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Comparison of in vitro activities of tigecycline, doxycycline, and tetracycline against the spirochete borrelia burgdorferi

Ticks and Tick-borne Diseases 1 (2010) 30–34 Comparison of in vitro activities of tigecycline, doxycycline, and tetracyclineagainst the spirochete Borrelia burgdorferi Louis Ates a, c, Christa Hanssen-H ¨ubner a, Douglas E. Norris b, Dania Richter d,Peter Kraiczy a, Klaus-Peter Hunfeld c,Ã a Institute of Medical Microbiology and Infection Control, University Hospital of Frankfurt, Frankfurt/Main, Germanyb The Harry W. Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Marylandc Institute of Laboratory Medicine, Northwest Medical Centre, Academic Teaching Hospital, Medical Faculty, University of Frankfurt, Steinbacher Hohl 2–26,D-60488 Frankfurt/Main, Germanyd Abt. Parasitologie, Institut f¨ur Pathologie, Charite´ Universit¨atsmedizin Berlin, Malteserstrasse 74–100, 12249 Berlin, Germany Tigecycline is a new glycylcycline that has recently been revealed to be very effective in vitro against a variety of Gram-negative and Gram-positive bacteria including multi-drug resistant microorganisms.
Using a standardized microdilution susceptibility testing method, we determined the minimal inhibitory concentrations (MICs) and the minimal bactericidal concentrations (MBCs) of tigecycline, in parallel with doxycycline, tetracycline, and other antibiotic agents relevant for Lyme borreliosis treatment such as ceftriaxone and cefotaxime. The activity of all agents against 16 different Borrelia isolates belonging to all borrelial genospecies known to be pathogenic for humans was investigated and analyzed under standardized conditions.
90s was tigecycline ( r 0.016 mg/L) 4 ceftriaxone (0.03 mg/L) 4 cefotaxime (r0.125 mg/L) 4 doxycycline (0.25 mg/L) 4 tetracycline (0.25 mg/L). The rank order of MBC90s was tigecycline (0.5 mg/L) 4 ceftriaxone (2 mg/L) 4 tetracycline (16 mg/L) 4 doxycycline(16 mg/L) 4 cefotaxime (4 16 mg/L). High in vitro activity of the new glycylcycline against Borrelia wasfurther substantiated by time-kill experiments performed with B. afzelii isolate EB1. Parallel testing oftigecycline and ceftriaxone demonstrated a bacteriostatic effect for 0.016 mg/L of tigecycline and for0.03 mg/L for ceftriaxone after 72 h of incubation. Moreover, tigecycline was bactericidal at aconcentration of 0.25 mg/L showing a 4 3 log10 unit reduction of the initial inoculum, whereas forceftriaxone a concentration of 2 mg/L was needed.
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neurological disorders and late manifestations including acroderma-titis chronica atrophicans or chronic arthritis ( Lyme borreliosis is a vector-borne disease that is transmitted by ixodid ticks and is caused by the spirochete Borrelia burgdorferi sensu Lyme borreliosis is frequently treated by orally administered lato (s.l.) complex. The 5 genospecies that are currently considered doxycycline or intravenous ceftriaxone, which appear to be equally to be human pathogens are B. burgdorferi sensu stricto (s.s.), B. afzelii, B. garinii, and B. spielmanii, and the proposed but not yet validated ). Other often administered antibiotics are penicillin, amoxicillin, novel species B. bavariensis ). In Europe, the cefuroxime, cefotaxime, and tetracycline. Although these drugs have incidence of Lyme borreliosis is estimated to range from 3.9 to 168/ been reported to be clinically effective in the majority of cases under controlled study conditions, treatment failures have been repeatedly manifest itself progressively as a multisystem disorder exhibiting a large variety of clinical symptoms ). Early on in the course of the infection, a bull’s-eye rash called erythema migrans Tigecycline, a glycylcycline and structural analog of minocycline is the most common disease manifestation appearing in 80–90% is a relatively new antibiotic agent that has been found to be of the patients. If left untreated, however, the infection may cause effective against many Gram-positive and Gram-negative bacteriaincluding multi-drug resistant pathogens such as ESBL-producingenterobacteriaceae, (MRSA), vancomycin-resistant enterococci (VRE), and multi-drug Corresponding author. Tel.: + 49 69 7601 3252; fax: + 49 69 7601 3907.
