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Research Article
1 January 2003

In Vitro Activities of ABT-773 and Other Antimicrobials against Human Mycoplasmas

ABSTRACT

The in vitro susceptibilities of 103 Mycoplasma pneumoniae isolates, 14 Mycoplasma hominis isolates, 12 Mycoplasma fermentans isolates, and 24 Ureaplasma species to ABT-773, an investigational ketolide, and seven other agents were determined. For M. pneumoniae, the ABT-773 MIC at which 90% of isolates are inhibited (MIC90; ≤0.001 μg/ml) was comparable to those of azithromycin, clarithromycin, and erythromycin and at least 128-fold lower than those of levofloxacin, gatifloxacin, moxifloxacin, and doxycycline. For M. fermentans, the ABT-773 MIC90 (≤0.008 μg/ml) was 2- to 128-fold lower than those of all other agents tested. For M. hominis, the ABT-773 MIC90 (0.031 μg/ml) was equivalent to that of moxifloxacin, 2-fold lower than those of gatifloxacin and clindamycin, and 16-fold lower than that of levofloxacin. ABT-773 was equally active against doxycycline-susceptible and doxycycline-resistant organisms. The ABT-773 MICs (0.016 μg/ml) for Ureaplasma species were the lowest of those of any drug tested. The MIC90 was 4- to 64-fold lower than those of clarithromycin, azithromycin, and erythromycin and ≥16-fold lower than those of all three fluoroquinolones. Minimal bactericidal concentrations determined for a subgroup of organisms were ≤0.063 μg/ml for M. pneumoniae and 0.25 μg/ml for M. fermentans, but they were several dilutions higher for M. hominis and Ureaplasma spp. ABT-773 has great potential for further study for the treatment of infections due to mycoplasmas and ureaplasmas.
Ketolides are semisynthetic erythromycin analogs that are structurally modified such that a ketone group replaces the cladinose at the 3 position. ABT-773, a new investigational ketolide, is further modified by an O-allyl-3-quinoline at the 6 position and a cyclized carbamate group between positions 11 and 12 (13). ABT-773 has previously been shown to possess a broad spectrum of antibacterial activity against both gram-positive and gram-negative bacteria including streptococci, staphylococci, enterococci, Listeria, Helicobacter, Haemophilus, Moraxella, mycobacteria, and atypical pathogens including legionellae and chlamydiae (9, 13, 18). Preliminary studies have indicated that ABT-773 has excellent in vitro activities against a small number of Mycoplasma pneumoniae isolates (13). The present study was undertaken to evaluate the in vitro activities of ABT-773 against a larger group of clinical isolates of M. pneumoniae and other Mycoplasma and Ureaplasma species of human origin in comparison with those of other antimicrobial agents currently available in the United States. We also assessed the bactericidal activities of ABT-773 and comparator agents against a subgroup of these organisms.
(This work was presented at the 22nd International Congress of Chemotherapy, Amsterdam, The Netherlands, June 2001, and the 6th International Conference on Macrolides, Azalides, Streptogramins, Ketolides, and Oxazolidinones, Bologna, Italy, January 2002.)

MATERIALS AND METHODS

Microorganisms.

One hundred three M. pneumoniae isolates were collected from six different countries between 1987 and 1999. All isolates originated from the respiratory tracts of individuals with proven respiratory disease. Twelve Mycoplasma fermentans isolates either were clinical strains or were derived from the mycoplasma collection at the National Institutes of Health. Fourteen Mycoplasma hominis isolates were derived from clinical specimens of the urogenital tract or wound cultures. Resistance to doxycycline (MICs, 8 to 16 μg/ml) had previously been shown by prior testing of five M. hominis isolates. Twenty-four Ureaplasma isolates representing both biovars, now designated separate species (Ureaplasma urealyticum and Ureaplasma parvum), were derived from cultures of specimens from the urogenital tracts of adults or the lower respiratory tracts of neonates.

Antimicrobial agents.

All antimicrobial agents except doxycycline and clindamycin were obtained as antimicrobial powders from their respective manufacturers. Doxycycline and clindamycin were purchased from Sigma Chemical Co. (St. Louis, Mo.). The following agents were used for comparison with ABT-773: levofloxacin, moxifloxacin, gatifloxacin, clarithromycin, azithromycin, erythromycin, doxycycline, and clindamycin. The powders were dissolved and diluted according to the recommendations of the manufacturers. Stock solutions of each drug were prepared fresh for each assay. Clarithromycin, azithromycin, and erythromycin were tested only against M. pneumoniae and Ureaplasma spp. Clindamycin was tested only against M. fermentans and M. hominis.

