The Effect of pH on Antibiotic Efficacy against Coxiella burnetii in Axenic Media

Cody B Smith,Gilbert J Kersh,Charles Evavold

doi:10.1038/s41598-019-54556-6

Cody B Smith, Gilbert J Kersh + Show 1 more

Open Access

https://doi.org/10.1038/s41598-019-54556-6

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Abstract

Coxiella burnetii, the etiologic agent of Q fever, replicates in an intracellular phagolysosome with pH between 4 and 5. The impact of this low pH environment on antimicrobial treatment is not well understood. An in vitro system for testing antibiotic susceptibility of C. burnetii in axenic media was set up to evaluate the impact of pH on C. burnetii growth and survival in the presence and absence of antimicrobial agents. The data show that C. burnetii does not grow in axenic media at pH 6.0 or higher, but the organisms remain viable. At pH of 4.75, 5.25, and 5.75 moxifloxacin, doxycycline, and rifampin are effective at preventing growth of C. burnetii in axenic media, with moxifloxacin and doxycycline being bacteriostatic and rifampin having bactericidal activity. The efficacy of doxycycline and moxifloxacin improved at higher pH, whereas rifampin activity was pH independent. Hydroxychloroquine is thought to inhibit growth of C. burnetii in vivo by raising the pH of typically acidic intracellular compartments. It had no direct bactericidal or bacteriostatic activity on C. burnetii in axenic media, suggesting that raising pH of acidic intracellular compartments is its primary mechanism of action in vivo. The data suggest that doxycycline and hydroxychloroquine are primarily independent bacteriostatic agents.

Highlights

Coxiella burnetii is a gram-negative bacterium that is the etiologic agent of the human disease Q fever
To establish the impact of pH on the ability of C. burnetii to replicate in ACCM-2 media, growth of C. burnetii Nine Mile Phase 2 (NMP2) was measured in ACCM-2 liquid culture at pH ranging from 4.5 to 7.5
The data presented here demonstrate the establishment of an axenic system for evaluating the impact of antimicrobial agents on C. burnetii

Summary

Introduction

Coxiella burnetii is a gram-negative bacterium that is the etiologic agent of the human disease Q fever. This bacterium has a reduced genome and requires infection and establishment of an intracellular niche for replication. Chronic Q fever presents most commonly as either culture negative endocarditis or vascular infection. It is estimated that 2–5% of C. burnetii infections will develop into chronic Q fever[7]. Patients with pre-existing valvulopathies or vascular disease are more at risk for development of chronic Q fever[8]. These chronic infections are difficult to treat, and are typically fatal if untreated[9]. There are many adverse side effects associated with long term use of doxycycline, including loss of appetite, nausea and vomiting, diarrhea, retinopathy, and sensitivity to sun exposure[16]

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