Undetected Multidrug-Resistant Tuberculosis Amplified by First-line Therapy in Mixed Infection

Abstract

Infections with >1 Mycobacterium tuberculosis strain(s) are underrecognized. We show, in vitro and in vivo, how first-line treatment conferred a competitive growth advantage to amplify a multidrug-resistant M. tuberculosis strain in a patient with mixed infection. Diagnostic techniques that identify mixed tubercle bacilli populations are needed to curb the spread of multidrug resistance.

Mixed Mycobacterium tuberculosis Complex Infections and False-Negative Results for Rifampin Resistance by GeneXpert MTB/RIF Are Associated with Poor Clinical Outcomes

“…In addition, our assessments of phenotypic and genotypic resistance were performed on separate (individual) samples as opposed to split single samples, making it possible that the strain diversity and composition of the cultured samples (which eventually had phenotypic DST) were different than those tested by the Xpert assay. Further, our ability to detect mixed MTBC infections may have been compromised by not having tested unprocessed sputum samples for the presence of resistant strains (directly in the sputum sample), given that cultures can alter the strain composition present in the initial sample (8,38,39).…”

Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens

“…In simple terms, the emergence of multiple resistance is much more likely from a singly resistant precursor than from a pan-susceptible precursor; the first resistance mutation may form a "slippery slope" facilitating the emergence and selection of further resistance mutations. In this mechanism, under multidrug therapy, the singly resistant state is unstable, and those strains will be replaced by strains that have acquired mutations for additional drug resistance, leading to an excess of MDR (61,62) (Fig. 1D).…”

“…One problem that has been observed in treatment of tuberculosis is the existence of mixed infections with a subpopulation of resistant organisms, which may be undetected when treatment is initiated but is rapidly selected by first-line treatment tailored to the assumed full susceptibility of the infecting strain (61,62).…”

“…Evidence for the importance of this mechanism would include a high frequency of MDR (but not singly resistant strains) developing during multidrug therapy of infections for which the drug susceptibility of the initial infection was unknown or mismeasured, perhaps due to a mixed infection or a reinfection (61,62). If genetic mechanisms of drug resistance are known, sequences of bacteria isolated at different time points from the same patients could be used to test this hypothesis.…”

“…Of course, if the singly resistant infection were known at the time of treatment initiation, it would be inappropriate to treat it as if it were pan-susceptible. Thus, to know about this problem (in a timely fashion) is to try to prevent it, and only retrospective investigations are likely to find evidence for this problem (61,62).…”