Journal of Antimicrobial Chemotherapy (2001) 47, 435-440
© 2001 The British Society for Antimicrobial Chemotherapy
In vitro pharmacodynamic modelling simulating free serum concentrations of fluoroquinolones against multidrug-resistant Streptococcus pneumoniae
a Department of Medical Microbiology, Faculties of b Medicine and c Pharmacy, University of Manitoba; d Departments of Clinical Microbiology and e Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada
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Abstract |
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An in vitro pharmacodynamic model was used to compare bacterial killing and the development of resistant mutants in the presence of respiratory fluoroquinolones and ciprofloxacin. Free (protein unbound) serum concentrations were simulated using peak serum concentrations and AUC24, achieved after standard oral doses for treatment of community-acquired respiratory infections. Respiratory fluoroquinolones reduced the inoculum of isolates of multidrug-resistant Streptococcus pneumoniae below the level of detection in the model at 12 h and did not allow regrowth to occur over 48 h. In contrast, ciprofloxacin had a bacteriostatic (<3 log10 reduction of the initial inoculum) effect, with rapid regrowth occurring over 48 h. Bacterial regrowth and the development of resistant mutants did not occur with any of the respiratory fluoroquinolones. Rapid regrowth and the development of resistant mutants, with MICs two- to eight-fold higher than the MIC before treatment, occurred with ciprofloxacin. These data suggest that the new respiratory fluoroquinolones with a free AUC24/MIC of 35–63 reduce the inoculum of multidrug-resistant S. pneumoniae below the level of detection without regrowth or development of resistance over 48 h. This study also demonstrated the poor activity of ciprofloxacin against S. pneumoniae.
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Introduction |
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Fluoroquinolones, primarily ciprofloxacin, have been used extensively for treating community-acquired respiratory infections.1,2 Ciprofloxacin has excellent activity against typical respiratory pathogens such as Haemophilus influenzae and Moraxella catarrhalis, high penetration into pulmonary tissues and fluids and documented clinical efficacy; it can be given twice daily, which enhances patient compliance, and extensive experience indicates its safety.2 The main disadvantage of using ciprofloxacin to treat community-acquired respiratory infections is its limited activity against Streptococcus pneumoniae.2–5 Published studies have reported breakthrough bacteraemia when ciprofloxacin was used for treatment of pneumococcal pneumonia, as well as the development of pneumococcal superinfection during therapy of nosocomial Pseudomonas aeruginosa pneumonia.4,5 Recently, new respiratory fluoroquinolones have been developed with significantly greater activity than ciprofloxacin against S. pneumoniae.1,2,6,7 These new agents have better pharmacodynamic activity than ciprofloxacin against S. pneumoniae because of their more potent intrinsic activity against this bacterium (manifested by lower MICs), as well as higher bioavailability providing greater AUC24s, which together lead to a greater AUC24/MIC.8–11
The AUC24/MIC can be used as an indicator of the pharmacodynamic potency of fluoroquinolones against pathogens.8–15 It has been reported that bacterial eradication is more likely to occur when ciprofloxacin is given intravenously to obtain an AUC24/MIC of 
125.12,14 In studies of patients treated with intravenous ciprofloxacin in which an AUC24/MIC of >100 was achieved, resistance did not develop during therapy.16 It should, however, be mentioned that these trials were performed primarily in patients with nosocomial lower respiratory tract infections, in critically ill ventilated patients in intensive care units. These patients were often infected with Gram-negative bacilli such as P. aeruginosa, Klebsiella pneumoniae and Enterobacter spp.12,16 The AUC24/MIC of respiratory fluoroquinolones required for the treatment of community-acquired respiratory infections such as pneumonia, or acute exacerbation of chronic bronchitis caused by S. pneumoniae is not clear. The AUC24/MIC of new respiratory fluoroquinolones against S. pneumoniae rarely approaches 125 and yet clinical trials have clearly demonstrated that these agents are bacteriologically effective for pneumococcal infections including pneumococcal bacteraemia.1,2,8,10,17–20 The purpose of this study was to compare respiratory fluoroquinolones (gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin and trovafloxacin) with ciprofloxacin by simulating free (protein unbound) serum concentrations in an in vitro pharmacodynamic model using multidrug-resistant S. pneumoniae.
