1 Division of Pediatric Infectious Diseases, 2 Department of Pathology, 3 Center for Clinical Laboratories, Mount Sinai School of Medicine, New York, NY, USA
Received 16 October 2002; returned 17 December 2002; revised 3 March 2003; accepted 4 March 2003
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Abstract |
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Methods: The activity of each drug alone was determined by an agar dilution method. Chequerboard synergy testing was then performed against all the isolates. Timekill assays were done on selected isolates to assess correlation with the chequerboard results.
Results: Synergy was demonstrated with the following combinations at achievable serum concentrations: gatifloxacin/piperacillin for 80% and gatifloxacin/cefepime for 60% of S. maltophilia; gatifloxacin/gentamicin for 60%, and gatifloxacin/cefepime for 50% of ESBL-producing K. pneumoniae, and in all drug combinations for 5070% of P. aeruginosa. Indifference was noted for the majority of B. cepacia and VRE isolates. Antagonism at therapeutic serum levels was observed with gatifloxacin/piperacillin against a single isolate of B. cepacia. No distinct trend in drug interaction was seen with the different drug combinations against MRSA. Timekill analyses against selected isolates confirmed the synergic activity of the following drug combinations seen in the chequerboard assays: gatifloxacin/cefepime and gatifloxacin/piperacillin against P. aeruginosa, gatifloxacin/gentamicin against B. cepacia, and gatifloxacin/gentamicin and gatifloxacin/meropenem against ESBL-producing K. pneumoniae.
Conclusions: Gatifloxacin was synergic with the ß-lactams piperacillin, cefepime and meropenem, and with gentamicin against some drug-resistant pathogens. Some of the timekill analyses against P. aeruginosa, B. cepacia and ESBL-producing K. pneumoniae were in accordance with chequerboard results. Timekill analyses against S. maltophilia did not confirm the synergy seen in chequerboard testing.
Keywords: synergy, fluoroquinolones, gatifloxacin, susceptibility testing
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Introduction |
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Gatifloxacin is an FDA-approved synthetic broad-spectrum fluoroquinolone useful for infections caused by both Gram-negative and -positive bacteria. It inhibits both bacterial DNA gyrase and topoisomerase IV.2,3 The structure of gatifloxacin differs from the earlier fluoroquinolones by the presence in the C-8 position of a methoxy group that enhances antibacterial activity against Gram-positive bacteria,4 improves its activity against DNA gyrase mutants of Escherichia coli5 and has the potential to reduce the rate of development of resistance to fluoroquinolones in general.3 The methoxy group in the C-8 position also diminishes photosensitivity reactions.6 In an in vitro study comparing the activity of gatifloxacin with those of ciprofloxacin and ofloxacin, gatifloxacin was more active against Stenotrophomonas maltophilia, equipotent against Burkholderia cepacia, but demonstrated less activity than ciprofloxacin against Pseudomonas aeruginosa.7 Gatifloxacin, ciprofloxacin, levofloxacin and moxifloxacin inhibited members of the family Enterobacteriaceae comparably.8,9 Gatifloxacin had good activity against Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus and Enterococcus faecalis.9 Gatifloxacin is more potent than ciprofloxacin against methicillin-resistant S. aureus (MRSA),9 although the clinical significance of this still needs to be investigated.
The primary objective of this study was to examine the in vitro activity of gatifloxacin when combined with the ß-lactam agents cefepime, meropenem and piperacillin, and with gentamicin against S. maltophilia, P. aeruginosa, B. cepacia, extended-spectrum ß-lactamase (ESBL)-producing strains of Klebsiella pneumoniae, MRSA and vancomycin-resistant Enterococcus faecium (VRE). The activity of each drug alone against these bacteria was also examined. The above pathogens are established causes of nosocomial infections in an appreciable number of medical facilities.1012 Combination therapy, primarily against the Gram-negative pathogens, may play a crucial role in eradicating these organisms in patients with sepsis caused by these bacteria. For the Gram-positive organisms, knowledge of the absence of in vitro antagonism between the antimicrobial combinations provides potentially useful information about the possible risks associated with initiating empirical antimicrobial therapy when infections involve multiple pathogens that may include antibiotic-resistant Gram-positive species.
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Materials and methods |
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Ten clinical isolates each of S. maltophilia, P. aeruginosa, B. cepacia, ESBL-producing K. pneumoniae, VRE and MRSA from patients at the Mount Sinai Medical Center were tested in this study. All organisms were collected within 2 months prior to testing, with the exception of eight B. cepacia and four S. maltophilia isolates that were recovered from our collection maintained at 70°C in skimmed milk. Isolates were selected based on their highly resistant antimicrobial susceptibility testing profile. Identification of the stock isolates was reconfirmed with the API 20NE System (bioMérieux, Hazelwood, MO, USA).
