Microbial Persistence

Abstract

In the preceding paper (1) evidence was presented that the phenomenon whereby large populations of tubercle bacilli can be made to "disappear" from the tissues of mice is produced by an alteration of the bacilli to a sterile ~ state. I t was further shown: that the phenomenon is a specific one produced by the actions of two drugs, pyrazinamide and isoniazid; that it occurs in all or virtually all of the animals in an experimental group; and that once assumed, the sterile state endures for a period measurable in months. Whether the sterile bacilli are morphologically altered cannot be stated from the available evidence. The only indication of a host influence in maintaining the microbial sterility is the increased incidence of microbial revival when large daily doses of cortisone are given in the 3rd or 4th month after sterilization. The present paper is concerned with observations that serve to characterize more sharply this phenomenon of the sterilization of tubercle bacilli in vivo.

Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations

“…The first reported experimental generation of VBNC Mtb was in Mtb-infected mice that after combination chemotherapy with INH and PZA yielded no cfus in culture of their organs or even the whole carcass (45)(46)(47). This apparent microbiologic cure was proven false when about a third of identically treated mice that were reserved for observation eventually relapsed, and nearly all did so when immunosuppressed with corticosteroids (45)(46)(47) or when deficient in inducible nitric oxide synthase (48). Mtb colonies recovered from relapsed mice remained susceptible to INH and PZA (45).…”

Bovine tuberculosis as a model for human tuberculosis: advantages over small animal models

“…In humans, both M. tuberculosis and M. bovis [27] can give rise to a clinically latent form that can be reactivated decades after the initial exposure. It is not clear whether mycobacteria in the Cornell model, an antibiotics-induced model for latency in mice, go into a true dormant state [28,29]. After treatment, bacteria cannot be detected in these mice, but reappear after a certain amount of time.…”

“…So, even though cattle may be the species in which latency resembles human latency optimally, there is a long road to go before a bovine model of latent tuberculosis is available, for example for testing post exposure vaccines against latency antigens. Research aiming at the development of a bovine model of latent tuberculosis may include the use of mycobacteria that are attenuated in cattle, like M. tuberculosis [32,33], or experimental treatment of M. bovis-infected animals with antibiotics in a way that is comparable to the Cornell model in mice [28,29].…”

Experimental Study on the Relapse of Tuberculosis after the Termination of Antituberculous Chemotherapy Using Immunodeficient Nude Mice

“…Though the precise mechanism by which corticosteroid effects the relapse of tubercle bacilli is not fully elucidated yet, the present experiment suggests that acquired immunity might be slightly reduced with the use of corticosteroid in dd mice. Reports on the experimental efficacy of PZA on relapse are rare (16), although there are some experimental studies on PZA (7,(12)(13)(14). It is interesting to note that the addition of PZA to the chemotherapy regimen seems to prevent relapse to some extent even in nude mice.…”

“…Most antituberculous drugs are bacteristatic, and so it is easily understandable that tubercle bacilli are not killed and multiply again after stopping the use of drugs (11,13,14). Although RFP is bactericidal, a small number of tubercle bacilli in the phagosomes of macrophages can survive exposure to the drug.…”