MIC determination.

A broth microdilution method for determination of the MICs was performed as described previously (4, 20). Serial twofold dilutions of antimicrobials were prepared in 10 B broth for Ureaplasma spp. and SP 4 broth for Mycoplasma spp. An inoculum of 104 to 105 color-changing units/ml for each isolate tested was obtained by inoculation of organisms from frozen stock cultures of known concentration into prewarmed broth and incubation for 2 h at 37°C. Following inoculation, the microtiter plates were sealed and incubated aerobically at 37°C. The plates were examined daily until a color change was detected in the drug-free growth control. The MIC was defined as the lowest concentration of a drug in which the metabolism of the organism was inhibited, as evidenced by a lack of color change in the medium at the time that the drug-free control first showed a color change. For Ureaplasma spp. growth was usually evident in the positive control between 16 and 24 h, and for M. hominis growth was usually evident in the positive control after 48 h, whereas M. pneumoniae typically required 4 to 8 days of incubation. Quality control procedures consisted of verification of the number of color-changing units of each isolate inoculated into the MIC system by using serial dilutions and plate counts on A 8 agar for ureaplasmas and SP 4 agar for mycoplasmas (20). In addition, a well-characterized low-passage clinical isolate of each species for which previously established MIC ranges of the comparator drugs of ±1 twofold dilution was tested by each assay. Results were considered valid only if the MICs for the control isolates were within the previously established ranges.

MBC determination.

A subgroup of isolates consisting of 12 M. pneumoniae, 2 M. hominis, 2 Ureaplasma spp., and 1 M. fermentans isolates was tested to determine the minimal bactericidal concentrations (MBCs) of ABT-773 in comparison to those of the other agents tested. These isolates were chosen from among the most recent cultures submitted for diagnostic purposes. MBC testing was performed directly from the microtiter plates used to determine the MICs. An aliquot (30 μl) from each well that had not changed color at the time that the MIC was read was added to 2.97 ml of the corresponding broth (1:100 dilution) to make certain that the drug was diluted below the inhibitory concentration and to therefore allow any living organisms to grow to detectable levels. An aliquot from the growth control was also subcultured to ensure the presence of viable organisms in the absence of antimicrobial. Broths were incubated at 37°C for various times depending on the species and their rates of growth. The MBC was defined as the concentration of antimicrobial in which no growth was detected, as evidenced by a lack of color change in broth after prolonged incubation (for M. pneumoniae, 0 days; for M. hominis, 14 days; for Ureaplasma spp., 7 days). The MBCs of drugs whose MICs were less than or equal to the lowest concentration tested could not be measured because the actual endpoint MIC necessary for interpretation of the results and the dilution required to reduce the concentration of antimicrobial below the levels sufficient to permit growth in the subculture could not be determined.

RESULTS

MICs.

