Exploiting ecology in drug pulse sequences in favour of population reduction

Abstract

A deterministic population dynamics model involving birth and death for a two-species system, comprising a wild-type and more resistant species competing via logistic growth, is subjected to two distinct stress environments designed to mimic those that would typically be induced by temporal variation in the concentration of a drug (antibiotic or chemotherapeutic) as it permeates through the population and is progressively degraded. Different treatment regimes, involving single or periodical doses, are evaluated in terms of the minimal population size (a measure of the extinction probability), and the population composition (a measure of the selection pressure for resistance or tolerance during the treatment). We show that there exist timescales over which the low-stress regime is as effective as the high-stress regime, due to the competition between the two species. For multiple periodic treatments, competition can ensure that the minimal population size is attained during the first pulse when the high-stress regime is short, which implies that a single short pulse can be more effective than a more protracted regime. Our results suggest that when the duration of the high-stress environment is restricted, a treatment with one or multiple shorter pulses can produce better outcomes than a single long treatment. If ecological competition is to be exploited for treatments, it is crucial to determine these timescales, and estimate for the minimal population threshold that suffices for extinction. These parameters can be quantified by experiment.

Quantifying the impact of a periodic presence of antimicrobial on resistance evolution in a homogeneous microbial population of fixed size

“…Our approach is complementary to previous studies providing a detailed modeling of specific treatments [33,34,20,35,36,37,38]. Indeed, the majority of them [33,39,34,20,35,36,40] neglect stochastic effects, while they can have a crucial evolutionary impact [41,25,42]. The deterministic approach is appropriate if the number N of competing microbes satisfies N µ 1 1, where µ 1 is the mutation rate [43,41].…”

Antibiotics can be used to contain drug-resistant bacteria by maintaining sufficiently large sensitive populations

“…In fact, recent work suggests that aggressive treatment strategies can hasten the emergence and spread of resistance [30][31][32][33][34][35][36][37][38][39][40][41]. In addition, numerous studies, both experimental and theoretical, provide evidence that less aggressive treatment strategies may be called for under some conditions [42][43][44][45][46][47][48][49][50], while several clinical trials have also demonstrated advantages of lower dose therapies [50][51][52][53][54][55][56][57][58]. The most frequently cited advantages of less aggressive therapies are reduced off-target selection for resistance and fewer adverse effects for the patient.…”

Resist or perish: fate of a microbial population subjected to a periodic presence of antimicrobial

“…Using 387 a general stochastic model which includes variations of both composition and size of 388 the microbial population, we have shed light on the impact of periodic alternations of 389 presence and absence of antimicrobial on the probability that resistance evolves de novo 390 and rescues a microbial population from extinction. The majority of previous studies of 391 periodic antimicrobial treatments [10,[50][51][52][53][54][55] neglect stochastic effects, while they can 392 have a crucial evolutionary impact [13,15], especially on population extinction [18,20]. 393 In addition, established microbial populations are structured, even within a single 394 patient [56], and competition is local, which decreases their effective size, thus making 395 stochasticity relevant.…”

“…This work opens many possible theoretical extensions. In particular, it will be very 431 interesting to include effects such as antibiotic tolerance, which tend to precede resis-432 tance under intermittent antibiotic exposure [4], as well as to consider the possibility of 433 concentrations above the mutant prevention concentration, such that resistant microbes 434 are also affected by the drug [4,54]. Another exciting extension would be to incorporate 435 spatial structure [60][61][62] and environment heterogeneity, in particular drug concentration 436 gradients.…”