Exploring factors shaping antibiotic resistance patterns in Streptococcus pneumoniae during the 2020 COVID-19 pandemic

Abstract

Non-pharmaceutical interventions implemented to block SARS-CoV-2 transmission in early 2020 led to global reductions in the incidence of invasive pneumococcal disease (IPD). By contrast, most European countries reported an increase in antibiotic resistance among invasive Streptococcus pneumoniae isolates from 2019 to 2020, while an increasing number of studies reported stable pneumococcal carriage prevalence over the same period. To disentangle the impacts of the COVID-19 pandemic on pneumococcal epidemiology in the community setting, we propose a mathematical model formalizing simultaneous transmission of SARS-CoV-2 and antibiotic-sensitive and -resistant strains of S. pneumoniae. To test hypotheses underlying these trends five mechanisms were built into the model and examined: (1) a population-wide reduction of antibiotic prescriptions in the community, (2) lockdown effect on pneumococcal transmission, (3) a reduced risk of developing an IPD due to the absence of common respiratory viruses, (4) community azithromycin use in COVID-19 infected individuals, (5) and a longer carriage duration of antibiotic-resistant pneumococcal strains. Among 31 possible pandemic scenarios involving mechanisms individually or in combination, model simulations surprisingly identified only two scenarios that reproduced the reported trends in the general population. They included factors (1), (3), and (4). These scenarios replicated a nearly 50% reduction in annual IPD, and an increase in antibiotic resistance from 20% to 22%, all while maintaining a relatively stable pneumococcal carriage. Exploring further, higher SARS-CoV-2 R₀ values and synergistic within-host virus-bacteria interaction mechanisms could have additionally contributed to the observed antibiotic resistance increase. Our work demonstrates the utility of the mathematical modeling approach in unraveling the complex effects of the COVID-19 pandemic responses on AMR dynamics.

Keywords: COVID-19 pandemic; SARS-CoV-2; Streptococcus pneumoniae; antibiotic resistance; ecology; epidemiology; global health; invasive pneumococcal disease; virus-bacteria interactions.

Figure 1.. Antibiotic resistance trends in invasive Streptococcus pneumoniae isolates for the years 2019 and 2020.

(A) The proportion of invasive S. pneumoniae isolates resistant to penicillin and macrolides (azithromycin/ clarithromycin/ erythromycin) reported to EARS-Net (European Antimicrobial Resistance Surveillance Network) for 24 European countries. Error bars show 95% confidence intervals. (B) The proportion of invasive S. pneumoniae isolates resistant to penicillin (MIC >0.064 mg/L) and macrolides (erythromycin) according to age. Error bars show 95% confidence intervals. The total number of invasive pneumococcal isolates reported in France decreased by 45.1% from 2019 to 2020 (from 1119–614). Data are provided by the French National Reference Center for Pneumococci.

Figure 1—figure supplement 1.. Antibiotic resistance trends in invasive Streptococcus pneumoniae isolates in France, 2017–2020.

The proportion of invasive S. pneumoniae isolates resistant to penicillin (A) and macrolides (B) according to age. Error bars show 95% confidence intervals. Across the period 2017–2020, a consistent decline in antibiotic resistance is observed for both penicillin and macrolides. Notably, this general trend experienced an anomaly in 2020, coinciding with the onset of the COVID-19 pandemic. Data are provided by the French National Reference Center for Pneumococci.

Figure 2.. A modelling framework describing the transmission of SARS-CoV-2 and Streptococcus pneumoniae in the community setting, in the context of both general antibiotic prescribing and azithromycin prescribing for COVID-19 infected individuals.

(A) Non-pharmaceutical interventions (NPIs) implemented to control SARS-CoV-2 transmission (lockdown, face mask use, improved hygiene practices, travel restrictions, quarantine, telemedicine, and physical distancing) may also modify transmission of other pathogens, in addition to impacting antibiotic prescribing due to altered inter-individual contact and health-care seeking behavior. (B) SEIR (Susceptible-Exposed-Infected-Recovered) model with antibiotic treatment compartments depicts interaction between SARS-CoV-2 infection and antibiotic prescribing, including both general community prescribing and azithromycin prescribing among individuals infected with SARS-CoV-2. (C) Diagram depicting how pneumococcal colonization and the community antibiotic prescribing are affected by the COVID-19 pandemic impacts. Initiation of antibiotic treatment is assumed independent of bacterial carriage, reflecting widespread bystander selection for commensal bacteria like S. pneumoniae. For a complete modeling framework, see section S2 in Supporting Information.