The MIC results by the microtiter susceptibility testing method were reproducible within ±1 dilution in the simultaneous duplicate runs and between assays done on different days. The comparative in vitro activities of ABT-773 and other antimicrobials against mycoplasmas and ureaplasmas are shown in Table 1. ABT-773 demonstrated excellent in vitro activities against all species tested, with MICs consistently being ≤0.031 μg/ml for all species tested.
The ABT-773 MIC range (≤0.001 to 0.016 μg/ml) and the MIC at which 90% of isolates are inhibited (MIC90; ≤0.001 μg/ml) for M. pneumoniae were comparable to those of azithromycin, clarithromycin, and erythromycin and ≥128-fold lower than those of the three fluoroquinolones and doxycycline. The MICs of ABT-773, azithromycin, and clarithromycin for all 12 M. pneumoniae isolates initially chosen to undergo testing for MBCs were ≤0.001 μg/ml, the lowest concentration tested. Therefore, additional concentrations down to 0.000001 μg/ml were tested against three M. pneumoniae isolates to allow more direct comparison of the results for these three agents with those for erythromycin and to enable determination of MBCs. The MICs for these three M. pneumoniae isolates were as follows: ABT-773, ≤0.000001, 0.000008, and 0.00008 μg/ml, respectively; azithromycin, 0.000016, 0.000063, and 0.000063 μg/ml, respectively; clarithromycin, 0.00025, 0.001, and 0.005 μg/ml, respectively; and erythromycin, 0.001, 0.001, and 0.002 μg/ml, respectively. ABT-773 was the most potent drug tested against these three M. pneumoniae isolates in terms of the MICs for the isolates, followed by azithromycin, clarithromycin, and erythromycin.
The ABT-773 MICs for all M. fermentans isolates were ≤0.008 μg/ml. This drug was ≥2- to 128-fold more active than all other agents tested on the basis of the MIC90s. Additional concentrations of ABT-773 were tested against the PG 18 type strain of this species to facilitate MBC determination. The endpoint MIC for ABT-773 was 0.000032 μg/ml.
ABT-773 inhibited all 14 M. hominis isolates in vitro at very low concentrations, with MICs ranging from ≤0.008 to 0.031 μg/ml. The MIC90 of ABT-773 (0.031 μg/ml) was equivalent to that of moxifloxacin, 2-fold lower than those of gatifloxacin and clindamycin, and 16-fold lower than that of levofloxacin. ABT-773 was equally active against doxycycline-susceptible and -resistant M. hominis isolates. Although we did not test the activities of the other macrolides against all 14 M. hominis isolates since most agents in this class are known to have very modest activities against this organism in vitro, representative MIC ranges for seven isolates tested for comparative purposes were 2 to 256 μg/ml for erythromycin, 2 to 64 μg/ml for clarithromycin, and 0.016 to 8 μg/ml for azithromycin.
ABT-773 inhibited all 24 Ureaplasma spp. at concentrations ≤0.031 μg/ml. The ABT-773 MIC90 (0.016 μg/ml) was 4- to 64-fold lower than those of clarithromycin, azithromycin, and erythromycin and ≥16-fold lower than those of all three fluoroquinolones and doxycycline.

MBCs.

MBC data are summarized in Table 2. The ABT-773 MBCs for all three M. pneumoniae isolates tested were ≥32 times the corresponding MICs. The azithromycin MBC for one isolate was 4 times the corresponding MIC, but the MBCs for the remaining two isolates were ≥16 times the MICs. The clarithromycin MBCs for all three isolates tested were eight or more times the MIC. The erythromycin MBCs for 10 of 12 isolates were eight or more times the MICs. Although the macrolide and ketolide MBCs were technically several dilutions higher than the MICs, the actual MBCs were quite low, ranging from 0.00025 to 0.5 μg/ml for all drugs in this group for M. pneumoniae. The doxycycline MICs for all 12 isolates were eight or more times the MICs. The MBCs of the fluoroquinolones were zero to four times the MICs for the majority of isolates tested.
The MBCs of all agents tested except gatifloxacin for the single M. fermentans isolate tested were eight or more times the corresponding MICs. The gatifloxacin MBC was four times the MIC. The ABT-773 MBC was 0.25 μg/ml.
The MBCs of ABT-773 for two isolates of M. hominis were eight or more times the MICs, with the actual MBCs being 1 and 8 μg/ml. The clindamycin MBC for one isolate was 4 times the MIC, whereas the clindamycin MBC for the other isolate was ≥32 times the MIC. The doxycycline MBCs for both isolates were ≥32 times the MICs. The MBCs of all three fluoroquinolone were one to four times the MICs, and the MBCs of all drugs in this group were ≤0.5 μg/ml.
The MBCs of all drugs tested for both isolates of Ureaplasma spp. were more than eight times the corresponding MICs. The MBCs of ABT-773 for the Ureaplasma spp. (1 and 2 μg/ml) were the lowest among those of the drugs tested; the MBCs of all other drugs were ≥16 μg/ml.