Agar dilution MIC determinations
Standard laboratory powders of gatifloxacin (Bristol-Myers Squibb, New Brunswick, NJ, USA), cefepime (Elan Pharmaceuticals, San Diego, CA, USA), meropenem (AstraZeneca, Wilmington, DE, USA), piperacillin (Lederle, Puerto Rico) and gentamicin (SigmaAldrich, St Louis, MO, USA) were used in the study. The MICs for all isolates of each drug alone was determined by the agar dilution method in accordance with NCCLS guidelines13 using cation-supplemented MuellerHinton agar (Becton Dickinson, Baltimore, MD, USA) before chequerboard testing. Agar dilution plates for all antimicrobials were prepared 24 h before inoculation and stored overnight at 4°C, except for dilutions of meropenem, which were prepared on the day of inoculation. Drug-free plates were used as growth controls. Purity of isolates was checked throughout the study by examination of colony morphology and Gram staining. Inoculum was prepared by the direct colony suspension method as follows: three to five identical colonies were selected after 1820 h of incubation on 5% sheep bloodtrypticase soy agar (TSA) plates (Becton Dickinson) and suspended in 0.9% NaCl to a density equivalent to a 0.5 McFarland standard. The suspension was further diluted to obtain a final inoculum of 104 cfu/spot of the Steers replicator. The density of each inoculum was determined by dilution studies. Plates were incubated at 35°C for 1820 h for the Gram-negative organisms and for 24 h for MRSA and VRE. Standard quality control strains of P. aeruginosa ATCC 27853 and S. aureus ATCC 29213 were included in each run.
Chequerboard synergy testing
The agar dilution method served to determine the activity of gatifloxacin in combination with cefepime, meropenem, piperacillin and gentamicin. Dilutions ranging from 256 to 0.03 mg/L were tested for all drug combinations. Organisms and agar dilution plates were prepared as described above for the MIC determination. The fractional inhibitory concentration (FIC) index was calculated using the formulae previously published:14 FIC index = (Ac/Aa) + (Bc/Ba), where A and B are the two drugs being tested, Aa and Ba are the MICs obtained when each drug was tested alone, and Ac and Bc are the concentrations of each compound at the lowest effective combination. Synergy (FIC index 0.5) was defined as a four-fold or greater decrease in MIC of both drugs in combination compared with the drugs tested individually. Partial synergy was defined as a four-fold or greater decrease in MIC with one agent with a two-fold decrease in the other agent (FIC >0.5 but <1). Additivity was defined as a two-fold drop in MIC with both agents (FIC = 1). Indifference was noted when there was no change in MIC whether the agents were tested alone or in combination (FIC >1 but <4) and results were interpreted as antagonistic when there was a four-fold increase in MIC for both agents when the drugs were tested in combination as compared with results when each drug was tested alone (FIC
4). Interpretation of the drug interactions was based on achievable serum concentrations of the drugs.
Broth macrodilution MIC determinations and timekill assays
Based on results of the chequerboard testing, isolates against which various drug combinations displayed synergy were selected for the timekill studies. Two isolates each of S. maltophilia and B. cepacia and one isolate each of ESBL-producing K. pneumoniae and P. aeruginosa were challenged with the various antibiotic combinations. Prior to performing the timekill analyses, MIC determinations using broth macrodilution method were performed against the selected isolates. Two-fold dilutions of antibiotic were prepared using cation-supplemented MuellerHinton broth (Becton Dickinson) with a final volume of 1 mL. A control tube containing broth without antimicrobial agent was used for each organism tested. The inoculum was prepared from organisms grown for 46 h in broth and diluted to obtain a suspension containing the desired initial inoculum of 105106 cfu/mL in the growth control tube. Inoculum count verification plates were prepared for each isolate to be tested. Tubes were incubated at 35°C for 2024 h. The MIC was defined as the lowest concentration of antibiotic that completely inhibited the growth of the organism. Strains of E. coli ATCC 25922 and P. aeruginosa ATCC 27853 were used as control organisms for each antibiotic tested.
