Exploring the collaboration between antibiotics and the immune response in the treatment of acute, self-limiting infections

Abstract

The successful treatment of bacterial infections is the product of a collaboration between antibiotics and the host's immune defenses. Nevertheless, in the design of antibiotic treatment regimens, few studies have explored the combined action of antibiotics and the immune response to clearing infections. Here, we use mathematical models to examine the collective contribution of antibiotics and the immune response to the treatment of acute, self-limiting bacterial infections. Our models incorporate the pharmacokinetics and pharmacodynamics of the antibiotics, the innate and adaptive immune responses, and the population and evolutionary dynamics of the target bacteria. We consider two extremes for the antibiotic-immune relationship: one in which the efficacy of the immune response in clearing infections is directly proportional to the density of the pathogen; the other in which its action is largely independent of this density. We explore the effect of antibiotic dose, dosing frequency, and term of treatment on the time before clearance of the infection and the likelihood of antibiotic-resistant bacteria emerging and ascending. Our results suggest that, under most conditions, high dose, full-term therapy is more effective than more moderate dosing in promoting the clearance of the infection and decreasing the likelihood of emergence of antibiotic resistance. Our results also indicate that the clinical and evolutionary benefits of increasing antibiotic dose are not indefinite. We discuss the current status of data in support of and in opposition to the predictions of this study, consider those elements that require additional testing, and suggest how they can be tested.

Keywords: immunology; population dynamics.

Fig. 1.

Schematic diagram showing the mathematical model of the population and evolutionary dynamics of bacteria with host immune responses and antibiotic treatment.

Fig. 2.

Bacterial population dynamics of a self-limited infection with immune action and antibiotic treatment. Changes in the densities of the bacteria (B₁, antibiotic-susceptible, undergoing active growth; B₂, intermediate-resistant, undergoing active growth; BP₁, refuge bacteria), resources (R), and immune cells (P, innate immune cells; I, adaptive immune cells) under the following conditions: (A) pathogen density-dependent (PDD) innate and adaptive immune action, (B) pathogen density-independent (PDI) innate and adaptive immune action, (C) PDD innate and adaptive immune action with antibiotic treatment (dose, 2 μg/mL), and (D) PDI innate and adaptive immune action with antibiotic treatment (dose, 2 μg/mL). The parameter values used for the simulations are listed in Table S1.

Fig. 3.

The effects of different treatment regimens and pathogen density-dependent (PDD) immune dynamics on the average time to clearance of the infection (left column) and fraction of 100 simulations in which bacteria with intermediate levels of resistance emerge (right column). Means and SEs for 10 independent simulations (left column) and means and SEs for 10 independent simulations each with 100 runs (right column). (A and B) Single daily doses of different concentrations of the antibiotic; (C and D) 20 µg/mL of the antibiotic administered at different frequencies ranging from one dose of 20 µg/mL to eight doses of 2.5 µg/mL per day; (E and F) different density thresholds for the cessation of antibiotic dosing in adaptive treatment regimens, standard treatment of 10 µg/mL per day.

Fig. 4.

The effects of different treatment regimens and pathogen density-independent (PDI) immune dynamics on the average time to clearance of the bacteria (left column) and fraction of simulations in which bacteria with intermediate levels of resistance emerge (right column). Means and SEs for 10 independent simulations (left column) and 10 independent simulations each with 100 runs (right column). (A and B) Single daily doses of different concentrations of the antibiotic; (C and D) 20 µg/mL of the antibiotic administered at different frequencies ranging from one dose of 20 µg/mL to eight doses of 2.5 µg/mL per day; (E and F) different density thresholds for the cessation of antibiotic dosing in adaptive treatment regimens, standard treatment of 10 µg/mL per day.

Fig. 5.

Bacterial population dynamics of a self-limited infection with preexisting high-level resistant bacteria and PDD immune dynamics. Changes in the densities of the bacteria (NB₁ = B₁ + BP₁, NB₂ = B₂ + BP₂, NB₃ = B₃ + BP₃) under the following conditions: (A) dose of 5 μg/mL; (B) dose of 20 μg/mL; (C) dose of 20 μg/mL, adaptive treatment threshold of 10⁵ bacteria per mL. The parameter values used for the simulations are listed in Table S1.