isolates were identical in their PGRS profile (Figure 2) and spoligotype patterns (Table 2), which is characteristic of the Haarlem3 type (4). Sequence analysis of mutator and drug resistance genes conclusively confirmed that the 19 MDR isolates with nearly identical IS6110 (both 12- and 11-band profiles) are genetically closely related. They all harbor the L209L, T15S, S531L, and S315T mutations in mutT3, ogt, rpoB, and katG genes, respectively (Table 2), whereas mutT1 and MutT2 showed a wild type genotype (data not shown). The occurrence of an additional uncommon mutation in the rpoB gene (V610M) confirmed the clonality of this MDR Haarlem strain since it was present only in 19 patients with MDR-TB. The variability of resistance to pyrazinamide and the mutational profile within the pncA gene (Table 2) strongly suggest that primary transmission from person to person occurred mainly with a strain that was simultaneously resistant to isoniazid and rifampicin. To extend our analysis of the situation that prevailed in this region, samples from 143 (83%) of 172 patients without MDR strains were spoligotyped. Of these 143 patients, 41 (29%) were female. Overall, 31 (22%) of the 143 patients had Haarlem3 genotype TB. In contrast to the MDR-TB outbreak that involved only men, 6 women had a non-MDR Haarlem3 strain. Aside from the absence of clustering, ligation-mediated PCR typing showed that none of these non-MDR Haarlem3 isolates displayed a profile similar to the 19 MDR isolates involved in the transmission chain. Sequencing of the rpoB gene of 10 isolates randomly selected from the 31 non-MDR Haarlem isolates showed the absence of the outbreak-associated mutation V610M. This finding is strongly indicative of a true clonal expansion and a typical MDR-TB outbreak. The W/Beijing type was absent in the analyzed pool of isolates. Conclusions The results indicate that an MDR strain of M. tuberculosis has been actively transmitted among 19 HIV-negative male patients in Tunisia. Several observations indicate that this particular Haarlem strain displays increased transmissibility trans·mis·si·ble adj. That can be transmitted: transmissible signals. trans·mis , virulence Virulence The ability of a microorganism to cause disease. Virulence and pathogenicity are often used interchangeably, but virulence may also be used to indicate the degree of pathogenicity. , or both. First, the outbreak peaked suddenly within a relatively short period of 21 months; 17 new cases (89%) were reported from September 2001 to June 2003. Inspection of the hospital register for 2000 showed only 3 new patients with MDR isolates, including outbreak-associated patients P5 and P7 (Table 1). Second, no epidemiologic links or contact points could be traced for several patients, which suggests that brief exposure would have been sufficient for effective transmission. Because patients with MDR-TB do not respond to treatment, they may serve as constant sources of transmission. Such a situation is likely to have occurred for the patients with established epidemiologic links. Third, the incidence of TB in the region in which the outbreak occurred is not particularly high. Fourth, patients were seronegative for HIV with no history of treatment causing immunosuppression. Fifth, no AIDS-associated TB outbreak that might have increased the adaptability of the strain within the indigenous population had occurred in the region. Sixth, although the Haarlem strain was MDR, it was able to cause an outbreak in those vaccinated with bacille Calmette-Guerin ba·cil·le Cal·mette-Gué·rin n. See bacillus Calmette-Guerin. and in persons who were not hospitalized. Among the identified M. tuberculosis strain families (4,5), the W/Beijing type has been associated with outbreaks or microepidemics worldwide (3). The Haarlem strain family appears to be widespread (4), but its ability to cause outbreaks has been reported only twice, once in Argentina (13) and once in the Czech Republic Czech Republic, Czech Česká Republika (2005 est. pop. 10,241,000), republic, 29,677 sq mi (78,864 sq km), central Europe. It is bordered by Slovakia on the east, Austria on the south, Germany on the west, and Poland on the north. (14). The distinctive feature of the present Haarlem MDR-TB outbreak is its accelerated transmission compared with the first 2 MDR-TB outbreaks. Alterations within DNA repair DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light can cause DNA damage, resulting in as many as 1 genes (mutator genes) are thought to favor the emergence of MDR strains with an increased adaptability (12). In this respect, both W/Beijing and Haarlem strains accumulated mutations within their putative mutator genes. Widespread MDR strains might also benefit from their intrinsic adaptability (15). From an epidemiologic point of view, TB programs must conduct extensive surveillance of MDR strains of M. tuberculosis strain families because they might cause serious outbreaks.