DISCUSSION

M. pneumoniae is a common cause of upper and lower respiratory tract infections that can affect persons of all ages (21). Other mycoplasmas, including M. hominis, M. fermentans, and Ureaplasma spp., can cause various diseases of the urogenital tract and sometimes the respiratory tract, affecting adult men and women, children, and infants. These organisms may rarely cause systemic infection involving other organ systems, particularly in persons with impaired host defenses (21). Treatment must usually be empirical whenever mycoplasmas are suspected since diagnostic tests for their direct or indirect detection through serology, as in the case for M. pneumoniae, are expensive, are often time-consuming, and are of limited availability.
Historically, macrolides have been considered the treatments of choice for respiratory tract infections due to M. pneumoniae when pathogen-specific therapy is used (22), and some agents in this group, such as azithromycin, may also be used as alternatives to tetracyclines or fluoroquinolones in the treatment of urogenital infections. Clinical trials with children with M. pneumoniae pneumonias have shown that oral treatment with agents such as clarithromycin or azithromycin in the outpatient setting are as effective clinically as erythromycin, consistent with their high in vitro potencies (8, 10, 19). Limited data suggest that M. pneumoniae may also be eradicated by these agents (3, 7). Ketolides such as ABT-773 may eventually prove to be another alternative for the treatment of infections due to mycoplasmas and ureaplasmas and have the added advantage of having broad spectra of activity against many other organisms that may produce similar illnesses, including Streptococcus pneumoniae isolates with macrolide resistance mediated by erm(B) and/or mef(A) (9).
Previous studies that have used either a broth microdilution or an agar dilution procedure to determine MICs have shown that other ketolides, including telithromycin (HMR 3647), have very good in vitro activities against some human mycoplasmas and ureaplasmas (1, 2, 10, 23). Telithromycin MIC ranges published previously were 0.00003 to 0.031 μg/ml for M. pneumoniae (2, 10, 23), 0.06 to 0.25 μg/ml for M. fermentans (2), and ≤0.015 to 0.25 μg/ml for Ureaplasma spp. (2, 10). Although we did not compare ABT-773 directly with telithromycin in the present study and the earlier studies did not test ABT-773, our MIC data for ABT-773 suggest that it has in vitro activities against these organisms at least as good as those of telithromycin. Nilius et al. (13) reported ABT-773 MICs ≤0.0005 μg/ml for eight M. pneumoniae isolates, consistent with our findings for the larger group of 103 clinical isolates evaluated in the present study.
The MICs of erythromycin and clarithromycin for M. hominis are generally 16 to >64 μg/ml (2, 10, 19), and the macrolide susceptibility profiles for M. fermentans are generally similar to those for M. hominis. While the MICs of azithromycin for M. hominis may be somewhat lower than those of erythromycin and clarithromycin, as we noted in the present study and as has been reported by others (2, 10), many isolates are highly resistant. M. hominis has previously been shown to be susceptible to 16-membered macrolides such as josamycin (MICs, 0.06 to 0.25 μg/ml) (2, 20, 21). Bébéar et al. (2) and Kenny and Cartwright (10) reported that telithromycin has less activity against M. hominis than it does against other mycoplasmas. The telithromycin MIC ranges of 2 to 32 μg/ml that those investigators found are consistent with the limited activities of many drugs in the macrolide class against this organism. Furneri et al. (5) suggested that the natural erythromycin resistance found in M. hominis arises from a guanine-to-adenine transition in position 2057 in the central loop of domain V of 23S rRNA (Escherichia coli numbering scheme).
We have shown that the ketolide ABT-773 consistently inhibited M. hominis at ≤0.031 μg/ml. This documentation of in vitro susceptibility at such low concentrations is significant and is very interesting since it shows that ketolides, like other macrolides, may have variable in vitro activities against this organism, with ABT-773 having the lowest MICs among the MICs of the ketolides reported to date (1, 2).
Treatment of M. pneumoniae respiratory infections with erythromycin typically results in a relatively rapid alleviation of symptoms, but viable organisms can frequently be isolated from infected individuals for a prolonged time following therapy (12, 14, 16, 17). Perhaps it is the bacteriostatic effect of erythromycin that allows M. pneumoniae to continue to be shed following therapy, since organisms that are naturally resistant to this drug de novo appear to be uncommon, although relatively small numbers have been screened. It has been speculated that the development of erythromycin resistance in M. pneumoniae during treatment could account for the long-term shedding of the organisms from the respiratory tract. This concept is supported by the facts that erythromycin-resistant M. pneumoniae has been isolated from patients following erythromycin treatment (12, 16, 17) and that erythromycin-resistant mutants can be readily derived by selection in vitro (11, 14, 16, 17).