Figure 3.. Annual incidence of invasive pneumococcal disease (IPD), antibiotic resistance (AR%), and pneumococcal carriage prevalence for three different subpopulations.

(A) The elderly (≥65 years-old) (B) general population (all ages), and (C) children (<5 years-old). Using pandemic scenario S19, which includes a combination of three different mechanisms: reduced community antibiotic prescribing, a reduced risk of developing an IPD, and community azithromycin use in COVID-19 infected individuals, we ran model simulations for three different subpopulations. For a full list of parameter values see Appendix 2—table 2. Annual IPD incidence (grey bars) decreased between 43% and 51% relative to the pre-pandemic (baseline) period with magnitude of a decrease depending on an age group and the level of azithromycin use in COVID-19 infected individuals. Antibiotic resistance (red bars) increased compared to the pre-pandemic (baseline) period in all age groups whenever azithromycin was used in COVID-19 infected. Black arrows indicate model outcomes that approximate the reported trends in antibiotic resistance in France for different age groups. Daily prevalence of total pneumococcal carriage remained relatively stable (solid-colored lines), exhibiting higher levels of decrease with increased azithromycin use. The prevalence of antibiotic-resistant pneumococcal carriage increased (dashed colored lines) over time in relation to SARS-CoV-2 outbreak (black dashed line) and higher azithromycin use. Highlighted time intervals (days 75–135 and 305–365) represent two lockdown periods.

Figure 4.. The impact of varying SARS-CoV-2 R₀ and percentage of COVID-19 infected individuals taking azithromycin in scenario S19 on antibiotic resistance (%) and the annual incidence of antibiotic-resistant invasive pneumococcal disease (IPD).

Hypothetical within-host interactions contribute to an excess incidence of antibiotic-resistant IPDs. (A) Cumulative incidence of antibiotic-resistant IPDs and antibiotic resistance increase with greater values of SARS-CoV-2 R₀ and higher percentage of the COVID-19 infected individuals taking azithromycin. The reproduction number for SARS-CoV-2 (R₀) in the community corresponds to the most common estimates of R₀ in France and other European countries ranging from R₀=2–4 (Allieta et al., 2022; D’Arienzo and Coniglio, 2020; Di Domenico et al., 2020; Flaxman et al., 2020; Liu et al., 2020; Roux et al., 2020; Salje et al., 2020). (B) Annual excess in cumulative antibiotic-resistant IPD incidence in scenario S19 due to synergistic within-host ecological interactions compared to the same scenario with no within-host interactions and no azithromycin use (1.17 resistant IPD cases/100,000 inhabitants). A rate of disease progression increased by a factor ${\psi }_c=1$ (no within-host interaction) and ${\psi }_c=40$ in scenario S19 applied to the general population assuming azithromycin use in 10% of the infected individuals resulted in approximately 0.06 and 0.75 additional cases of antibiotic-resistant disease per 100,000 inhabitants over the course of 1 year, respectively, compared to the scenario S19 assuming no within-host interaction and no azithromycin use (indicated by the black arrow). For more details, see Appendix 2—figure 1.

Appendix 2—figure 1.. Hypothetical within-host interactions in scenario S19 promote the incidence of antibiotic-resistant invasive pneumococcal disease (IPD).

(A) Impacts of ecological interactions between pathogens. When SARS-CoV-2 infection leads to faster progression from pneumococcal colonization to disease , surges in COVID-19 cases accompanied by increasing levels of azithromycin use lead to substantial increases in the daily incidence of antibiotic-resistant IPD. (B) Annual excess in cumulative IPD incidence due to synergistic within-host ecological interactions. A rate of disease progression increased by a factor (no within-host interaction) and in scenario S19 applied to the general population resulted in approximately 0.06 and 0.75 additional cases of antibiotic-resistant disease per 100,000 inhabitants over the course of one year, respectively, compared to the scenario S19 assuming no within-host interaction and no azithromycin use indicated by the black arrow (1.17 cases/100,000 inhabitants).

Appendix 2—figure 2.. Model schematic describing co-circulation of SARS-CoV-2 infection and pneumococcal carriage transmission.

(A) Individuals in each of the SARS-CoV-2 transmission model compartments (S, E, I, R) can be either (B) uncolonized (U) or colonized by the bacteria (C^S, C^R, C^SS, C^RR, C^SR) with or without concomitant antibiotic treatment (subscript _atb denotes compartments exposed to antibiotics – both standard baseline antibiotic exposure and azithromycin exposure). Full list of model parameters can be found in Appendix 2—table 2.

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