Table 1. Clinical characteristics of 21 patients with
multidrug-resistant tuberculosis (MDR-TB), Bizerte,
Tunisia, 2001-2004 *
Case Isolate used for
Patient Age (y) Sex history molecular typing
P1 24 M PT Follow-up, Oct 2001
P2 26 M NC Initial
P3 25 M NC Initial
P4 62 M NC Initial
P5 26 M PT Follow-up, Feb 2002
P6 23 M PT Follow-up, Feb 2002
P7 24 M PT Follow-up, Mar 2002
P8 27 M NC Initial
P9 34 M PT Follow-up, Jun 2002
P10 21 M NC Initial
P11 42 M NC Initial
P12 23 M NC Initial
P13 29 M PT Follow-up, Aug 2002
P14 34 M NC Initial
P15 51 M PT Follow-up, Nov 2002
P16 17 M NC Initial
P17 17 M NC Initial
P18 21 M NC Initial
P19 42 M NC Initial
P20 53 M NC Follow-up, Oct 2003
P21 ND M NC Initial
Initial diagnosis Epidemiologic
Patient Age (y) of MDR-TB characteristic
P1 24 Sep 2001 Brother of patient 14
P2 26 Oct 2001 Same penitentiary as
patients 7 and 9
P3 25 Oct 2001 None apparent
P4 62 Nov 2001 None apparent
P5 26 Sep 2000 Brother of patient 18
P6 23 Feb 2001 None apparent
P7 24 Sep 2000 Same penitentiary as
patients 2 and 9
P8 27 Jun 2002 None apparent
P9 34 Aug 2001 Same penitentiary as
patients 2 and 7
P10 21 Jun 2002 None apparent
P11 42 Jul 2002 None apparent
P12 23 Jul 2002 None apparent
P13 29 Sep 2001 None apparent
P14 34 Nov.2002 Brother of patient 1
P15 51 ND None apparent
P16 17 Mar 2002 None apparent
P17 17 May 2003 Nephew of patient 14
P18 21 Jun 2003 Brother of patient 5
P19 42 Jun 2003 No interview
(lost case)
P20 53 Oct 2002 None apparent
P21 ND Apr 2004 Cousin of patient 14
Patient Age (y) Chest radiography
P1 24 Right apical cavity
nodular lesion
P2 26 Left mid-lung nodular
opacity with excavation
P3 25 Bi-apical nodular opacity
P4 62 Right apical nodular
opacity
P5 26 Diffuse nodular lesions
and multiple cavities
P6 23 Right apical and median
bilateral nodular opacity
P7 24 Right lobe apical nodular
opacity
P8 27 Right apical nodular
opacity
P9 34 Right apical nodular
opacity and left diffuse
nodular opacity
P10 21 Right lobe apical nodular
opacity and cavity
P11 42 Basal nodular opacity of
the right and left lung
P12 23 Left apical cavity and
nodular opacity
P13 29 Bilateral apical and
diffuse opacity
P14 34 Left apical cavity and
nodular lesion
P15 51 Bilateral cavity
P16 17 Bilateral nodular
infiltration and cavity in
the left lung
P17 17 Wright apical cavity and
left lung nodular opacity
P18 21 Right apical cavity and
nodular opacity
P19 42 Diffuse nodular opacity
and multiple cavities
P20 53 Right apical cavities and
left lobe infiltrate
P21 ND ND
* PT, previously treated, NC, new case, ND, not determined.