Naturally occurring and laboratory-derived erythromycin-resistant mutants of M. pneumoniae have been shown to contain A-to-G transitions within highly conserved regions of the central loop of domain V of 23S rRNA, believed to be the ribosomal binding site for macrolide-lincosamide-streptogramin B antibiotics (6, 8, 11, 14, 15). However, the dearth of reported cases of well-documented macrolide treatment failures and the mild nature of many M. pneumoniae infections imply that resistance to these agents does not have great clinical significance at this time. No studies have documented whether persistence of M. pneumoniae in the respiratory tract following treatment with clarithromycin, azithromycin, or the ketolides is less likely than persistence following treatment with erythromycin.
Bébéar et al. (2) reported that telithromycin is bactericidal against a reference strain of M. pneumoniae but not against M. hominis or Ureaplasma spp. The telithromycin MBC for M. pneumoniae was ≤0.12 μg/ml, similar to the values obtained for other macrolides. We found the macrolides and ABT-773 to have MBCs that were several dilutions higher than the corresponding MICs, in contrast to the fluoroquinolones, whose MBCs were generally within 2 dilutions of the MICs for M. pneumoniae and M. hominis. However, the MBCs of ABT-773 as well as those of the other macrolides tested against the three M. pneumoniae isolates tested were all ≤0.063 μg/ml, technically within the range of concentrations achievable in clinical settings.
In conclusion, the present study has shown that ABT-773 is inhibitory against M. pneumoniae, M. fermentans, M. hominis, and Ureaplasma spp., with MICs ≤0.031 μg/ml for all 153 isolates tested, making it as active or more active overall than all other agents tested in this investigation. ABT-773 is a promising drug for the treatment of infections caused by Mycoplasma and Ureaplasma species.
TABLE 1.
TABLE 1. MICs of ABT-773 and comparator agents for M. pneumoniae, M. fermentans, M. hominis, and Ureaplasma species
Organism and drugMIC (μg/ml)  
 Range50%90%
M. pneumoniae (n = 103)   
    ABT-773≤0.001-0.016≤0.001≤0.001
    Levofloxacin0.063-2.00.52
    Gatifloxacin0.016-0.250.0630.125
    Moxifloxacin0.016-0.250.0630.125
    Doxycycline0.016-20.250.5
    Azithromycin≤0.001≤0.001≤0.001
    Clarithromycin≤0.001-0.004≤0.001≤0.001
    Erythromycin≤0.001-0.016≤0.001≤0.004
M. fermentans (n = 12)   
    ABT-773≤0.008≤0.008≤0.008
    Levofloxacin0.031-0.0630.0630.063
    Gatifloxacin≤0.008-0.1≤0.0080.016
    Moxifloxacin≤0.008-0.1≤0.0080.016
    Doxycycline≤0.008-10.0631
    Clindamycin≤0.008-0.031≤0.0080.031
M. hominis (n = 14)   
    ABT-773≤0.008-0.0310.0160.031
    Levofloxacin0.125-0.50.1250.5
    Gatifloxacin0.016-0.0630.0310.063
    Moxifloxacin≤0.008-0.0310.0160.031
    Doxycycline≤0.008-160.516
    Clindamycin≤0.008-0.1250.0160.063
Ureaplasma species (n = 24)   
    ABT-773≤0.008-0.031≤0.0080.016
    Levofloxacin0.5-20.51
    Gatifloxacin0.125-10.250.5
    Moxifloxacin0.063-0.50.1250.25
    Doxycycline0.016-2.00.0310.25
    Azithromcyin0.063-4.00.251
    Clarithromcycin≤0.008-0.0630.0310.063
    Erythromycin0.125-2.00.51
TABLE 2.
TABLE 2. MBCs of ABT-773 and comparator agents for 12 M. pneumoniae isolates
DrugaNo. of isolates for which MBC was:   
 1× MIC2× MIC4× MIC≥8× MIC
ABT-7730003
Levofloxacin0273
Gatifloxacinb2333
Moxifloxacin0633
Azithromycin0012
Clarithromycin0003
Erythromycin01110
Doxycycline00012
a
Additional lower concentrations of ABT-773, azithromycin, clarithromycin, and erythromycin were tested against three M. pneumoniae isolates to allow more direct comparison among the drugs and to enable determination of the MBCs for these three isolates only.
b
One isolate had bacterial contamination and could not be evaluated.

Acknowledgments

This work was supported by a grant from Abbott Laboratories, North Chicago, Ill.

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cover image Antimicrobial Agents and Chemotherapy
Antimicrobial Agents and Chemotherapy
Volume 47Number 1January 2003
Pages: 39 - 42
PubMed: 12499166

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Received: 3 June 2002
Revision received: 24 August 2002
Accepted: 1 October 2002
Published online: 1 January 2003

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Ken B. Waites [email protected]
Departments of Pathology
Microbiology, University of Alabama at Birmingham, Birmingham, Alabama
Donna M. Crabb
Microbiology, University of Alabama at Birmingham, Birmingham, Alabama
Lynn B. Duffy
Microbiology, University of Alabama at Birmingham, Birmingham, Alabama

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