Pre-exposure of infected human endometrial epithelial cells to penicillin in vitro renders Chlamydia trachomatis refractory to azithromycin

Wyrick, Priscilla B.; Knight, Stephen

doi:10.1093/jac/dkh283

Cited by 66 publications

(63 citation statements)

References 31 publications

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“…Additionally, shedding was undetectable immediately after AMX stress but resumed thereafter in all mice receiving AMX alone (persistently infected controls), as previously observed (4). Taken together, these data suggest that persistent/stressed chlamydiae are more resistant to AZM in vivo, as reported in cell culture (5).…”

supporting

confidence: 84%

Induction of the Chlamydia muridarum Stress/Persistence Response Increases Azithromycin Treatment Failure in a Murine Model of Infection

Phillips-Campbell

Kintner

Schoborg

2014

Antimicrob Agents Chemother

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Viable but noninfectious (stressed/persistent) chlamydiae are more resistant to azithromycin (AZM) in culture than are organisms in the normal developmental cycle. Chlamydia muridarum-infected mice were exposed to amoxicillin to induce the organisms to enter the persistent/stressed state and subsequently treated with AZM. AZM treatment failure was observed in 22% of persistently infected mice, with an average of 321,667 inclusion-forming units (IFU) shed after AZM treatment. Productively infected mice had a 9% rate of AZM treatment failure and shed an average of 12,083 IFU. These data suggest that stressed chlamydiae are more resistant to frontline antichlamydial drugs in vivo. Chlamydial species exhibit a unique biphasic developmental cycle, interchanging between the infectious elementary body (EB) and the replicative, noninfectious reticulate body (RB). Internalized EBs form vacuoles that fuse to form an inclusion, the membrane-bound structure in which EBs transform to RBs. After multiple rounds of division, RBs condense to form EBs, which are released to infect new host cells. In culture, exposure to environmental insults, including immunological stressors like gamma interferon (IFN-␥) and beta-lactam antibiotics such as amoxicillin (AMX), induces chlamydiae to reversibly detour from this normal developmental cycle (1, 2), entering a noninfectious, viable state alternately termed persistence or the chlamydial stress response. Interestingly, aberrant bodies (ABs) have been observed in vivo in the absence of a known stressor, suggesting that host environmental fluctuations induce at least a small subset of infecting organisms to enter persistence (3). Recently, we demonstrated this state in AMX-stressed Chlamydia muridarum-infected BALB/c mice. In our model, AMX treatment decreased vaginal shedding of infectious chlamydiae by Ͼ99% without affecting viability. Shedding of infectious EBs resumed within 1 week after treatment cessation (4). These data demonstrate that AMX can be used to reversibly induce chlamydial persistence in vivo.In culture, persistent chlamydiae are refractory to treatment with first-choice antibiotics. Persistent/stressed C. trachomatis strains within penicillin-exposed Hec1B cells are resistant to treatment with azithromycin (AZM) (5), and IFN-␥ exposure makes C. trachomatis more resistant to doxycycline killing (6). Additionally, doses of AZM or ofloxacin up to 4ϫ the MIC are ineffective against persistent C. pneumoniae infection in culture (7). Thus, many investigators have proposed that persistent chlamydiae may contribute to chronic disease by evading antibiotic treatment. While there is evidence that persistent infection occurs in vivo (8, 9), the absence of an experimentally tractable animal model of viable but noninfectious chlamydial infection has hampered direct testing of this prediction. This study will seek to determine if persistent organisms are resistant to treatment by the first-choice antibiotic, AZM, in our newly characterized mouse model (4). All animal experiments descr...