Drug concentrations used for the timekill assays were based on three criteria: (i) concentrations likely to produce synergy as seen in chequerboard testing; (ii) concentrations that were within clinically achievable serum levels for each drug; and (iii) concentrations that were no more than twice the MIC of each drug. Timekill assays were performed in 10 mL of cation-supplemented MuellerHinton broth (Becton Dickinson). Each assay included a growth control tube with no antibiotic. The inoculum was prepared from organisms grown for 46 h in cation-supplemented MuellerHinton broth and diluted to obtain the desired initial inoculum of 105106 cfu/mL in the growth control tube. The antibiotic-containing tubes and the growth control tubes were incubated at 35°C and sampled at 0, 2, 4, 8 and 24 h from the time of inoculation for colony viability counts. Aliquots of 0.1 mL from serial 10-fold dilutions of each tube were spread onto TSA agar plates in duplicate, incubated at 35°C for 48 h for S. maltophilia and B. cepacia, and for 24 h for the other organisms, at which time colonies were enumerated. Colony counts were performed only on plates with 30300 colonies. Data were analysed based on viability counts at 24 h. Antimicrobial agents were considered bactericidal at a given concentration if they reduced the original inoculum by 99.9% (>3 log10 cfu/mL) for each time period and bacteriostatic if the inoculum was reduced by 03 log10 cfu/mL. The interpretation of results of antimicrobial interaction using timekill methodology was based on the discussion by Eliopoulos & Moellering.14 Synergy was interpreted as a 2 log10 decrease in viable count with the combination at 24 h compared with the most active single drug. Indifference was defined as a <10-fold decrease in viable count at 24 h with the combination, compared with the most active single antimicrobial alone. Antagonism was defined as
2 log10 increase in colony count at 24 h with the combination, compared with the most active single drug alone.14
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Results |
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Results of the chequerboard synergy testing are summarized in Table . The combination of gatifloxacin/piperacillin exhibited synergy for 80% and gatifloxacin/cefepime for 60% of S. maltophilia, whereas gatifloxacin/gentamicin showed partial synergy for 80% of the strains tested. Indifference was noted with gatifloxacin/meropenem for all isolates of S. maltophilia. For P. aeruginosa, all drug combinations displayed synergy against at least 50% of the isolates, and gatifloxacin/meropenem was synergic against 70%. All drug combinations were indifferent against at least 50% of B. cepacia isolates, with gatifloxacin/piperacillin antagonistic with one isolate. Gatifloxacin/gentamicin was synergic against 60% and gatifloxacin/cefepime against 50% of ESBL-producing K. pneumoniae. Indifference was noted with all drug combinations for at least 80% of VRE. Synergy was seen against only 2030% of MRSA with all drug combinations.
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Timekill responses of P. aeruginosa are depicted in Figure 2. Gatifloxacin at 2 mg/L in combination with cefepime at 8 mg/L, and gatifloxacin at 2 mg/L in combination with piperacillin at 64 mg/L, resulted in at least a 2 log10 decrease in viable colonies, and by definition were synergic. The effect of these combinations was bacteriostatic. Increasing the dose of gatifloxacin to 4 mg/L in combination with cefepime at 8 mg/L and in combination with piperacillin at 64 mg/L resulted in enhanced activity. For the combination of gatifloxacin and piperacillin, growth at 2 and 4 h followed the growth curve with either gatifloxacin alone or piperacillin alone. This may suggest that the addition of one of either drug may have prevented the emergence of resistant subpopulations of P. aeruginosa. The combination of gatifloxacin/gentamicin at achievable serum concentrations showed indifference. Meropenem at 0.06 mg/L with gatifloxacin at 4 mg/L failed to inhibit the growth of the organism tested.
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Discussion |
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Several in vitro studies have been performed to examine the susceptibilities of both Gram-negative and -positive clinical isolates to gatifloxacin.79,16,17 Overall, the growth of S. maltophilia, P. aeruginosa and VRE isolates tested in this study was inhibited by gatifloxacin concentrations within the ranges described in earlier studies.8,9,16,17 In a study comparing the activity of ciprofloxacin, gatifloxacin and levofloxacin against 210 P. aeruginosa isolates from the urinary tract, there were no significant differences in susceptibility patterns of the three fluoroquinolones tested.18 Notable is the enhanced activity of gatifloxacin against S. maltophilia in comparison with older fluoroquinolones such as ciprofloxacin.7,8,17 The MICs of gatifloxacin for B. cepacia, ESBL-producing K. pneumoniae and MRSA isolates in this study were generally higher than those previously reported in studies involving these organisms.79,16 It does appear in this study that gatifloxacin, like other fluoroquinolones,19 has less activity against many strains of ESBL-producing K. pneumoniae.
