Background In the United States there have been recent outbreaksof multidrug-resistant tuberculosis. These outbreaks have primarilyinvolved persons infected with the human immunodeficiency virus(HIV).
Methods We collected clinical information on 17 patients seenat a New York City hospital who had repeatedly positive culturesfor Mycobacterium tuberculosis. Analysis of restriction-fragment-lengthpolymorphisms (RFLPs) was performed on serial isolates of M.tuberculosis obtained from these patients.
Results Six patients had isolates that remained drug-susceptible,and the RFLP patterns of these isolates did not change overtime. Eleven patients had isolates that became resistant toantimicrobial agents. The RFLP patterns of the isolates fromsix of these patients remained essentially unchanged (two strainsshowed one additional band) despite the development of drugresistance. In five other patients, however, the RFLP patternsof the isolates changed dramatically at the time that drug resistancewas detected. The change in the RFLP pattern of the isolatefrom one patient appeared to be the result of contaminationduring processing in the laboratory. In the remaining four patients,all of whom had advanced HIV disease, the clinical and microbiologicevidence was consistent with the presence of active tuberculosiscaused by a new strain of M. tuberculosis.
Conclusions Resistance to antituberculous drugs can developnot only in the strain that caused the initial disease, butalso as a result of reinfection with a new strain of M. tuberculosisthat is drug-resistant. Exogenous reinfection with multidrug-resistantM. tuberculosis can occur either during therapy for the originalinfection or after therapy has been completed.
Until recently, it was unusual to isolate drug-resistant Mycobacteriumtuberculosis in the United States. Tuberculosis caused by suchorganisms occurred sporadically, and only rarely could epidemiologicconnections be demonstrated between cases1,2. During the pastthree years, however, there have been numerous outbreaks oftuberculosis caused by organisms resistant to multiple antituberculousdrugs3,4,5,6,7,8,9,10,11. Most such outbreaks have primarilyinvolved persons infected with the human immunodeficiency virus(HIV), who are thought to have been exposed to the strains inmedical or correction facilities. The purpose of our study wasto examine the means by which patients acquire multidrug-resistanttuberculosis, since this information is needed for rationalpreventive strategies12.
Multidrug-resistant tuberculosis is thought to occur eitherthrough infection by organisms that are already resistant toantimicrobial agents (primary drug resistance), or through thedevelopment of drug resistance during therapy by a strain thatwas originally drug-sensitive (acquired drug resistance). Thelatter process is believed to be due to the selection of drug-resistantmutants of the original strain as a consequence of inadequatetherapy13.
Analysis of restriction-fragment-length polymorphisms (RFLPs)is a well-established method of "DNA fingerprinting" that hasbeen used to trace the transmission of particular strains ofM. tuberculosis during investigations of outbreaks5,7,8,9,14,15,16,17,18,19,20,21.This report describes the use of RFLP analysis to determinehow multidrug-resistant tuberculosis may have developed in agroup of patients who continued to have positive cultures forM. tuberculosis after the institution of antimicrobial therapy.
Methods
Kings County Hospital is a 1200-bed municipal hospital in centralBrooklyn that provides primary care to residents of the surroundingcommunity and to New York City's correctional facility on Riker'sIsland. In this hospital at least 300 patients, approximatelyhalf of whom are infected with HIV,22,23 have been found tohave microbiologically confirmed tuberculosis each year forthe past five years.
Specimen registries of the hospital mycobacteriology laboratorywere reviewed for the period from April 1987 to July 1991. Duringthis time antimicrobial-susceptibility testing was performedroutinely on all initial isolates of M. tuberculosis and wasrepeated every three months on all subsequent isolates fromthe same patient. The susceptibility of the isolates to isoniazid(0.1 or 0.2 µg per milliliter), rifampin (2.0 µgper milliliter), streptomycin (6.0 µg per milliliter),and ethambutol (7.5 µg per milliliter) was determinedwith a radiometric broth method (BACTEC system, Johnston Laboratories,Towson, Md.). Specimens processed after October 1990 were alsotested for their susceptibility to pyrazinamide (100 µgper milliliter).
