Antibiotic Resistance, Biofilm Formation, and Intracellular Survival As Possible Determinants of Persistent or Recurrent Infections by Staphylococcus aureus in a Vietnamese Tertiary Hospital: Focus on Bacterial Response to Moxifloxacin

Abstract

Resistance is notoriously high in Asia but may not entirely explain therapeutic failures. Specific modes of bacterial life, such as biofilm or intracellular survival, may also contribute to the persistent and/or recurrent character of infections. Most Staphylococcus aureus isolates form biofilm and many survive and even thrive intracellularly. We collected 36 non-duplicate S. aureus isolates (including 18 MRSA) from patients with clinical evidence of persistent or recurrent infections in a large tertiary Vietnamese hospital. We examined their antibiotic resistance profile (MIC determination) and clonal relatedness (spa and agr typing, PFGE profiles). We then assessed the activity of moxifloxacin in both biofilms and infected phagocytes (moxifloxacin previously proved to be one of the most active antibiotics against reference strains in these models). spa-types t189 and t437 and agr group I were the most frequent. 30/36 isolates were multidrug resistant but 30/36 were recovered from patients having received an active drug. All tested isolates produced biofilm and survived inside phagocytes. At its human Cmax, moxifloxacin was inactive on biofilms made by moxifloxacin-susceptible as well as moxifloxacin-resistant isolates. It caused only modest intracellular CFU decrease against moxifloxacin-susceptible isolates and was inactive against those resistant to moxifloxacin. While our data confirm for this

The Persister Character of Clinical Isolates of Staphylococcus aureus Contributes to Faster Evolution to Resistance and Higher Survival in THP-1 Monocytes: A Study With Moxifloxacin

“…Moxifloxacin was selected as a highly bactericidal antibiotic, fulfilling therefore the condition set for evidencing the occurrence of persisters (Balaban et al, 2019). In our set-up, it also offered the advantage of being clinically approved for the treatment of staphylococcal infections, while showing a balanced proportion of susceptible and resistant clinical isolates [a condition that becomes increasingly difficult to meet with other antibiotics when dealing with hospitalized patients, as exemplified here by our previous analysis of the resistance patterns of the Vietnamese collection (Nguyen et al, 2020)]. Three key observations are presented, which collectively may help in understanding how persistence to antibiotics may eventually account for clinical failures in spite of well-conducted antibiotic treatments.…”

“…Staphylococcus aureus ATCC 25923 and RN 4220 are reference strains from the American Tissue Culture Collection (ATCC), Manassas, VA, United States. Thirty-six clinical isolates were collected at the Bach Mai Hospital (Hanoi, Vietnam) from patients with infections that did not resolve after 5 days of treatment by antibiotics to which the initial isolates were reported as susceptible or that reactivated after treatment discontinuation (Nguyen et al, 2020). Eighteen isolates from the collection of the Belgian National Reference Centre for Staphylococci were randomly selected and included to give a more general character to our observations.…”

“…In an attempt to address these unanswered questions, we assembled 36 non-duplicated isolates from patients hospitalized in Hanoi, Vietnam, and presenting infections that did not resolve or reactivated after 5 days of treatment with an active antibiotic (Nguyen et al, 2020), complemented with 18 randomly selected clinical isolates from the Belgian reference center for Staphylococci to give a more generalizable character to this collection. We first looked for the relative abundance of persisters in stationary cultures of these isolates, using the fluoroquinolone moxifloxacin as selecting agent based on its highly bactericidal activity against susceptible S. aureus in broth, and as being also one of the most active antibiotics against intracellular susceptible S. aureus invading and thriving in human permissive monocytes (Barcia-Macay et al, 2006;Lemaire et al, 2011;Peyrusson et al, 2020).…”

Antibiotic Tolerance of Staphylococcus aureus Biofilm in Periprosthetic Joint Infections and Antibiofilm Strategies

“…Such models could be mandatory to analyze the antimicrobial efficiency and improve other antibiofilm strategies. To help to understand PJIs’ persistence and recurrence, Figure 2 represents a non-exhaustive overview of several factors that play a role in the tolerance and the persistence of PJIs [ 10 , 27 , 92 , 93 ].…”

Control of Methicillin-Resistant Staphylococcus aureus Strains Associated With a Hospital Outbreak Involving Contamination From Anesthesia Equipment Using UV-C

“…In contrast, protein A (Spa), cell wall secretory protein (IsaA), and surface receptors (MnhA, MnhF, and MnhG) are deregulated by RNAIII from the agr system (Jenul and Horswill, 2018). The typing of polymorphisms in the agr system has facilitated the identification and classification of MRSA clinical isolates in Europe, America, India, Vietnam, and Iran (Hetem et al, 2016;Goudarzi et al, 2017;Aggarwal et al, 2019;Nguyen et al, 2020). Although the agr system is conserved in most strains of S. aureus, four polymorphisms in the agr locus have been identified based on the variable region between AgrD, the C-terminal portion of AgrB, and the N-terminal portion of AgrC (Gilot et al, 2002).…”