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Materials and methods |
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Bacterial strains and culture conditions
Three multidrug-resistant isolates of S. pneumoniae were evaluated in this study. Each isolate was resistant to penicillin, erythromycin, clindamycin, trimethoprim–sulphamethoxazole, tetracycline and second-generation cephalosporins such as cefuroxime (Table I
). Each isolate was obtained from a recently performed cross-Canada respiratory organism susceptibility study, originated from a different region within Canada and was of a different serotype (isolates 2587, 2680 and 2663 were of serotypes 14, 19 and 23, respectively).21 Logarithmic phase cultures were prepared using a 0.5 McFarland (1 x 108 cfu/mL) standard by suspending several colonies in cation-supplemented Mueller–Hinton broth with 2.5% lysed horse blood. This suspension was diluted 1 in 100 and 20 µL of diluted suspension was further diluted in 60 mL of cation-supplemented Mueller–Hinton broth with 2.5% lysed horse blood (Oxoid, Nepean, Ontario). The resulting suspension was allowed to grow overnight at 37°C. In the morning the suspension was further diluted 1 in 10 and c. 60 mL of the diluted suspension was added to the in vitro pharmacodynamic model. Viable bacterial counts consistently yielded a starting inoculum of approximately 1 x 106 cfu/mL.14
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Antibiotic preparations and susceptibility testing
Antibiotics were obtained as laboratory-grade powders from their respective manufacturer (ciprofloxacin and moxifloxacin from Bayer, Mississauga, Ontario; gatifloxacin from Bristol Myers Squibb, Montreal, Quebec; grepafloxacin from GlaxoWellcome, Toronto, Ontario; levofloxacin from Janssen Ortho, Ajax, Ontario; and trovafloxacin from Pfizer, Montreal, Quebec), stock solutions were prepared and dilutions were made according to the NCCLS M7-A4 method.22,23 Following two subcultures from frozen stock, the MICs of the antimicrobial agents for the isolates were determined by the NCCLS broth microdilution method.22 All MIC determinations were performed in triplicate on separate days.
In vitro pharmacodynamic model/pharmacodynamic experiments
The in vitro pharmacodynamic model used in this study has been described previously.9,24 Logarithmic phase cultures were diluted into fresh cation-supplemented Mueller– Hinton broth with 2.5% lysed horse blood to achieve a final inoculum of approximately 1 x 106 cfu/mL. This initial inoculum was introduced into the central compartment (volume 610 mL) of the in vitro pharmacodynamic model and exposed to ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin or trovafloxacin, simulating free (protein unbound) serum concentrations obtained after standard dosing (flow rates ranging from 0.59 to 1.77 mL/ min) (see below). Pharmacodynamic experiments were performed in ambient air at 37°C. At 0, 1, 2, 4, 6, 12, 24, 26, 28, 30, 36 and 48 h, samples were removed from the central compartment and viable bacterial counts performed by plating serial 10-fold dilutions on to cation-supplemented Mueller–Hinton agar with 2.5% lysed horse blood. Plates were incubated overnight at 37°C in ambient air. The lowest dilution plated was 0.1 mL of undiluted sample and the lowest level of detection was 200 cfu/mL.