The results of all drug-susceptibility tests were reviewed toidentify patients who had repeatedly positive cultures for M.tuberculosis at Kings County Hospital that either remained sensitiveto all antituberculous drugs for more than one year or becameresistant to isoniazid, rifampin, or both drugs.
Slant cultures of Lowenstein-Jensen medium inoculated from theprimary cultures, which had been maintained at 4 °C, weresubcultured. These isolates were retested for antimicrobialsusceptibility in the California State Department of HealthServices Microbial Diseases Laboratory with the proportion method24.The medium included the following concentrations of antimicrobialagents: isoniazid, 0.2 µg per milliliter; rifampin, 1µg per milliliter; streptomycin, 2 µg per milliliter;and ethambutol, 5 µg per milliliter24. The isolates wereconsidered to be resistant if there was more than 1 percentgrowth on medium containing antituberculous drugs as comparedwith the growth on drug-free medium.
The RFLP patterns of the isolates were determined accordingto internationally standardized procedures25. In brief, theorganisms were grown in Dubos broth base supplemented with Dubosmedium albumin (Difco Laboratories, Detroit) at 37 °C fortwo to four weeks. Bacterial cell walls were digested with lysozyme,proteinase K, and sodium dodecyl sulfate. Genomic DNA was extractedwith cetyltrimethylammonium bromide, chloroform-isoamyl alcohol,and isopropanol and then digested with the restriction endonucleasePvuII. The resulting fragments were electrophoretically separatedand transferred to nylon membranes, which were probed with a245-base-pair fragment of the insertion sequence IS6110. Hybridizingfragments were detected by chemiluminescence (ECL kit, Amersham,Arlington Heights, Ill.).
Clinical data were collected by reviewing hospital and outpatientrecords. None of the patients received supervised therapy asoutpatients; therefore, the degree of compliance with treatmentwas based on the patients' statements and clinic attendance.
Results
From April 1987 to July 1991, a total of 1318 patients had culturesthat grew M. tuberculosis. Forty-eight of these patients metthe selection criteria, in that they had persistently positivecultures for more than one year with drug-sensitive organisms(17 patients) or they had persistently positive cultures withincreasingly drug-resistant organisms (31 patients). Sets ofmultiple isolates were available from 6 of the 17 patients withorganisms that remained drug-sensitive for more than one yearand from 11 of the 31 patients with organisms that manifestedincreasing drug resistance (Table 1). Sequential isolates fromthe remainder of the patients were not available, were not viable,or had become contaminated. This report focuses on the 17 patientswith isolates that could be evaluated.
Table 1. Epidemiologic and Clinical Characteristics of 6 Patients with Persistently Drug-Susceptible M. tuberculosis Isolates and 11 Patients with Drug-Resistant Isolates.
RFLP analysis of serial isolates from six patients (Patients1 through 6 in Table 1) from whom drug-sensitive M. tuberculosiswas persistently isolated demonstrated stable patterns (Figure 1).Likewise, the RFLP patterns of serial isolates from fourpatients (Patients 7, 8, 9, and 10 in Table 1) with organismsthat became resistant during therapy also remained stable. Thepatterns of sequential isolates from two additional patients(Patients 11 and 12) infected with strains that had become resistantto rifampin during therapy were identical except for the developmentof one additional band (Figure 2). Thus, on the basis of thestability of these RFLP patterns over time, 12 of the 17 patientswith serially positive cultures were judged to have been persistentlyinfected with the strain originally isolated.
Figure 1. RFLP Patterns of the Initial (A) and Final (B) Isolates from Six Patients with Persistently Drug-Susceptible Isolates of M. tuberculosis.
The specimens were obtained at the times shown in Table 1. The serial RFLP patterns of each pair of isolates were identical, indicating the continuing presence of the original strain. The last two lanes contain negative (M. avium complex) and positive (M. tuberculosis strain H37Rv) control DNA.
Figure 2. RFLP Patterns of the Initial (A) and Final (B) Isolates from Six Patients Infected with Increasingly Drug-Resistant Strains of M. tuberculosis.
Except for the presence of one additional band (arrows) in Patients 11 and 12, the serial RFLP patterns of each pair of isolates were identical, indicating that the initially infecting strain acquired antimicrobial resistance during therapy. The last two lanes contain negative (M. avium complex) and positive (M. tuberculosis strain H37Rv) control DNA.
