Clin Infect mycobacteriais. 2001 Braden e42 7

e42 • CID 2001:33 (15 September) • Braden et al.

M A J O R A R T I C L E

Simultaneous Infection with Multiple Strainsof Mycobacterium tuberculosis

Christopher R. Braden,1,a Glenn P. Morlock,1 Charles L. Woodley,1 Kammy R. Johnson,2,3,b A. Craig Colombel,3

M. Donald Cave,4 Zhenhua Yang,4,d Sarah E. Valway,1 Ida M. Onorato,1,c and Jack T. Crawford1

1Division of Tuberculosis Elimination, National Center for Human Immunodeficiency Virus, Sexually Transmitted Disease (STD), and Tuberculosis(TB) Prevention, and Division of Acquired Immune Deficiency Syndrome, STD, and TB Laboratory Research, National Center for InfectiousDiseases, Centers for Disease Control and Prevention (CDC); and 2Epidemic Intelligence Service, Division of Applied Public Health Training, CDC,Atlanta; 3Washington State Department of Health, Olympia and Seattle; and 4Central Arkansas Veterans Health Care System, Little Rock

Drug-susceptible and drug-resistant isolates of Mycobacterium tuberculosis were recovered from 2 patients, 1

with isoniazid-resistant tuberculosis (patient 1) and another with multidrug-resistant tuberculosis (patient 2).

An investigation included patient interviews, record reviews, and genotyping of isolates. Both patients worked

in a medical-waste processing plant. Transmission from waste was responsible for at least the multidrug-

resistant infection. We found no evidence that specimens were switched or that cross-contamination of cultures

occurred. For patient 1, susceptible and isoniazid-resistant isolates, collected 15 days apart, had 21 and 19

restriction fragments containing IS6110, 18 of which were common to both. For patient 2, a single isolate

contained both drug-susceptible and multidrug-resistant colonies, demonstrating 10 and 11 different restriction

fragments, respectively. These observations indicate that simultaneous infections with multiple strains of M.

tuberculosis occur in immunocompetent hosts and may be responsible for conflicting drug-susceptibilityresults,

though the circumstances of infections in these cases may have been unusual.

The prevailing model for tuberculosis pathogenesis is

based on exposure of a susceptible person to an “in-

fectious quantum,” an undefined infectious dose of ba-

cilli dispersed into the air by an infectious source and

inhaled into alveoli of the new host [1]. Once infected,

the host is considered to have relative immunity to

additional M. tuberculosis infections; thus, if either pri-

Received 7 November 2000; revised 22 February 2001; electronically published6 August 2001.

Financial support: Centers for Diseases Control and Prevention and NationalTuberculosis Genotyping and Surveillance Network (cooperative agreement).

Current affiliations: aDivision of Bacterial and Mycotic Diseases (C.R.B.), bDivisionof Environmental Hazards and Health Effects (K.R.J.), and cDivision of HIV/AIDSPrevention (I.M.O.), CDC, Atlanta; and dEpidemiology Department, School of PublicHealth, University of Michigan at Ann Arbor, Michigan (Z.Y.).

Reprints or correspondence: Dr. Christopher R. Braden, Centers for DiseaseControl and Prevention, Mailstop A-38, 1600 Clifton Rd., Atlanta, GA 30333([email protected]). Alternate corresponding author: Dr. Jack T. Crawford, Centers forDisease Control and Prevention, Mailstop F-08, 1600 Clifton Rd., Atlanta, GA 30333([email protected]).

Clinical Infectious Diseases 2001; 33:e42–7� 2001 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2001/3306-00E1$03.00

mary or reactivation tuberculosis disease develops, the

original infecting single strain of M. tuberculosis is con-

sidered responsible for tuberculosis disease at all ana-

tomic sites and any potential relapse of disease after

treatment. The degree of immunity to a second M.

tuberculosis infection is not known, however, and si-

multaneous infection by multiple strains or reinfection

by a second M. tuberculosis strain may be responsible

for a portion of tuberculosis cases.

