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Cross-over assessment of serum bactericidal activity of moxifloxacin and levofloxacin versus penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae in healthy volunteers
Diagnostic Microbiology and Infectious Disease 58 (2007) 375 – 378 www.elsevier.com/locate/diagmicrobio
Cross-over assessment of serum bactericidal activity of moxifloxacin and levofloxacin versus penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae in healthy volunteers Daniel Hart4, Melvin P. Weinstein Division of Allergy, Immunology, and Infectious Diseases, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA Received 1 November 2006; accepted 6 February 2007
Abstract We compared the serum bactericidal activity (SBA) of moxifloxacin and levofloxacin against penicillin-susceptible and penicillinresistant Streptococcus pneumoniae in 12 healthy volunteers. Each subject received 3 days of oral moxifloxacin 400 mg daily and levofloxacin 750 mg daily, respectively, with a 2- to 4-week washout period between regimens. Blood was drawn at 6 time points after the third dose of each antibiotic. Mean serum bactericidal titers (MSBTRs) for moxifloxacin were 4-fold higher than the mean titers for levofloxacin at each time point. For each drug, MSBTRs at each time point were the same or within one 2-fold dilution when analyzed according to the penicillin susceptibility of the strains or the sex of the subjects. The difference in SBA of the 2 drugs may have implications for the emergence of resistance and clinical outcome. D 2007 Elsevier Inc. All rights reserved. Keywords: Serum bactericidal activity; Moxifloxacin; Levofloxacin; Streptococcus pneumoniae
A continuing lesson of the antibiotic era is that the longer an agent or class of agents is used, the more likely it is that microbial resistance will develop. The fluoroquinolone class of antibiotics is no exception. Quinolone prescriptions in Canada increased from 0.8 to 5.5 per 100 persons per year from 1988 to 1997 (Chen et al., 1999). Concordantly, the percentage of pneumococci with reduced susceptibility to quinolones increased from 0 in 1993 to 1.7 in 1997 and 1998 (Chen et al., 1999). In the United States, pneumococcal resistance to quinolones has increased, whereas resistance to other drug classes has decreased or plateaued (Doern et al., 2005). Not surprisingly, there are reports of fluoroquinolone failure clinically, including levofloxacin
This research was presented in part as a poster at the 43rd Annual Meeting of the IDSA, San Francisco, CA, October 2005 (Abstract #476). 4 Corresponding author. Division of Allergy, Immunology, and Infectious Diseases, UMDNJ—Robert Wood Johnson Medical School, One Robert Wood Johnson Place, New Brunswick, NJ 08903-0019, USA. Tel.: +1-732-235-8012; fax: +1-732-235-7951. E-mail address: [email protected] (D. Hart). 0732-8893/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2007.02.006
failure in pneumococcal pneumonia (Davidson et al., 2002; Empey et al., 2001; Kays et al., 2002; Urban et al., 2001) and acute exacerbation of chronic obstructive pulmonary disease (Perez-Trallero et al., 2005). Fuller and Low (2005) recently reviewed published cases of fluoroquinolone treatment failures in respiratory infections with quinoloneresistant pneumococci. All failures involved ciprofloxacin or levofloxacin. Moxifloxacin was cleared for use by the Food and Drug Administration in 1999 and has demonstrated greater in vitro activity against pneumococci in comparison with other fluoroquinolones including levofloxacin (Reinert et al., 1998; Saravolatz et al., 2001). Conventional in vitro susceptibility testing does not fully consider the pharmacokinetic properties of an antimicrobial agent. By contrast, the serum bactericidal test (SBT) accounts more completely for the pharmacokinetic properties of the antimicrobial agents being administered (Schlichter and MacLean, 1947; Schlichter et al., 1949), measuring the inhibitory activity of serum, from a patient receiving antibiotic therapy, against the bacterial pathogen isolated from the patient’s blood. Over the years, the SBT
376
D. Hart, M.P. Weinstein / Diagnostic Microbiology and Infectious Disease 58 (2007) 375 – 378
After administration of the third dose of each antibiotic, subjects stayed at the Clinical Research Center at Robert Wood Johnson University Hospital (RWJUH, New Brunswick, NJ) and had blood drawn at 1, 2, 4, 8, 12, and 24 h after dosing. Three isolates of pen-S (MICs: 0.016, 0.012, and 0.023 Ag/mL) and 3 isolates of pen-R (MICs: 8, 2, and 2 Ag/mL) S. pneumoniae were used in the study. All isolates were susceptible to levofloxacin (MICs: 0.38, 0.75, 0.38, 0.25, 0.5, and 0.38 Ag/mL) and moxifloxacin (MICs: 0.064, 0.125, 0.047, 0.047, 0.094, and 0.047 Ag/mL). All isolates were from bacteremic patients at RWJUH. SBTs were performed by the standardized microdilution method according to the CLSI/NCCLS guidelines (NCCLS, 1999). Twelve subjects who met the enrollment criteria completed the study. Mean serum bactericidal titers (MSBTRs) for levofloxacin and moxifloxacin are categorized by subject’s sex and by penicillin susceptibility of the tested isolates in Table 1. Maximal MSBTRs were 1:16 for levofloxacin and 1:64 for moxifloxacin. Twenty-four hours after drug administration, mean titers were b1:2 for levofloxacin and 1:8 for moxifloxacin. MSBTRs for all subjects combined were at least 4-fold higher for moxifloxacin compared with levofloxacin at each time point over a 