Five patients whose initial isolates had been drug-sensitive(Patients 13 through 17) had an organism resistant to at leastisoniazid and rifampin isolated during the study period. Ineach case, the RFLP patterns of the original drug-sensitivestrains dramatically differed from the pattern of the multidrug-resistantstrains obtained subsequently (Figure 3), indicating that thepatients may have been infected with a new strain during therapyfor the initial infection. The RFLP patterns of the multidrug-resistantstrains isolated from these five patients were identical (exceptfor one additional band in an isolate from Patient 17), pointingto the possibility that the same strain may have infected allthese patients. Indeed, three of these patients (Patients 15,16, and 17) had been hospitalized in the same open tuberculosisunit and at the same time as other patients who were infectedwith this strain. The same RFLP pattern as that for the multidrug-resistantstrains isolated from Patients 13 through 17 has now been identifiedin multidrug-resistant strains isolated from at least 13 otherpatients at this hospital (unpublished data) and has been sporadicallyisolated in other New York City hospitals. However, althoughthis is a common RFLP pattern in this region, it is differentfrom the patterns of multidrug-resistant isolates from other,recently analyzed outbreaks of multidrug-resistant tuberculosis(Crawford JT: personal communication).
Figure 3. RFLP Patterns of the Initial (A) and Final (B) Isolates from Five Patients Whose Cultures Became Positive for Multidrug-Resistant Tuberculosis during or after Therapy for a Drug-Sensitive Isolate.
The serial RFLP patterns show dramatic changes, indicating exogenous reinfection with a multidrug-resistant strain. The apparent reinfection of Patient 13 was due to the artifactual acquisition of a new strain as a result of cross-contamination in the laboratory. The reinfecting multidrug-resistant organisms (B lanes) are identical, indicating probable recent infection from a common source. The last two lanes contain negative (M. avium complex) and positive (M. tuberculosis strain H37Rv) control DNA.
All five of the patients whose cultures grew this multidrug-resistantstrain were treated initially with standard therapy for tuberculosisand showed appropriate clinical improvement (including negativemycobacterial cultures) before the cultures became positivewith the multidrug-resistant strain. In four of these five patients(Patients 14, 15, 16, and 17), isolation of the multidrug-resistantstrain was associated with clinical and microbiologic deterioration.The clinical course of these four patients is depicted in Figure 4.Multiple cultures from each of these patients grew the multidrug-resistantstrain of M. tuberculosis shown in Figure 3. Two weeks afterbeing discharged from the hospital after treatment for Pneumocystiscarinii pneumonia, Patient 14 had new pulmonary symptoms inassociation with the appearance of the multidrug-resistant strainin his sputum; at the time he was still receiving isoniazidand rifampin for the initial, drug-sensitive strain. Patient15 was treated as an inpatient for three weeks and then as anoutpatient for six additional weeks for his drug-sensitive strainbefore he discontinued therapy. His cultures became positivefor the multidrug-resistant strain nine weeks after he was dischargedfrom the hospital and only three weeks after he discontinuedtherapy. A sputum culture obtained from Patient 16 on the dayantituberculous agents were discontinued for the initial infectiongrew the multidrug-resistant strain of M. tuberculosis. He hadpersistent symptoms and an additional 15 positive cultures overthe ensuing nine-month period. Patient 17 was readmitted withmultidrug-resistant tuberculosis 10 weeks after having beendischarged from the hospital after treatment for P. cariniipneumonia.
Figure 4. Clinical Course of the Four Patients with the Acquired Immunodeficiency Syndrome Who Were Exogenously Reinfected with Multidrug-Resistant Tuberculosis.
The chart spans the time from the diagnosis of tuberculosis until death for Patients 14, 15, and 17. Patient 16 died six months after the last contact shown. The large, solidly outlined boxes represent periods of in-hospital therapy and indicate the chief reasons for the hospitalizations: tuberculosis (TB) or P. carinii pneumonia (PCP). The triangles represent outpatient visits. The circles indicate negative cultures for M. tuberculosis, and the boxes positive cultures. The large dashed boxes indicate the duration of therapies (those shown are limited to the antituberculous agents administered). I denotes isoniazid, R rifampin, E ethambutol, P pyrazinamide, and S streptomycin.