To what extent simultaneous infections or reinfection

with M. tuberculosis is responsible for primary, reacti-

vation, or relapse tuberculosis has been the subject of

controversy. One leading tuberculosis epidemiologist

has argued convincingly that disease due to reinfection

is a relatively rare event [2], and another argued that

in areas or times with a very high risk of infection,

reinfection plays a predominant part in the pathogen-

esis of tuberculosis in adults [3]. A recent study from

an area of South Africa where tuberculosis is endemic

revealed that 12 of 16 patients had exogenous reinfec-

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M. tuberculosis Multistrain Infection • CID 2001:33 (15 September) • e43

Figure 1. Time line of onset of cough, treatment-start dates, andspecimen collections for patients 1 and 2.

tion that was responsible for relapse of tuberculosis after cu-

rative treatment [4]. More recently, this topic has taken on

greater relevance in the era of HIV infection because of the

potential loss of immune protection against reinfection [5].

Infection with multiple M. tuberculosis strains has clinical

and programmatic implications. Current recommendations for

treatment of latent tuberculosis infection [6] and use of BCG

vaccine are predicated on a solitary strain theory, whereby ben-

eficial effects of a course of therapy for latent tuberculosis in-

fection or vaccination last for life [7].

In this report, we describe 2 HIV-negative patients with tu-

berculosis caused by multiple M. tuberculosis strains. One pa-

tient had 2 related subpopulations of an M. tuberculosis strain

in 2 clinical specimens collected 15 days apart: 1 isoniazid-

susceptible, the other isoniazid-resistant. The second patient

had 2 distinct strains of M. tuberculosis in 1 clinical specimen:

1 multidrug-resistant (MDR) and the other fully susceptible.

Both patients worked in a medical-waste treatment facility at

the time of the diagnoses. In addition to other types of medical

and laboratory waste, this facility received and processed culture

material that had not been decontaminated by autoclave or

other microbicidal processes. Results of epidemiological, en-

vironmental, and laboratory investigations strongly suggest that

MDR tuberculosis in the second patient was due to exposures

to infectious aerosols in the workplace [8]. The sources of the

other M. tuberculosis infections in these 2 patients could not

be determined.

METHODS

To determine potential sources of tuberculosis infection, the

patients were interviewed and their medical records were re-

viewed. In order to investigate whether mislabeling or labo-

ratory cross-contamination could be responsible for the un-

expected mycobacteriology results, all hospitals, clinics, and

clinical laboratories involved in the care of the patients and in

mycobacterial testing of specimens were identified from a re-

view of medical records and interviews with patients and hos-

pital and laboratory staff members. Hospital infection-control

records were reviewed to identify other tuberculosis patients in

the facilities at the same time as the 2 case-patients, and clinical

laboratory mycobacteriology procedures and records were re-

viewed to identify potential sources of contamination in clinical

laboratories. Potential sources of contamination included any

acid-fast bacilli (AFB) culture–positive specimen or isolate re-

ceived in the laboratory within 2 weeks before or after the date

of receipt of the specimen in question.

Multiple isolates from each case and any potential source

isolate for laboratory contamination underwent DNA finger-

print analysis by IS6110 restriction fragment length polymor-

phism (RFLP), with use of standard methods [9]. Drug sus-

ceptibility testing was performed with both the BACTEC

(Becton Dickinson) and agar proportion methods. Gene mu-

tations responsible for antituberculosis drug resistance were

identified by automated sequencing of PCR products.