Antibiotic carry-over effects were prevented by adding 1% (w/v) MgCl2 to the Mueller–Hinton agar supplemented with 2.5% lysed horse blood to samples before plating. To evaluate the selection of mutants, samples were removed from the central compartment after 12, 24, 36 and 48 h and plated on to Mueller–Hinton agar with 2.5% lysed horse blood containing the respective fluoroquinolone at 2, 4 or 8 x MIC.14
Pharmacokinetics of fluoroquinolones in the in vitro pharmacodynamic model
Experiments were performed simulating peak serum concentrations (Cpmax) and AUCs of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin and trovafloxacin achieved in human serum after standard oral doses (ciprofloxacin 500 mg bd or 750 mg bd, gatifloxacin 400 mg od, grepafloxacin 600 mg od, levofloxacin 500 mg od, moxifloxacin 400 mg od, trovafloxacin 200 mg od) (Table II).1,2 Protein-free (unbound) serum concentrations were simulated using known protein binding fractions (ciprofloxacin, 30%; gatifloxacin, 20%; grepafloxacin, 50%; levofloxacin, 30%; moxifloxacin, 50%; trovafloxacin, 75%).2 Clearance was simulated using reported serum half-lives, which were 4 h for ciprofloxacin, 7 h for gatifloxacin and levofloxacin and 12 h for grepafloxacin, moxifloxacin and trovafloxacin.2 The pharmacokinetics of fluoroquinolones were evaluated by dosing these agents using standard doses in the central compartment and sampling from this compartment at 0, 0.5, 1, 2, 4, 8, 12, 12.5, 13, 14, 16, 20 and 24 h. Drug concentrations in each sample were measured by disc diffusion bioassay using a susceptible strain of Bacillus subtilis.14 The linear range of the bioassay was 0.1–7 mg/L. The AUC24 (mg•h/L) for each fluoroquinolone was calculated using the trapezoidal rule.14 The AUC24/ MIC of each fluoroquinolone against the specific S. pneumoniae isolates studied was calculated by dividing the AUC24 of the specific fluoroquinolone by the MIC for the S. pneumoniae isolate tested.
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Results |
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The MICs of the study agents for all three isolates of S. pneumoniae were identical (Table I
). The pharmacokinetic profiles of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin and trovafloxacin in the central compartment of the pharmacodynamic model were within 15% of predicted pharmacokinetic values. For example, 0.5 h after a simulated 750 mg bd dose, the peak ciprofloxacin concentration was 3.0 ± 0.3 mg/L within the central chamber. The corresponding total AUC24 was 28 mg•h/L and the simulated free AUC24 was 20 mg•h/L (Table II). Adjusting for protein binding, the free AUC24/MIC ranged from 7 for ciprofloxacin to 63 for trovafloxacin (Table II). The respiratory fluoroquinolones produced free AUC24/MICs that were four to nine times greater than those of ciprofloxacin.
The killing (log10 reduction of the original inoculum) of S. pneumoniae by fluoroquinolones simulating free serum concentrations is shown in Table III. The respiratory fluoroquinolones, gatifloxacin, levofloxacin, moxifloxacin and trovafloxacin, were all bactericidal at 6 h, whereas grepafloxacin was bactericidal at 12 h. At the 12 h time point, gatifloxacin, levofloxacin, moxifloxacin and trovafloxacin demonstrated bacterial eradication from the model. At the 24, 36 and 48 h time points, all respiratory fluoroquinolones reduced bacterial numbers below the level of detection in the model. Ciprofloxacin, on the other hand, demonstrated bacteriostatic activity (simulating both 500 mg and 750 mg bd) over the first 12 h, with subsequent bacterial regrowth over 24, 36 and 48 h time points.
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The observed MICs of the various fluoroquinolones for S. pneumoniae studied over time in the in vitro model are shown in Table IV
. With ciprofloxacin the MIC for all S. pneumoniae strains studied was 2 mg/L before treatment; this increased to 4–8 mg/L at 24 h, 4–16 mg/L (500 mg bd) at 36 h and 4–16 mg/L at 48 h. Simulating ciprofloxacin 750 mg bd dosing led to smaller increases in MICs over time compared with simulating ciprofloxacin 500 mg bd dosing (Table IV).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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In this study, an in vitro pharmacodynamic model was used to simulate the pharmacokinetic parameters Cpmax and AUC24/MIC of respiratory fluoroquinolones and ciprofloxacin. Standard oral doses of these agents used in the treatment of community-acquired respiratory infections such as pneumonia were simulated (Table II
).1,2 As protein binding varies from as little as 20% for gatifloxacin to as much as 75% for trovafloxacin, pharmacodynamic experiments were performed simulating free fluoroquinolone serum concentrations.2 The three isolates of S. pneumoniae chosen were studied because of their multidrug-resistant phenotype and their typical susceptibility patterns to fluoroquinolones (Table I).2,6,7,21
The order of S. pneumoniae killing by the new respiratory fluoroquinolones simulating free serum concentrations was gatifloxacin = levofloxacin = moxifloxacin = trovafloxacin > grepafloxacin (Table III). All respiratory fluoroquinolones reduced bacterial numbers below the level of detection by 24 h and no recovery was found up to 48 h, indicating complete eradication. Resistant mutants were not detected with any of these agents. In contrast, ciprofloxacin was bacteriostatic and rapid regrowth occurred over 48 h. Resistant mutants were obtained over 48 h with MICs increasing by two- to eight-fold (Table IV).