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L. Ates et al. / Ticks and Tick-borne Diseases 1 (2010) 30–34 Tigecycline is a primarily bacteriostatic agent that binds to B. valaisiana and 2 B. lusitaniae isolates were tested. The clinical, the bacterial 30S subunit of the bacterial ribosome ().
geographic, and phenotypic characteristics of 12 of the tested Recently, tigecycline was also found to be effective in vitro against several strains of B. burgdorferi s.l. (However, the number of isolates tested in this study was small and so far ). In the present study, we also tested B. lusitaniae isolate tigecycline has not been tested in parallel with other tetracyclines MT0407 M3 (tick isolate, Portugal), B. lusitaniae isolate IP10907 against borreliae under well-controlled conditions. In this study, we N1 (tick isolate, Germany), B. valaisiana isolate ZWU3 0507 N3 used a well-evaluated and standardized methodology to investigate (tick isolate, Germany), and B. valaisiana isolate Bv9 (tick isolate, the in vitro activity and bactericidal properties of tigecycline against Germany). Genospecies were identified by restriction fragment 16 isolates of the B. burgdorferi s.l. complex in comparison to a series length polymorphism patterns after digestion with endonuclease of compounds relevant for the treatment of Lyme borreliosis in the MluI and by application of plasmid analysis as described clinical setting, including doxycycline, tetracycline, ceftriaxone, and sequencing a 600-nucleotide fragment of the gene encoding the16SrRNA and comparing it to the same fragment of variousgenospecies type strains The susceptibility of a total of 16 isolates belonging to 5 human MIC values were obtained by applying our previously pathogenic species of the B. burgdorferi s.l. complex as well as 2 Table 1Individual antibiotic susceptibilities of 16 B. burgdorferi s.l. isolates to tigecycline, doxycycline, tetracycline, ceftriaxone, and cefotaxime (MICs and MBCs in milligram per liter).
E. coli (ATCC 25922)Median MIC in BSK medium a Antimicrobial susceptibility was determined on 3 different days, and MIC and MBC values for each isolate were reported as the median of 3 experiments.
b The test ranges (in mg/L) were as follows: tigecycline: 0.016–2; doxycycline: 0.016–32; tetracycline: 0.125–16; ceftriaxone: 0.004–8; cefotaxime: 0.125–16.
c To investigate significant antibiotic–medium interaction, MICs for S. aureus (ATCC 29213) and E. coli (ATCC 25922) were determined on 3 different days, referring to the CLSI method except for the use of BSK and preincubation of the antibiotic–medium test preparation for 48 h before testing. Results were reported as themedian of all 3 experiments.
L. Ates et al. / Ticks and Tick-borne Diseases 1 (2010) 30–34 were provided in lyophilized form on 96-well microtiter plates inserially diluted concentrations. The plates were supplied and To detect possible variations in the antibiotic susceptibility quality controlled by the manufacturer (Merlin GmbH, Bornheim- pattern of the different borrelial genospecies, all MIC and MBC Hersel, Germany). An inoculum (200 ml) of 5 Â 106 borreliae/well, values were analyzed for intragenospecies-specific differences in the log phase of growth, was incubated in Barbour-Stoenner- applying the Kruskal-Wallis test. Calculations were performed with the statistical program BIAS, version 8.3.8 (Epsilon Verlag, with phenol red for 72 h at 33 1C. The absorbance of the test medium was measured at 0, 24, 48, and 72 h using a spectro-photometer (PowerWave 200, Bio-Tec Instruments, USA), andgrowth curves were calculated by utilizing a software-assisted method (MicroWin 3.0, Mikrotek Germany). Growth of samplesand controls was determined for each well based on the decrease of absorbance after 72 h (Et72) in comparison to the initialabsorbance values (Et0). A sample was judged to exhibit growth When comparing antibiotic activities of the different sub- if the decrease from Et0 to Et72 accounted for more than 10% stances against the tested isolates, the rank order of in vitro activity against all tested borrelial genospecies considering the isolate failed to grow in the presence of antibiotics was median MICs of the individual substances for all tested isolates interpreted as the colorimetric MIC ). Every in milligram per liter was as follows: tigecycline (MIC90: substance was tested in triplicate on different days, but all substances were tested in parallel to each other, together with a (MIC90: r0.125 mg/L), doxycycline (MIC90: 0.25 mg/L), tetracy- control without antibiotic substance and a control without cline (MIC90: 0.25 mg/L) ). The most active antibiotic borreliae. The reported MIC is the median of all 3 independent agent was tigecycline exhibiting an MIC of r0.016 mg/L in every tested isolate. Doxycycline and tetracycline had identical median As an additional quality control measure and to exclude MIC values, but since the average sensitivity for doxycycline in the significant antibiotic–medium interactions, the method was also tested isolates was lower, doxycycline was considered the more applied using Escherichia coli ATCC 25922 and Staphylococcus active substance. Antibiotic susceptibilities between the 7 tested aureus ATCC 29213 in triplicate experiments following the CLSI genospecies did not differ significantly (Kruskal-Wallis test, (formerly NCCLS) standard protocols except for preincubation of po0.05). In addition, no significant MIC deviations attributable the used antibiotic–BSK preparation for 48 h before testing ( to interactions of the tested antimicrobial agents with compo- nents of the BSK medium were detected in our quality controlexperiments with the reference organisms S. aureus ATCC 29213and E. coli ATCC 25922 for any of the antibiotics used ().