RESULTS

Patient descriptions. Patient 1 was a 52-year-old white non-

Hispanic woman who was born in West Virginia, moved to

Washington State at age 14, and lived in the same county for

∼20 years. She had no history of chronic illness, foreign travel,

substance abuse, incarceration, stays in long-term-care facilities,

employment as a health care worker, or BCG vaccination. She

had no known exposure to M. tuberculosis and had never un-

dergone a tuberculin skin test. In 1992, she began working at

a medical-waste treatment facility. She developed a cough in

December 1996 and presented with fatigue and shortness of

breath in March 1997 (figure 1). Chest radiographs revealed

right apical lung densities, and by late April 1997, right upper

and left lower lobe infiltrates with cavities were present. Three

sputum samples collected over 5 days were AFB smear–positive

and yielded M. tuberculosis susceptible to all drugs tested (table

1).

The next sputum specimen, collected 15 days later, yielded

M. tuberculosis that was resistant to isoniazid. All of the sub-

sequent 6 specimens collected over the ensuing 32 days were

culture-positive, with isolates resistant to isoniazid. Sputum

specimens thereafter were culture-negative. The patient was

treated with isoniazid, rifampin, pyrazinamide, and ethambu-

tol, beginning on the fourth day of initial sputum collection

and 16 days before collection of the sputum specimen yielding

the isoniazid-resistant isolate. Isoniazid was withdrawn after sus-

ceptibility test results documenting isoniazid resistance were con-

firmed. She completed 1 year of therapy without complications.

Patient 2 was a previously healthy 33-year-old white non-

Hispanic man who was born in Washington State and had lived



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Table 1. Percentage of resistance, to antibiotics, as determinedby the agar proportions method, of M. tuberculosis isolates fromsputum samples.

Drug (mg/mL)

Percentage of isolate resistance,per sample-collection daya

Patient 1 Patient 2

1 5 20 29 1 2 41 52

INH (0.2) 0 0 25 50 100 100 0 100

INH (1.0) 0 0 0 0 100 100 0 100

RIF (1.0) 0 0 0 0 100 100 0 100

EMB (10.0) 0 0 0 0 0 0 0 0

STREP (2.0) 0 0 0 0 50 50 0 50

PZA (25) 0 0 0 0 0 0 0 0

NOTE. INH, isoniazid; RIF, rifampin; EMB, ethambutol; STREP, strepto-mycin; PZA, pyrazinamide.

a First specimen collection day and days thereafter; not all subsequent spec-imens are included.

in the same county since 1990. He denied foreign travel but

had been in a residential drug treatment unit for several weeks

in 1988 and 1989. He had not received BCG vaccination or

undergone tuberculin skin tests. He began working at the same

medical-waste treatment facility in April 1995 and was exposed

to patient 1 during her infectious period. He had no other

known tuberculosis exposures. He had a cough that began in

July 1997 (figure 1). A chest radiograph in late August revealed

bilateral apical densities, and therapy with isoniazid, rifampin,

ethambutol, and pyrazinamide was begun. Two sputum spec-

imens were AFB smear–negative but yielded M. tuberculosis

resistant to isoniazid, rifampin, and streptomycin (table 1).

Because of these results, therapy was changed to administration

of ethambutol, levofloxacin, para-aminosalicylic acid, and

cycloserine.

The next culture-positive sputum specimen, collected 41 days

after the first specimen, yielded an isolate susceptible to all

drugs tested. However, specimens collected at 52 and 56 days

yielded isolates resistant to isoniazid, rifampin, and strepto-

mycin. He completed 2 years of therapy and remained clinically

well.

Investigation of mislabeling or laboratory cross-contami-

nation of specimens. Between these 2 patients, initial care

was received at 1 clinic, 2 hospitals, and 4 clinical laboratories.

Records and procedures at all facilities were reviewed. Myco-

bacteriological testing included fluorescence acid-fast stains and

cultures on Lowenstein-Jensen medium, on 7H10 or 7H11 agar,

and in the BACTEC TB-460 system. Identification was accom-

plished by DNA probe and biochemical testing, and suscepti-

bility testing was done with the BACTEC and 7H11 agar

plate–proportion methods.

