Recent studies have shown that most of deaths in the 1918 influenza pandemic were caused by secondary bacterial infections, primarily pneumococcal pneumonia. Given the availability of antibiotics and pneumococcal vaccination, how will contemporary populations fare when they are next confronted with pandemic influenza due to a virus with the transmissibility and virulence of that of 1918? To address this question we use a mathematical model and computer simulations. Our model considers the epidemiology of both the influenza virus and pneumonia-causing bacteria and allows for co-infection by these two agents as well as antibiotic treatment, prophylaxis and pneumococcal vaccination. For our simulations we use influenza transmission and virulence parameters estimated from 1918 pandemic data. We explore the anticipated rates of secondary pneumococcal pneumonia and death in populations with different prevalence of pneumococcal carriage and contributions of antibiotic prophylaxis, treatment, and vaccination to these rates. Our analysis predicts that in countries with lower prevalence of pneumococcal carriage and access to antibiotics and pneumococcal conjugate vaccines, there would substantially fewer deaths due to pneumonia in contemporary populations confronted with a 1918-like virus than that observed in the 1918. Our results also predict that if the pneumococcal carriage prevalence is less than 40%, the positive effects of antibiotic prophylaxis and treatment would be manifest primarily at of level of individuals. These antibiotic interventions would have little effect on the incidence of pneumonia in the population at large. We conclude with the recommendation that pandemic preparedness plans should consider co-infection with and the prevalence of carriage of pneumococci and other bacteria responsible for pneumonia. While antibiotics and vaccines will certainly reduce the rate of individual mortality, the factor contributing most to the relatively lower anticipated lethality of a pandemic with a 1918-like influenza virus in contemporary population is the lower prevalence of pneumococcal carriage.

In vitro measures of the pharmacodynamics of antibiotics that account for the factors anticipated for bacteria in infected patients are central to the rational design of antibiotic treatment protocols. We consider whether or not continuous culture devices are a way to obtain these measures. Staphylococcus aureus PS80 in high-density continuous cultures were exposed to oxacillin, ciprofloxacin, vancomycin, gentamicin, daptomycin and linezolid. Contrary to results from low density retentostats as well as to predictions of traditional PK/MIC ratios, daily dosing with up to 100× MIC did not clear these cultures. The densities of S. aureus in these cultures oscillated with constant amplitude and never fell below 105 CFU per ml. Save for daptomycin “treated” populations, the densities of bacteria in these cultures remained significantly below that of similar antibiotic-free cultures. Although these antibiotics varied in their pharmacodynamic properties there were only modest differences in their mean densities. Mathematical models and experiments suggest that the dominant factor preventing clearance was wall-adhering subpopulations reseeding the planktonic population which can be estimated and corrected for. Continuous cultures provide a way to evaluate the potential efficacy of antibiotic treatment regimes in vitro under conditions that are more clinically realistic and comprehensive than traditional in vitro PK/PD indices.

Phage therapy is the use of bacterial viruses (phages) to treat bacterial infections, a medical intervention long abandoned in the West but now experiencing a revival. Currently, therapeutic phages are often chosen based on limited criteria, sometimes merely an ability to plate on the pathogenic bacterium. Better treatment might result from an informed choice of phages. Here we consider whether phages used to treat the bacterial infection in a patient may specifically evolve to improve treatment on that patient or benefit subsequent patients. With mathematical and computational models, we explore in vivo evolution for four phage properties expected to influence therapeutic success: Generalized phage growth, phage decay rate, excreted enzymes to degrade protective bacterial layers, and growth on resistant bacteria. Within-host phage evolution is strongly aligned with treatment success for phage decay rate but only partially aligned for phage growth rate and growth on resistant bacteria. Excreted enzymes are mostly not selected for treatment success. Even when evolution and treatment success are aligned, evolution may not be rapid enough to keep pace with bacterial evolution for maximum benefit. An informed use of phages is invariably superior to naive reliance on within-host evolution.

The maximum exponential growth rate, the Malthusian parameter (MP), is commonly used as a measure of fitness in experimental studies of adaptive evolution and of the effects of antibiotic resistance and other genes on the fitness of planktonic microbes. Thanks to automated, multi-well optical density plate readers and computers, with little hands-on effort investigators can readily obtain hundreds of estimates of MPs in less than a day. Here we compare estimates of the relative fitness of antibiotic susceptible and resistant strains of E. coli, Pseudomonas aeruginosa and Staphylococcus aureus based on MP data obtained with automated multi-well plate readers with the results from pairwise competition experiments. This leads us to question the reliability of estimates of MP obtained with these high throughput devices and the utility of these estimates of the maximum growth rates to detect fitness differences.