In one of the five patients in whom multidrug-resistant tuberculosishad apparently developed during therapy for drug-sensitive tuberculosis(Patient 13), the isolation of the multidrug-resistant strainmay not have reflected the onset of a new clinical episode,but rather may have been due to the contamination of a sterileculture during the processing of the patient's specimen in thelaboratory. This patient had improved clinically with initialantimicrobial therapy and had multiple negative sputum cultures.Then, unexpectedly and without new clinical findings, he wasfound to have the multidrug-resistant strain of M. tuberculosisin one of numerous, otherwise negative sputum cultures. He continuedto be clinically well despite only having received antimicrobialagents to which the newly isolated organism was resistant. Areview of the mycobacteriology-laboratory records showed thata sputum specimen from another patient with the multidrug-resistantstrain of M. tuberculosis was processed the same day as thespecimen from Patient 13 (data not shown). Thus, cross-contaminationhad probably occurred in the laboratory, a problem that hasbeen previously documented with phage typing26 and has beenproved to have occurred on several occasions during the RFLP-basedinvestigations (unpublished data).
Discussion
The resurgence of tuberculosis in the United States has beenaccompanied by alarming outbreaks of the disease caused by organismsresistant to multiple antituberculous drugs. The organisms isolatedfrom patients in these outbreaks have generally been resistantto both isoniazid and rifampin, the most effective antituberculousdrugs available3,4,5,7,8,9,10,11. A large proportion of thesepatients have been infected with HIV, and the case fatalityrate has been extremely high10. The multidrug-resistant organismshave also been transmitted to persons without HIV infectionin health care facilities11. Together with the lack of effectivedrugs for second-line treatment and methods of chemoprophylaxis,the transmission of multidrug-resistant strains of M. tuberculosismay be creating a substantial reservoir of latently infectedpeople that will result in clinical multidrug-resistant tuberculosisfor many years to come. Thus, there is an urgent need to understandthe means by which this disease develops so that appropriatepreventive strategies can be devised and implemented.
It is currently assumed, on the basis of studies conducted inthe pre-HIV era, that drug resistance in tuberculosis developsby one of two mechanisms. Acquired drug resistance developsduring treatment for drug-sensitive tuberculosis with regimensthat are poorly conceived or poorly complied with, allowingthe emergence of naturally occurring, drug-resistant mutants.Resistant organisms from affected patients may subsequentlyinfect other people who have not been previously infected withM. tuberculosis, resulting in primary drug resistance13. Inthe current study, the use of RFLP analysis confirmed the developmentof acquired drug resistance in Patients 7 through 12. More importantly,however, it demonstrated through the RFLP analysis of isolatesfrom Patients 14 through 17 that drug-resistant tuberculosiscan develop by a third mechanism -- namely, exogenous reinfectionwith a new multidrug-resistant strain of M. tuberculosis duringor after therapy for drug-sensitive tuberculosis.
The six patients in this study (Patients 7 through 12) whoseoriginal strains became resistant to antimicrobial agents duringtreatment had persistently positive cultures consisting of thesame strain of M. tuberculosis with which they were initiallyinfected (Figure 2). This demonstrated that their original strainshad acquired drug resistance as classically defined. The developmentof acquired drug resistance can be prevented by ensuring thatall patients comply with appropriate multidrug regimens.
In contrast, the dramatic change in the RFLP patterns of isolatesfrom four patients (Patients 14, 15, 16, and 17) indicates thatthe multidrug-resistant strain isolated late in the course ofinfection in these patients was different from the strains thatinitially caused their tuberculosis. The isolation of a newmultidrug-resistant strain from these patients indicates exogenousreinfection after successful eradication of the initial strain.In each of these cases the multidrug-resistant strain was isolatedon multiple occasions during clinical episodes of active tuberculosis,so these patients had authentic infections with this strain,not artifactual infections due to cross-contamination of negativecultures in the laboratory.