For patient 1, the identification of an isoniazid-resistant iso-

late within 15 days of the collection of a specimen yielding a

fully susceptible isolate, while the patient was receiving 4 an-

tituberculosis drugs, prompted an investigation of both spec-

imens to identify mislabeling or laboratory cross-contamina-

tion. Hospital and clinic records failed to identify another

tuberculosis patient receiving care at the same time whose spec-

imen may have been mislabeled as being from patient 1. Lab-

oratory records revealed no potential source of cross-contam-

ination in laboratories. Subsequent retesting of the isolates from

patient 1 confirmed that the first 2 isolates were isoniazid-

susceptible and that multiple subsequent isolates were isonia-

zid-resistant.

For patient 2, the first MDR isolate was suspected of being

a contaminant because the source of infection was thought to

be patient 1 and because the resistance pattern identified is rare

in the area. He received care at 1 clinic, and his specimens were

tested at 2 laboratories. There was no other patient with tu-

berculosis with whom a specimen could have been switched.

A possible source of laboratory cross-contamination was iden-

tified: an M. avium complex isolate resistant to isoniazid, ri-

fampin, and streptomycin, among other drugs. However, DNA

probes specific for M. avium complex (Gen-Probe) did not

hybridize to nucleic acid of AFB in the original culture bottle

or in drug-susceptibility culture bottles for the specimen from

patient 2. A high degree of hybridization was observed for DNA

probes for M. tuberculosis complex in all these bottles. We con-

cluded that contamination with the M. avium complex isolate

was not responsible for the observed resistance pattern. No

other potential sources of contamination were identified in

laboratories.

Three subsequent isolates from patient 2 with the same re-

sistance pattern confirmed the initial finding. Another inves-

tigation was performed as a result of identifying the third isolate

from patient 2, which was collected 41 days after the first and

was susceptible to all drugs. Another fully susceptible isolate

from the state public health laboratory (where susceptibility

testing was performed) was identified as a potential source of

contamination; however, this isolate had a DNA fingerprint

pattern distinct from that of the susceptible isolate from patient

2.

DNA fingerprint analysis. DNA fingerprint patterns of

isolates from patient 1 and patient 2 were distinct from one

another (figures 2 and 3). DNA fingerprint patterns of se-

quential isolates from patient 1 revealed a significant change

in pattern coincident with identification of isoniazid resistance.

The 2 fully susceptible isolates had identical DNA fingerprint

patterns with 21 hybridizing fragments; 3 subsequent isoniazid-

resistant isolates had identical patterns with 19 hybridizing frag-

ments, 18 of which were common to the patterns of the sus-

ceptible isolates (figure 2).

DNA fingerprint analysis of 4 sequential isolates from patient

2 yielded 3 distinct patterns (figure 3). The first isolate had a



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Figure 2. DNA fingerprint analyses of isolates from patient 1. S:molecular weight standard; lane 1: isoniazid-resistant isolate with 19fragments; lane 2: isoniazid-susceptible isolate with 21 fragments. Arrowsindicate the difference of fragments in lane 2 compared to lane 1.

Figure 3. DNA fingerprint analyses of isolates from patient 2. S:molecular weight standard; lanes 1–9: fingerprints of individual coloniesfrom second isolate, showing 2 separate strains (lanes 1–5, 10 fragments,drug-susceptible; lanes 6–9, 11 fragments, multidrug-resistant); lane 10:fingerprint of mixed DNA from individual colonies from second isolatewith 21-band pattern; lane 11: fingerprint of whole second isolate withsame 21-band pattern; lane 12: fingerprint of first isolate with 11-bandpattern of multidrug-resistant strain.

DNA fingerprint pattern with 11 hybridizing fragments, the

second isolate had a pattern with 21 hybridizing fragments, and

the third isolate, which was fully susceptible, had a fingerprint

pattern with 10 fragments. Subsequent MDR isolates had the

11-fragment pattern identical to that of the first isolate. The

10- and 11-fragment patterns shared no fragment sizes in com-

mon, but taken together, they accounted for all fragments in

the 21-fragment pattern (figure 3).