Conventional MBC values of doxycycline, tetracycline, ceftriaxone, and cefotaxime were determined for at least one The MBC (defined as 100% killing) value of each isolate was isolate of each genospecies by obtaining aliquots of 18 ml from obtained after a 72-h exposure to the antibiotic substances each well without growth after 72 h and transferring these followed by an additional 3-week incubation of subcultures.
samples into vials containing 1332 ml of fresh BSK medium When taking the median MBCs of all tested isolates in milligram per liter into account, the rank order of MBC90s in the tested low MIC values measured for tigecycline, an aliquot of 1.8 ml isolates was: tigecycline (0.5 mg/L), ceftriaxone (2 mg/L), tetra- was transferred into 1348 ml of BSK (dilution factor 1:750) for cycline (16 mg/L), doxycycline (16 mg/L), cefotaxime ( Z16 mg/L) this agent. Subcultures were then incubated at 33 1C for another 3 weeks. After slight agitation of the medium, 10 microscopicalfields were examined for the presence or absence of viable spirochetes using dark-field microscopy (Carl Zeiss MicroIma-ging, G ¨ottingen, Germany).
The acitivity of tigecycline and ceftriaxone against the B. afzelii isolate EB1 was further examined by time-kill experiments.
Tigecycline inhibited growth of the initial inoculum for 72 h at a concentration of 0.016 mg/L, whereas ceftriaxone required con-centrations of 0.03 mg/L (). Tigecycline achieved a 43 log10- Time-kill experiments were performed by culturing B. afzelii unit reduction of the initial inoculum after 24 h at a concentration isolate EB1 in the presence of 0.016, 0.03, 0.25, and 2 mg/L of 0.25 mg/L, whereas in ceftriaxone a concentration of 2 mg/L tigecycline or ceftriaxone as described in the MIC experiments.
The time-kill curve was constructed by counting the number ofviable spirochetes under a dark-field microscope using a KOVAcounting chamber (Hycor Biomedical inc., Garden grove, CA) after 0, 24, 48, 72, and 96 h. Experiments were performed in duplicateand the data are depicted as the average of 2 experiments as Doxycycline, and occasionally other tetracyclines, are fre- described recently The concentration of the antibiotic agent that inhibited growth of the inoculum for 72 h was defined as the MIC. The concentration that achieved a effective in the majority of clinical cases ( 4 3 log10 reduction of the inoculum after 72 h was defined as the early Lyme borreliosis occur in 5–10% of all patients including L. Ates et al. / Ticks and Tick-borne Diseases 1 (2010) 30–34 the in vitro activity of tigecycline was tested in well-controlled assays and compared to other clinically relevant antibiotics.