The possibility that persons previously infected with M. tuberculosiscan be exogenously reinfected has been debated for decades27,28,29.However, it was thought to occur rarely because of the immunityconferred by the initial infection. On the few occasions inwhich exogenous reinfection has been documented, it has involvedonly selected populations -- for example, alcoholic residentsof a homeless shelter1. The four HIV-infected patients in thisreport (Patients 14, 15, 16, and 17) who were documented byRFLP analysis to have had a new infection with a multidrug-resistantstrain are likely to have been reinfected because they werereexposed to M. tuberculosis and had not acquired protectiveimmunity to the bacteria during their original infection. Thislack of acquired immunity to M. tuberculosis, which permittedreinfection with a multidrug-resistant strain, presumably wouldalso predispose HIV-infected persons to reinfection with drug-sensitiveorganisms. If so, exogenous reinfection might lead to secondepisodes of tuberculosis among substantial numbers of HIV-infectedpersons. Whether normal hosts can also be exogenously reinfected,and if so, how frequently, has not been determined.
The observation that HIV-infected patients with treated or curedtuberculosis might have subsequent episodes of tuberculosisas a result of exogenous reinfection with M. tuberculosis complicatesthe evaluation of clinical trials of chemotherapeutic and chemoprophylacticregimens. Currently, relapses after therapy are assumed to resultfrom inadequacies in the regimen's efficacy or in patient compliance.However, if exogenous reinfection is found to be common, relapsemay reflect the reinfection of persons whose initial therapywas completely adequate. RFLP analysis on the initial isolatesand those obtained during relapse can detect exogenous reinfection.Similarly, patients with advanced HIV infection who have completedeffective chemoprophylactic regimens may remain susceptibleto reinfection that would appear to result from failure of chemoprophylaxis.
The lack of protective immunity to M. tuberculosis after therapyin HIV-infected patients also complicates efforts to controlthe disease. Persons who have been infected previously withM. tuberculosis are assumed to be resistant to reinfection,and as such they are neither specifically instructed to avoidfurther exposure nor reevaluated if such exposure occurs. However,the apparent susceptibility of HIV-infected patients to exogenousreinfection suggests that those who have a history of tuberculosisor known tuberculin reactivity need to be evaluated for thepossible development of a new episode of tuberculosis aftercontact with someone whose disease is infectious, as has beenrecommended by the Centers for Disease Control and Prevention30.Open tuberculosis units, which are maintained in only a fewAmerican hospitals but which are common in developing countries,may place immunocompromised patients at considerable risk forreinfection.
It is not possible to infer from this study the frequency withwhich patients are reinfected with M. tuberculosis. Future studiesare needed to define the frequency, settings, and specific riskfactors for exogenous reinfection with M. tuberculosis. If futurestudies demonstrate that reinfection is common in this patientpopulation, a fundamental change in the emphasis of effortsto control the disease may be necessary. The occurrence of persistent,exquisite susceptibility of HIV-infected patients to M. tuberculosiswould mandate a shift in focus from the current, two-prongedapproach of identifying and treating persons with latent infectionand active disease31 to include a third prong, the identificationand elimination of circumstances that foster the transmissionof M. tuberculosis.
Supported by the Howard Hughes Medical Institute, the CaliforniaStatewide AIDS Task Force, and Public Health Service grants(AI07089-11 and AI27762-03).
We are indebted to Janice Lopez of the Microbial Diseases Laboratory,California Department of Health Services, for performing susceptibilitytests according to the proportion method.
Source Information
From the Department of Medicine, Division of Infectious Diseases and Geographic Medicine, and the Howard Hughes Medical Institute (P.M.S., S.P.S., G.K.S.) and the Department of Medicine, Centers for AIDS Research (R.W.S.), Stanford University, Stanford, Calif.; the Medical Service, San Francisco General Hospital and the University of California, San Francisco (P.C.H.); the Department of Medicine, Division of Infectious Diseases (M.J.M.), and the Department of Pathology (M.F.S.), State University of New York Health Sciences Center at Brooklyn, Brooklyn; and the California Department of Health Services Microbial Diseases Laboratory, Berkeley (E.D.).
Address reprint requests to Dr. Small at the Howard Hughes Medical Institute, Rm. 251, Beckman Ctr., Stanford, CA 94306.
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