The second isolate with a 21-fragment pattern was cultured

on solid media, and 10 individual colonies were picked from

the plate and grown separately for DNA fingerprint analysis.

One of these colony cultures was lost to contamination. The

remaining 9 colony cultures revealed 4 with the 11-fragment

pattern and 5 with the 10-fragment pattern (figure 3). Com-

bining DNA from colonies with these 2 patterns yielded a fin-

gerprint pattern identical to the 21-fragment pattern seen for

this isolate as a whole.

Resistance mutations. To determine if transposition of

insertion sequence IS6110 was causally associated with devel-

opment of isoniazid resistance in the isolate from patient 1, we

identified the mutation responsible for isoniazid resistance in

her third isolate (table 1). An inhA mutation CrT was iden-

tified in the presumed promoter region. For patient 2, the MDR

isolate had the common katG Ser315rThr mutation, the rarer

rpoB mutation Asp516rVal, and a silent (no amino acid

change) pncA mutation Ala38rAla.

DISCUSSION

We have identified 2 patients simultaneously infected with M.

tuberculosis isolates demonstrating distinct characteristics. For

patient 1, the isolates identified had different susceptibilities to

isoniazid and IS6110 RFLP patterns that differed by the ad-

dition or movement of 3 hybridizing fragments. Whether these

differences constitute different strains is a matter of judgement.

Since these 2 isolates were from the same patient and their

DNA fingerprint patterns exactly matched for 18 of at most 21

fragments, we considered them as subpopulations with the

same clonal origin. We do not believe that isoniazid resistance

developed in patient 1 from selective pressure of drug therapy.

Therapy with isoniazid, rifampin, ethambutol, and pyrazin-

amide was started 16 days prior to collection of the first iso-

niazid-resistant isolate, and the patient reportedly took all drugs



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prescribed and did well throughout her clinical course. How-

ever, she was not receiving directly observed therapy.

We do not believe that the unexpected susceptibility test

results were due to a switch in specimens or cross-contami-

nation of cultures in laboratories; no other samples to switch

or contaminate were identified, and multiple samples from this

patient eventually confirmed the findings. The mutation likely

responsible for isoniazid resistance was a point mutation, not

the transposition of IS6110 into an isoniazid-resistance gene.

Whether patient 1 was originally exposed and infected with

these 2 subpopulations or they diverged during development

of infection and disease within this patient is impossible to

determine.

For patient 2, we identified 2 distinct strains of M. tuberculosis

within the same specimen. Laboratory cross-contamination of

the culture was not identified as an explanation, and separate

sputum samples each yielded the different strains. Thus, in

some separate sputum samples, only one or the other of the 2

strains was detected, whereas in one sample, the 2 strains were

detected in approximately equal proportions. An hypothesis to

account for this observation is that the 2 strains inhabited

separate anatomic sites in the lung. These sites then contributed

to sputum samples separately or in combination over time. As

for patient 1, it is impossible to determine if patient 2 was

exposed and infected simultaneously or in succession with the

2 different strains.

Previous reports have documented infections with multiple

M. tuberculosis strains. Using phage typing, Bates et al. [10]

identified 3 patients in whom tubercle bacilli with different

phage types were isolated from different anatomic sites. In a

study of 233 isolates from Eskimo patients, 33 had “mixed”

phage types, 9 of which were determined to be major changes

involving as many as 7 phages and differences in drug suscep-

tibility [11]. Raleigh et al. [12] studied pretreatment and relapse

M. tuberculosis isolates from 26 patients; in 9 patients they

found a major change in phage type. In yet another study

involving an outbreak of tuberculosis in a shelter for homeless

persons in Boston, 25 patients shared the same strain, identified

by phage typing and resistance to isoniazid and streptomycin.