In our present study, tigecycline clearly had a low MIC90 ( r0.016 mg/L) for all tested isolates. In fact, tigecycline was moreactive than doxycycline (MIC90: 0.25 mg/L) and appeared even more active in vitro than ceftriaxone (MIC90: 0.03 mg/L) for all isolates tested. Furthermore, tigecycline was the most borreliaci-dal compound of all tested substances resulting in an MBC90 of /well *10
0.5 mg/L for the tested isolates. Taking all MBC90 values into account, tigecycline was 4 times more effective in vitro than the Borrelia
second most active antibiotic, ceftriaxone (MBC90: 2 mg/L), and upto 32 times more effective than doxycycline (range of MBCs: 8–16 mg/L). Our observation of a high in vitro activity oftigecycline was further confirmed by time-kill experiments usingthe B. afzelii isolate EB1. Tigecycline inhibited the growth of the initial inoculum at 0.016 mg/L and reduced the inoculum by4 3 log 10 at 0.25 mg/L after 72 h of incubation, thereby corre- sponding to the low MIC90 and MBC90 values as determined by our microdilution susceptibility experiments. As depicted in, the in vitro susceptibility values of the other tested tetracyclines and cephalosporins were found to be in goodaccordance with values published in the recent literature(). Moreover, our quality control experi- ments clearly confirmed that in vitro test results were notsignificantly hampered by possible interactions of the antibiotic Interestingly, tigecycline was shown to be more effective than related classical tetracyclines in many Gram-positive and Gram- /well *10
negative bacteria including multi-drug resistant pathogens withRND-efflux pumps Such RND-type efflux pumps are Borrelia
prevalent in a wide variety of other Gram-negative bacteriae, such as E. coli and Acinetobacter baumanii, where they appear to decrease thesusceptibility of these organisms to a large number of antibiotic agents including tetracyclines (. Interestingly, such a mechanism of antibiotic resistance has recently been described also for B. burgdorferi demonstrating the efflux of antibiotics fromthe spirochete by use of a resistance nodulation-cell division (RND) type efflux pump called BesABC ). A knockout ofBesC in a genetically modified B. burgdorferi s.s. strain was Fig. 1. Time-kill curves of B. afzelii isolate EB1 cultured with different concentra- demonstrated to result in an increased susceptibility to multiple tions of tigecycline (A), or ceftriaxone Concentrations forceftriaxone were chosen as half the MIC (0.016 mg/L), the MIC (0.03 mg/L), 8 classes of antibiotics used in the therapy of Lyme borreliosis. For times the MIC (0.25 mg/L), and the MBC (2 mg/L) as defined by the microdilution tetracycline, an 8-fold decrease of the MIC90 (0.31 mg/L in the wild- test method Concentrations for tigecycline were 0.016 mg/L correspond- type strain vs. 0.04 mg/L in the BesC knockout strain) and a 15-fold ing to the MIC (growth inhibition of the initial inoculum), and 0.25 mg/L decrease of the MBC (2.5 mg/L in the wild-type strain vs. 0.16 mg/L corresponding to the MBC (>3 log10 reduction of the initial inoculum after 72 h).
Two experiments were performed in parallel. Depicted is the mean of the 2 in the BesC knockout strain) was observed using our standardized susceptibility-testing assay One of theproposed reasons for the increased activity of tigecycline againstborrelia compared to classical tetracyclines as observed in our study may be the fact that tigecycline is obviously more resistant to efflux as mediated by RND-type efflux systems than are the classical ). The clinical success rate in patients with early or late neuroborreliosis that were treated with doxycycline or ceftriax- consideration the results of our study, the susceptibility testing of borrelial mutants with altered tetracycline resistance against Doxycycline seems to be as effective as ceftriaxone in tigecycline would be a very interesting future approach of antibiotic European patients affected by neuroborreliosis ( research in borrelia. Furthermore, tigecycline has a much larger However, treatment failures may be more likely in later volume of distribution Vd compared to the classical tetracyclines stages of Lyme borreliosis than in the early phase characterized by () (>10 L/kg vs. 0.14–1.6 L/kg) which is, however, erythema migrans or neuroborreliosis ).
similar to the Vd of ceftriaxone ). These In recent years, new substances for the treatment of bacterial considerations and its high in vitro activity against Borrelia clearly infections have become available. In our present study, we warrant further clinical studies on tigecyline in the treatment of performed in vitro susceptibility testing experiments with tigecy- disseminated late manifestations of Lyme borreliosis, i.e. arthritis or cline, a new tetracycline and a structural analog of minocycline.
acrodermatitis chronica atrophicans.
Tigecycline was recently reported to be effective in vitro against In summary, we have further confirmed that tigecycline is very B. burgdorferi However, data on its in vitro effective in vitro against a wide variety of B. burgdorferi s.l.
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