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confidence: 84%

Induction of the Chlamydia muridarum Stress/Persistence Response Increases Azithromycin Treatment Failure in a Murine Model of Infection

Phillips-Campbell

Kintner

Schoborg

2014

Antimicrob Agents Chemother

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“…Problems associated with persistent chlamydial growth include the possibilities that it (i) permits immune evasion (6), (ii) provides a reservoir of bacteria that can be reactivated when conditions in the infected microenvironment are permissive (9,10), and (iii) may underlie the recalcitrance of chlamydiae to some commonly used antibiotics (11,12,39,60). In this study, we explored the effects of the specific IDO1 inhib- We hypothesize that the mechanism underlying the ability of L-1MT to rescue C. trachomatis from IFN-␥-mediated persistence, while limiting the productive multiplication of the bacterium, involves the temporal depletion of tryptophan (Table 4).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Indoleamine 2,3-Dioxygenase Activity by Levo-1-Methyl Tryptophan Blocks Gamma Interferon-Induced Chlamydia trachomatis Persistence in Human Epithelial Cells

et al. 2011

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“…Although little is known about chlamydial persistence in response to tetracycline treatment, it has been noted that persistence to one antibiotic may impact upon the susceptibility of Chlamydia to another. For example, it has been found that when persistence is induced by penicillin treatment, azithromycin resistance can result, despite a previously high degree of susceptibility (Wyrick & Knight, 2004). Incidentally, the patients carrying IU824 and IU888 had both previously been treated with other antibiotics (erythromycin and cephalosporin in addition to tetracycline) for their respective infections, so this might have contributed to the in vivo tolerance of these isolates to tetracycline treatment.…”

Section: E O'neill and Othersmentioning

confidence: 99%

Chlamydia trachomatis clinical isolates identified as tetracycline resistant do not exhibit resistance in vitro: whole-genome sequencing reveals a mutation in porB but no evidence for tetracycline resistance genes

et al. 2013

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Chlamydia trachomatis is the most common bacterial sexually transmitted infection worldwide and the leading cause of preventable blindness in developing countries. Tetracycline is commonly the drug of choice for treating C. trachomatis infections, but cases of antibiotic resistance in clinical isolates have previously been reported. Here, we used antibiotic resistance assays and wholegenome sequencing to interrogate the hypothesis that two clinical isolates (IU824 and IU888) have acquired mechanisms of antibiotic resistance. Immunofluorescence staining was used to identify C. trachomatis inclusions in cell cultures grown in the presence of tetracycline; however, only antibiotic-free control cultures yielded the strong fluorescence associated with the presence of chlamydial inclusions. Infectivity was lost upon passage of harvested cultures grown in the presence of tetracycline into antibiotic-free medium, so we conclude that these isolates were phenotypically sensitive to tetracycline. Comparisons of the genome and plasmid sequences for the two isolates with tetracycline-sensitive strains did not identify regions of low sequence identity that could accommodate horizontally acquired resistance genes, and the tetracycline binding region of the 16S rRNA gene was identical to that of the sensitive control strains. The porB gene of strain IU824, however, was found to contain a premature stop codon not previously identified, which is noteworthy but unlikely to be related to tetracycline resistance. In conclusion, we found no evidence of tetracycline resistance in the two strains investigated, and it seems most likely that the small, aberrant inclusions previously identified resulted from the high chlamydial load used in the original antibiotic resistance assays.

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Pre-exposure of infected human endometrial epithelial cells to penicillin in vitro renders Chlamydia trachomatis refractory to azithromycin

Abstract: Thus, this study provides evidence at the cellular microbiology level in vitro for mechanisms that could exist in vivo to create sustained, but perhaps clinically inapparent inflammation, which might eventually lead to conditions such as silent pelvic inflammatory disease.

Cited by 66 publications

References 31 publications

Induction of the Chlamydia muridarum Stress/Persistence Response Increases Azithromycin Treatment Failure in a Murine Model of Infection

Induction of the Chlamydia muridarum Stress/Persistence Response Increases Azithromycin Treatment Failure in a Murine Model of Infection

Inhibition of Indoleamine 2,3-Dioxygenase Activity by Levo-1-Methyl Tryptophan Blocks Gamma Interferon-Induced Chlamydia trachomatis Persistence in Human Epithelial Cells

Chlamydia trachomatis clinical isolates identified as tetracycline resistant do not exhibit resistance in vitro: whole-genome sequencing reveals a mutation in porB but no evidence for tetracycline resistance genes

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