Persistence ofChlamydia trachomatisIs Induced by Ciprofloxacin and Ofloxacin In Vitro

Abstract

An in vitro cell culture model was used to investigate the long-term effect of ciprofloxacin and ofloxacin on infection with Chlamydia trachomatis. Standard in vitro susceptibility testing clearly indicated successful suppression of chlamydial growth. To mimic better in vivo infection conditions, extended treatment with the drugs was started after infection in vitro had been well established. Incubation of such established chlamydial cultures with ciprofloxacin and ofloxacin not only failed to eradicate the organism from host cells, but rather induced a state of chlamydial persistence. This state was characterized by the presence of nonculturable, but fully viable, bacteria and the development of aberrant inclusions. In addition chlamydia exhibited altered steadystate levels of key chlamydial antigens, with significantly reduced major outer membrane protein and near constant hsp60 levels. Resumption of overt chlamydial growth occurred after withdrawal of ciprofloxacin, confirming the viability of persisting chlamydia. In vitro ciprofloxacin results are consistent with clinical data, thereby providing an explanation for treatment failures of ciprofloxacin. Parallel in vitro studies with ofloxacin suggest a better correlation between clinical and laboratory-defined efficacy, although the clinical studies on which this assessment is based did not include monitoring of chlamydial persistence. The data presented here clearly demonstrate that under at least some circumstances, standard determination of MICs and minimal bactericidal concentrations for C. trachomatis allows no more than a simple definition of whether an antibiotic has some anti chlamydial activity; however, such testing is not always sufficient to verify that the antibiotic will eliminate the organism in vivo.Chlamydia trachomatis is an obligate intracellular bacterial parasite whose life cycle involves alternation between the infectious extracellular, metabolically inactive elementary body (EB) form and the intracellular, metabolically active reticulate body form; the latter is the vegetative growth stage of the organism. Depending on the specific serovar involved, human infection with C. trachomatis causes a variety of ocular, pulmonary, and genital diseases. Genital infection with chlamydial serovars D to K is considered to be of major public health importance, since C. trachomatis is the most common sexually transmitted bacterium worldwide (54). Further, acute urogenital infections can progress to persistent infection, which in turn may initiate a pathogenic process leading to chronic diseases, including pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, and chlamydia-induced arthritis (12, 53). Importantly, C. trachomatis has been shown to be fully viable and metabolically active in both the acute and chronic, persistent infection state. In acute infections, the bacterium can be recovered usually by standard laboratory culture. Chronic chlamydial infections are often characterized by culture negativity, although viability has...

Chlamydia: Possible Mechanisms of the Long Term Complications

“…In an in-vitro study, the persistence of C. trachomatis was demonstrated in the presence of ciprofloxacin and to a lesser extent of ofloxacin. These results reflect the clinical data that antibacterial susceptibility does not always guarantee the in-vivo success of the therapy (Dreses-Werringloer et al, 2000).…”

Role of Chlamydia in the Development of Ocular Adnexal Lymphoma

“…Conversely, ciprofloxacin and ofloxacin have shown to be not eradicating the organism from host cells in vitro, but rather to induce a state of Chlamydia persistence characterized by the presence of noncultivable, but fully viable bacteria and the development of aberrant inclusions [9]. Despite this, however, the association of both compounds has been effective in eradicating C. trachomatis Hsp-60 cDNA in clinical specimens as demonstrated by RT-PCR [99].…”

“…In vitro studies have shown that several factors including nutrient depletion, cytokines (INF-γ), iron restriction, amino acids, Ca++, and certain antibiotics can induce the Chlamydial persistent stage [9,41,42]. In particular IFN-γ directly inhibits bacterial growth [43] and induces Chlamydia persistence by allowing 60 and 12 kDa cystein protein inhibition and tryptophan depletion which can stop the expression of late proteins such as major outer membrane protein (MOMP) that in turn stop the progress of RB division and RB conversion into EBs leading to aberrant Chlamydial RBs [41,44].…”

“…One of the bacterial agents which in recent years has gained attention is the bacterium Chlamydia psittaci implicated as potentially oncogenic for its tendency to cause chronic and persistent infections [8][9][10].…”

Analysis of antibiotic resistance markers in Chlamydia trachomatis clinical isolates obtained after ineffective antibiotic therapy

“…Persistence of Chlamydia is a part of vital cycle of these microorganisms, it can be easily reproduced in cell culture under the effects of some factors, including AB [4]. Azithromycin, ciprofloxacin, and ofloxacin are inductors of Chlamydia persistence, they interrupt the productive intracellular cycle of Chlamydia, the microorganisms stop active multiplication, but retain metabolic activity, which is seen from negative result of cultural study and detection of short-living rRNA transcripts [3,4].…”