Table 2. Laboratory findings and genotyping of multidrug-resistant
isolates from 21 tuberculosis patients, Bizerte, Tunisia,
2001-2004 *
Resistance RFLP
Smear pattern ([double PGG
Patient result ([dagger]) dagger]) Spoligotype ([section])
P1 +++ HSREZ 11 Haarlem3 2
([paragraph])
P2 + HSREZ 11 Haarlem3 2
P3 ++ HSREZ 12 Haarlem3 2
P4 - HSREZ 11 Haarlem3 2
P5 - HSREZ 12 Haarlem3 2
P6 + HSREZ 11 Haarlem3 2
P7 - HSREZ 11 Haarlem3 2
P8 - HSRE 11 Haarlem3 2
P9 + HSRE 11 Haarlem3 2
P10 - HSREZ 11 Haarlem3 2
P11 - HSREZ 12 Haarlem3 2
P12 - HSREZ 11 Haarlem3 2
P13 - HSRE ND (#) Haarlem3 2
P14 - HRZ 11 Haarlem3 2
P15 - HSREZ 11 Haarlem3 2
P16 ++ HSR 12 Haarlem3 2
P17 - HSREZ 11 Haarlem3 2
P18 - HSREZ 12 Haarlem3 2
P19 - HSRE 9 Other ** 2
P20 ++ HSR 10 Haarlem3 2
P21 ++ HR 11 Haarlem3 2
Mutational analysis
Patient rpoB katG pncA mutT3 Ogt
P1 S531L+V610M S315T A-11C L209L T15S
P2 S531L+V610M S315T A-11C L209L T15S
P3 S531L+V610M S315T T11G L209L T15S
(L4W)
P4 S531L+V610M S315T A-11C L209L T15S
P5 S531L+V610M S315T WT L209L T15S
P6 S531L+V610M S315T WT L209L T15S
P7 S531L+V610M S315T A-11C L209L T15S
P8 S531L+V610M S315T WT L209L T15S
P9 S531L+V610M S315T A-11C L209L T15S
P10 S531L+V610M S315T WT L209L T15S
P11 S531L+V610M S315T WT L209L T15S
P12 S531L+V610M S315T A-11C L209L T15S
P13 S531L+V610M S315T WT L209L T15S
P14 S531L+V610M S315T G insertion L209L T15S
(391-392)
P15 S531L+V610M S315T A-11C L209L T15S
P16 S531L+V610M S315T T11G L209L T15S
(L4W)
P17 S531L+V610M S315T G insertion L209L T15S
(296-297)
P18 S531L+V610M S315T T11G L209L T15S
(L4W)
P19 [DELTA]N S315T G insertion WT WT
(AAC)519 (296-297)
P20 S531L S315 WT L209L T15S
P21 S531L+V610M S315T WT L209L T15S
* RFLP, restriction fragment length polymorphism; PGG, principal
genetic grouping; WT, wild type (identical to strain H37Rv);
ND, not determined.
([dagger]) H, isoniazid; S, streptomycin; R, rifampicin; E,
ethambutol; Z, pyrazinamide.
([double dagger]) Number of IS6110 bands.
([section]) Principal genetic grouping according to gyrA and
katG polymorphisms (11).
([paragraph]) Absence of spacers 31 and 33-36.
(#) IS6110 typing was determined by ligation-mediated polymerase
chain reaction and the profile was identical to the other
outbreak-associated strains.
** Absence of spacers 15, 21-24, and 33-36.
Acknowledgments We thank Fethi Diouani for mapping the MDR cases, Maherzia Ben Fadhel for sequencing, and Rob M. Warren for thoughtfully reviewing the manuscript. This study was supported by the United Nations Development Program/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases (TDR TDR - time domain reflectometer ). References (1.) Espinal MA. The global situation of MDR-TB. Tuberculosis (Edinb). 2003:83:44-51. (2.) Frieden TR. Sterling TR, Munsiff SS, Watt CJ, Dye C. Tuberculosis. Lancet. 2003:362:887-99. (3.) Glynn JR, Whiteley J, Bifani PJ, Kremcr K, van Soolingen D. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg Infect Dis. 2002;8:843-9. (4.) Filliol I, Driscoll JR, van Soolingen D, Kreiswirth BN, Kremer K, Valetudie G, et al. Global distribution of Mycobacterium tuberculosis spoligotypes. Emerg Infect Dis. 2002;8:1347-9. (5.) Kremer K, van Soolingen D, Frothingham R, Haas WH, Hermans PW, Martin C, et al. Comparison of methods based on different molecular epidemiological markers for typing of Mycobacterium tuberculosis complex strains: interlaboratory study of discriminatory power and reproducibility. J Clin Microbiol. 1999;37:2607-18. (6.) Munsiff SS, Bassof T, Nivin B, Li J, Sharma A, Bifani P, et al. Molecular epidemiology molecular epidemiology Molecular medicine An evolving field that combines the tools of standard epidemiology–case studies, questionnaires and monitoring of exposure to external factors with the tools of molecular biology–eg, restriction endonucleases, of multidrug-resistant tuberculosis, New York City New York City: see New York, city. New York City City (pop., 2000: 8,008,278), southeastern New York, at the mouth of the Hudson River. The largest city in the U.S. , 1995-1997. Emerg Infect Dis. 2002; 8:1230-8. (7.) van Embden JD, Cave MD, Crawford JT, Dale JW, Eisenach KD, Gicquel B, et al. Strain identification of Mycobacterium tuberculosis by DNA fingerprinting DNA fingerprinting or DNA profiling, any of several similar techniques for analyzing and comparing DNA from separate sources, used especially in law enforcement to identify suspects from hair, blood, semen, or other biological materials found at : recommendations for a standardized methodology. J Clin Microbiol. 