This study has demonstrated that S. pneumoniae can be eradicated from an in vitro pharmacodynamic model without bacterial regrowth despite achieving a free AUC24/ MIC of only 35–63. Unlike previous investigators, we did not demonstrate a requirement for an AUC24/MIC of 125 for eradication of the pathogen.12 Although the discrepancy between these observations may seem perplexing, ample clinical data have been published with the respiratory fluoroquinolones documenting bacteriological eradication of S. pneumoniae and clinical success in treating patients with community-acquired respiratory infections.1–3,17–20,25 Other investigators have also documented excellent bacteriological eradication of S. pneumoniae with respiratory fluoroquinolones despite achieving AUC24/ MIC of only 30–64.9–11,14,26,27 Differences in required AUC24/MIC may depend on host or pathogen. Previous reports of a required AUC24/MIC of 125 were based on studies of pathogen eradication in hospitalized patients with respiratory infections.8,12,16 Specifically, the patient population studied included individuals with nosocomial lower respiratory tract infections, who were critically ill, in the intensive care unit, required ventilation and frequently were infected with Gram-negative bacilli such as P. aeruginosa, K. pneumoniae and Enterobacter spp.8,12,16 These investigators also reported that obtaining an AUC24/MIC of >100 prevented the development of resistance during therapy in this patient population.8,12,16 It seems plausible that when treating ambulatory, immunocompetent patients with community-acquired respiratory infections, such as pneumonia caused by S. pneumoniae, AUC24/MICs do not have to be as high as when treating the critically ill patients mentioned above. Our study is consistent with previously published findings that an AUC24/MIC of the new respiratory fluoroquinolones ranging from 30 to 64 may be sufficient to eradicate even multidrug-resistant S. pneumoniae from in vitro models and prevent the development of resistance during therapy.9,10,14
The inferior activity of ciprofloxacin simulating 500 or 750 mg bd against S. pneumoniae has been reported by other investigators.10,14 The development of resistant mutants as early as 24 h into experiments was noted (Table IV). These results may help explain the clinical failures that have been reported using ciprofloxacin for respiratory infections.4,5
The new respiratory fluoroquinolones, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin and trovafloxacin, demonstrated better pharmacodynamic activity than ciprofloxacin: they showed superior bacterial killing of multidrug-resistant S. pneumoniae, the absence of bacterial regrowth over 48 h and lack of development of resistant mutants. Free AUC24/MIC of 35–63 eradicated S. pneumoniae from the in vitro model and thus did not allow any regrowth to occur. This study clearly supports the excellent bacteriological and clinical cure rates obtained with the new respiratory fluoroquinolones in the treatment of community-acquired respiratory infections. It also demonstrates the inferior activity of ciprofloxacin against S. pneumoniae and the rapid development of ciprofloxacin-resistant mutants during ciprofloxacin treatment.
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Acknowledgments |
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This study was supported in part by Bayer Canada Inc. and Janssen-Ortho Canada Inc. M.W. was supported by a Medical Research Council of Canada Summer Studentship. G.Z. is supported by a Merck Frosst Chair in Pharmaceutical Microbiology.
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Notes |
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* Correspondence address. Microbiology, Health Sciences Centre, MS673, 820 Sherbrook Street, Winnipeg, Manitoba, Canada R3A 1R9. Tel: +1-204-787-4902; Fax: +1-204-787-4699; E-mail: ggzhanel{at}pcs.mb.ca
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Received 26 April 2000; returned 17 August 2000; revised 20 October 2000; accepted 20 November 2000
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