Combinations of fluoroquinolones with other antimicrobial agents have been investigated extensively.2023 Most studies combining fluoroquinolones with aminoglycosides have shown indifference against members of the Enterobacteriaceae and against P. aeruginosa, whereas fluoroquinolones with antipseudomonal penicillins have been reported to be synergic against 2050% of P. aeruginosa isolates.22 In one study using the chequerboard methodology evaluating ciprofloxacin with ticarcillinclavulanate against S. maltophilia, synergy was seen against 24 of 31 strains.17
To date, there have been three in vitro studies published examining the antimicrobial interaction of gatifloxacin with non-fluoroquinolone compounds against the same species of bacteria tested in this study.2426 In one study using both chequerboard and timekill analysis against P. aeruginosa ATCC 27853, there was no synergy or antagonism demonstrated with the following combinations: gatifloxacin/amikacin, gatifloxacin/imipenem and gatifloxacin/cefepime.24 In another published study using timekill analyses, synergy was seen with the following combinations: gatifloxacin/ticarcillinclavulanate and gatifloxacin/ceftazidime against five of eight S. maltophilia strains; gatifloxacin/cefepime against three of eight, gatifloxacin/piperacillin against seven of eight P. aeruginosa strains; and gatifloxacin/ceftazidime against five of six B. cepacia strains.25 A recent timekill study against 10 P. aeruginosa isolates combining ceftazidime or cefepime with gatifloxacin, ciprofloxacin, levofloxacin or moxifloxacin indicated that in vitro synergy was demonstrable against 6080% of isolates tested, and that no significant differences existed among the cephalosporin/fluoroquinolone combinations.26
In this study, the chequerboard analysis showed that gatifloxacin in combination with gentamicin or one of the three ß-lactam agents demonstrated synergic activity against many strains of S. maltophilia, P. aeruginosa and ESBL-producing K. pneumoniae isolates. Using both chequerboard and timekill methods to assess the antibiotic combinations against these non-fermenters, there was no antagonism between the combined agents tested at concentrations up to 8 x MIC for these pathogens (data not shown). By chequerboard analysis, only the gatifloxacin/gentamicin combination demonstrated synergic activity against B. cepacia, VRE and MRSA, and then only for 20% of the strains tested.
Using the timekill method in this study, some, but not all, of the combinations tested against the selected isolates confirmed the synergic activity demonstrated with the chequerboard method. This may be because the concentrations tested in the timekill method were not optimal. Using higher concentrations of antimicrobials closer to the maximum achievable serum concentrations may yield more favourable results. Differences in results between chequerboard and timekill method may also stem from the inherent limitation of chequerboard analysis to provide only an all-or-none response at one point in time. Results reported are not quantifiable and may only reflect inhibitory, but not bactericidal, activity. In general, chequerboard assays are considered screening assays to assess possible synergic activity based on bacteriostatic activity, but bactericidal activity may not be appreciated; this can only be assessed by a method such as a killing curve.
With the combinations of gatifloxacin/piperacillin against P. aeruginosa, and gatifloxacin/gentamicin and gatifloxacin/meropenem against ESBL-producing K. pneumoniae (Figures 2b, and 4a and b), it is worthwhile to note that the timekill curves for the drug combinations at 24 h indicate synergy, although the 2 and 4 h kill curves reflect the activity of the more active drug. In these cases, it may be that the addition of the second antimicrobial prevents the emergence of resistant subpopulations of the strains tested. Prevention of emergence of resistance may be clinically as important as synergic bactericidal activity for these difficult to treat pathogens.
The significance of the above in vitro findings must be confirmed in the clinical setting, but properly randomized and controlled clinical trials may not be feasible to perform. The concentrations of the antimicrobials used in the timekill analyses were all within clinically achievable levels. This emphasizes the potential beneficial value of these combinations for treatment of seriously ill patients with infections caused by the pathogens tested, especially when there is a paucity of other therapeutic options. Each clinical case needs to be individualized, however. Both the chequerboard and timekill approaches demonstrated that the bacteria in this investigation, chosen on the basis of their general in vitro unresponsiveness to usual therapeutic agents, reacted favourably to combinations of gatifloxacin, a recently released fluoroquinolone, with an aminoglycoside as well as with several ß-lactams. If clinical experience supports these observations, synergy studies to evaluate appropriate combinations of antimicrobial agents may guide therapy for unresponsive infectious complications. Greater efforts to simplify the analytical approach of antimicrobial combinations, based on dilutions and/or multiples of achievable blood levels, are needed to promote greater appreciation of rational antimicrobial combination therapeutic regimens. Such guidance may lessen the selective pressures existing in many medical facilities with constantly increasing resistant microbial populations challenging the rapid recovery of patients.
In summary, chequerboard analysis showed that gatifloxacin is synergic or partially synergic with the ß-lactams cefepime, meropenem and piperacillin, as well as with gentamicin against many drug-resistant pathogens. Antagonism was only seen with a single isolate of B. cepacia when tested with the combination of gatifloxacin and piperacillin. Indifference was noted with all drug combinations for at least 80% of VRE. Synergy was seen against only 2030% of MRSA with all drug combinations. Timekill analyses of the different combinations correlated with chequerboard results with some of the selected isolates tested. The clinical impact of these findings remains to be further elucidated.
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Acknowledgements |
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Footnotes |
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Present address: Long Island Jewish Medical Center, New Hyde Park, NY, USA.
¶ Present address: Carolinas Medical Center, Charlotte, NC, USA.
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