1993;31:406-9. (8.) Prod'hom G, Guilhot C, Gutierrez MC, Varnerot A, Gicquel B, Vincent V. Rapid discrimination of Mycobacterium tuberculosis complex strains by ligation-mediated PCR fingerprint analysis. J Clin Microbiol. 1997;35:3331-4. (9.) Kamerbeek J, Schouls L, Kolk A, van Agterveld M, van Soolingen D, Kuijper S, et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol. 1997;35:907-14. (10.) Warren R, Richardson M, Sampson S, Hauman JH, Beyers N, Donald PR, et al. Genotyping Genotyping refers to the process of determining the genotype of an individual with a biological assay. Current methods of doing this include PCR, DNA sequencing, and hybridization to DNA microarrays or beads. of Mycobacterium tuberculosis with additional markers enhances accuracy in epidemiological studies. J Clin Microbiol. 1996;34:2219-24. (11.) Sreevatsan S, Pan X, Stockbauer KE, Connell ND, Kreiswirth BN, Whittam TS, et al. Restricted structural gene polymorphism polymorphism, of minerals, property of crystallizing in two or more distinct forms. Calcium carbonate is dimorphous (two forms), crystallizing as calcite or aragonite. Titanium dioxide is trimorphous; its three forms are brookite, anatase (or octahedrite), and rutile. in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proc Natl Acad Sci USA. 1997;94:9869-74. (12.) Rad ME, Bifani P, Martin C, Kremer K, Samper S, Rauzier J, et al. Mutations in putative mutator genes of Mycobacterium tuberculosis strains of the W-Beijing family. Emerg Infect Dis. 2003;9:838-45. (13.) Ritacco V, Di Lonardo M, Reniero A, Ambroggi M, Barrera L, Dambrosi A, et al. Nosocomial nosocomial /noso·co·mi·al/ (nos?o-ko´me-il) pertaining to or originating in a hospital. nos·o·co·mi·al adj. 1. Of or relating to a hospital. 2. spread of human immunodeficiency immunodeficiency Defect in immunity that impairs the body's ability to resist infection. The immune system may fail to function for many reasons. Immune disorders caused by a genetic defect are usually evident early in life. virus-related multidrug-resistant tuberculosis in Buenos Aires Buenos Aires (bwā`nəs ī`rēz, âr`ēz, Span. bwā`nōs ī`rās), city and federal district (1991 pop. . J Infect Dis. 1997; 176:637-42. (14.) Kubin M, Havelkova M, Hynccicova I, Svecova Z, Kaustova J, Kremer K, et al. A multidrug-resistant tuberculosis microcpidemic caused by genetically closely related Mycobacterium tuberculosis strains. J Clin Microbiol 1999;37:2715-6. (15.) Andersson DI. Persistence of antibiotic resistant bacteria. Curr Opin Microbiol. 2003;6:452-6. Helmi Mardassi, * Amine amine (əmēn`, ăm`ēn): see under amino group. amine Any of a class of nitrogen-containing organic compounds derived, either in principle or in practice, from ammonia (NH3). Namouchi, * Raja Haltiti, ([dagger]) Mourad Zarrouk, ([dagger]) Besma Mhenni, * Anis ANIS Association pour le Développement National de l'Internet dans la Santé ANIS Animations Karboul, * Neila Khabouchi, * Nico C. Gey Gey may refer to:
n. A reference mark (  ) used in printing and writing. Also called diesis.Noun 1. ]) Elizabeth M. Streicher, ([double dagger]) Jean Rauzier, ([section]) Brigitte Gicquel, ([section]) and Koussay Dellagi * * Institut Pasteur de Tunis, Tunis-Belvedere, Tunisia; ([dagger]) Hopital Regional de Menzel-Bourguiba, Menzel-Bourguiba, Tunisia; (double dagger]) University of Stellenbosch, Stellenbosch, South Africa South Africa, Afrikaans Suid-Afrika, officially Republic of South Africa, republic (2005 est. pop. 44,344,000), 471,442 sq mi (1,221,037 sq km), S Africa. ; and ([section]) Institut Pasteur, Paris, France Dr. Mardassi is head of a research group at the Institut Pasteur de Tunis. His research interests include the molecular epidemiology of M. tuberculosis and gene expression within the mycobacterial mycobacterial emanating from or pertaining to mycobacterium. mycobacterial granuloma may be caused by Mycobacterium tuberculosis (see cutaneous tuberculosis), M. host cell. Address for correspondence: Helmi Mardassi, Laboratoire des Mycobacteries, Institut Pasteur de Tunis, 13, Place Pasteur, BP 74, 1002, Tunis-Belvedere, Tunisia; fax: 216-71-791-833; email: helmi.merdassi@ pasteur.rns.tn |
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