Seven of the 25 patients shared this strain, despite documen-

tation of tuberculosis infection or disease prior to their ex-

posure to the source case in the outbreak, a finding suggesting

they were reinfected by the outbreak strain [13].

The advent of DNA fingerprint analysis of M. tuberculosis

has vastly improved the ability to distinguish strains, and several

reports have identified different strains associated with devel-

opment of drug resistance or relapse of disease in both HIV-

infected and HIV-noninfected patients [5, 14–17]. Still, the

proportion of second-episode or relapse tuberculosis cases due

to reinfection is unknown, and therefore, the relative protection

offered by natural infection remains a mystery.

Given that reinfection may occur, the failings of immune

protection from BCG vaccination are understandable and have

important implications for the current efforts to develop new

and better vaccines. However, the determination of relative

immune protection by natural infection vis-a-vis reinfection is

theoretically complicated by simultaneous infection with mul-

tiple strains of M. tuberculosis, as implicated in the cases pre-

sented above. Multiple strains may infect simultaneously or

over a short period of time, escaping immune protection in a

immune-naıve host. Multiple episodes of tuberculosis or disease

affecting multiple sites in the body may then occur, owing to

some potential selective advantage of one strain over another,

such as antituberculosis drug resistance or a general propensity

to reactivate. Thus, multistrain infections may be responsible

for observations attributed to reinfection.

Infection with multiple M. tuberculosis strains may be very

difficult to detect. For instance, 1 or multiple strains may be

sequestered at a different anatomic location at the time of test-

ing and not be present in the sample provided, or the strains

may be such a small proportion of the entire bacillary popu-

lation of the sample that their identity is impossible to

determine.

In addition, the ability of laboratory testing to discriminate

mixed strains is very limited. The only routine clinical labo-

ratory test that has ability to discriminate among some M.

tuberculosis strains is drug-susceptibility testing, given that

strains involved have differing drug-susceptibility profiles to

first-line antituberculosis drugs. One may suspect multiple

strains if differing drug-susceptibility profiles are obtained for

clinical specimens from 2 different anatomic sites or from one

site over time. Drug-susceptibility testing cannot differentiate

mixed strains within a single sample unless individual colonies

from the isolate are tested.

DNA fingerprint analysis provides a much more discrimi-

nating tool, but the DNA fingerprint pattern for a sample con-

taining a mix of multiple strains would most likely represent

the predominant strain or a composite pattern for multiple

strains, as was seen with the 21-band pattern for patient 2. To

distinguish among multiple strains in a single sample, finger-

print analysis of individual colonies from the isolate would be

required, as shown in figure 2.

Both patients in this report worked in a medical-waste pro-

cessing facility where there was a potential for unprotected

exposure to aerosols of infectious wastes, including nondecon-

taminated M. tuberculosis cultures [8]. Though it is not possible

to determine definitively the source of all their infections, the

possibility exists that they were infected with multiple strains

via this unusual exposure. Therefore, our observations con-

cerning these 2 patients may be due to the unique epidemio-

logical circumstances of their workplace and may not represent



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risk for multiple-strain infections among tuberculosis patients

in general.

However, these observations and past experience with phage

typing and DNA fingerprinting would indicate that multiple-

strain infections may be responsible for conflicting drug-sus-

ceptibility results. Especially in areas where the incidence of

tuberculosis is high, exposures to multiple strains may occur.

When conflicting drug-susceptibility test results are observed,

accuracy of tests should be assessed first, along with the po-

tential exchange of patients’ samples and laboratory cross-con-

tamination of cultures, as is described in this investigation. If

the explanation is not found with these preliminary investi-

gations, then additional testing by means of DNA fingerprinting

may be sought to confirm infection with multiple strains.

Acknowledgments

We are indebted to Dona Osmond and the State of Wash-

ington Public Health Laboratory, for thoughtful analysis of clin-

ical laboratory results and the laboratory’s role as a central

repository for M. tuberculosis isolates in this study.

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