24-h period. For each drug at each time point, mean titers were either identical or within one 2-fold dilution regardless of subject’s sex or penicillin susceptibility of the isolates. In a previous study of 12 healthy volunteers dosed with 500 mg of levofloxacin, there was no difference in the level or duration of SBA based on penicillin susceptibility (Shah, 1999). Not surprisingly, in our study, MSBTRs for either moxifloxacin or levofloxacin were not affected by the penicillin susceptibility status of the pneumococci. A sex difference was noted for both drugs with regard to the time of peak SBA. In males, maximal MSBTRs were observed at 1 h after either drug was administered; however, for females, maximal titers were observed at 2 or 4 h postdosing. Subjects were allowed to take the antibiotic with or without food; the option chosen was not recorded. This difference has not been observed
has undergone modifications (Reller and Stratton, 1977; Stratton and Reller, 1977), eventually resulting in guidelines from the Clinical and Laboratory Standards Institute (CLSI—formerly National Committee for Clinical Laboratory Standards, NCCLS, 1999). By factoring in absorption, distribution, protein binding, and elimination of a drug, the SBT has the potential to be a more reliable predictor of clinical and microbiologic outcome than conventional in vitro susceptibility testing. The SBT has been evaluated as an adjunct in the management of infective endocarditis (Weinstein et al., 1985) and acute and chronic osteomyelitis (Weinstein et al., 1987). Furthermore, serum from healthy volunteers to whom antibiotics have been administered can be used ex vivo to compare bactericidal activity of drugs against potential pathogens. In this study, we compare the serum bactericidal activity (SBA) of moxifloxacin and levofloxacin against both penicillin-susceptible (pen-S) and penicillin-resistant (penR) Streptococcus pneumoniae in 12 healthy volunteers (6 males and 6 females). Subjects were required to be 18 to 40 years old and within 10% of ideal body weight. Health was assessed by the investigators based on history, physical examination, routine laboratory screening, and electrocardiogram. Subjects were required to discontinue any medications for 24 h before starting either study drug. Exclusion criteria consisted of known hypersensitivity to quinolones, history of alcohol/substance abuse, pregnancy, or use of an investigational drug within the preceding 30 days. Patients could also be excluded for a history of cardiopulmonary, renal, gastrointestinal, or hepatic disease or any current or chronic infection. Each subject received 3 days of oral moxifloxacin 400 mg daily and levofloxacin 750 mg daily; the 2 regimens were separated by a 2- to 4-week period to allow sufficient time for washout of the first study drug. The order in which each antibiotic series was administered was random, resulting in 6 patients starting with moxifloxacin and 6 with levofloxacin.
Table 1 Mean reciprocal serum bactericidal titers of levofloxacin and moxifloxacin according to susceptibility of S. pneumoniae strains to penicillin and sex of study subjects Drug
Penicillin susceptibility
Levofloxacin
a
Susceptible Resistantb
Moxifloxacin
All isolates Susceptiblea Resistantb All isolates
a b
Penicillin susceptible: V 0.06 Ag/mL. Penicillin resistant: z 2.0 Ag/mL.
Sex
M F M F M F M F
Time postdose (h) 1
2
4
8
12
24
16 8 16 8 8 32 32 32 32 32
8 16 8 16 16 32 64 32 64 64
8 8 8 16 8 32 64 32 64 32
4 8 4 8 4 32 32 16 32 32
2 4 2 4 4 16 16 8 16 16
b2 b2 b2 b2 b2 8 8 8 8 8
D. Hart, M.P. Weinstein / Diagnostic Microbiology and Infectious Disease 58 (2007) 375 – 378
previously by the manufacturer of either antimicrobial agent (personal communication), and the significance of this finding is unclear. Moxifloxacin had superior SBA against S. pneumoniae compared with levofloxacin in this study. This difference may have implications for clinical outcome and for preventing the emergence of resistance. There is very little data comparing clinical efficacy of moxifloxacin and levofloxacin directly in humans with pneumonia. Both were well tolerated and efficacious in a study that focused on the safety and efficacy of moxifloxacin and levofloxacin in elderly patients hospitalized with community-acquired pneumonia (Anzueto et al., 2006). The 2 antibiotics have been compared in animal models, including an evaluation against quinoloneresistant strains of S. pneumoniae (Alkorta et al., 2005). In this study, gemifloxacin and moxifloxacin had better efficacy than levofloxacin in a mouse model. The authors suggested that the predicted in vivo efficacy of quinolones should be based on minimum bactericidal concentrations (MBCs) in addition to the presence of molecular mutations conferring quinolone resistance. Whether or not the greater SBA and in vitro activity of moxifloxacin compared with that of levofloxacin will be associated with delayed emergence of resistance is unknown. However, an in vitro microbial resistance hypothesis, the mutant selection window, has been proposed (Drlica, 2003; Zhao and Drlica, 2001). The mutant selection window is the concentration range between the point where growth inhibition begins (which correlates with the MIC) and the point at which no resistant isolates are detected when N 1010 cells are plated in the presence of drug (which correlates with the mutant prevention concentration [MPC]). Only bacterial isolates with 2-step fluoroquinolone mutations would grow above the MPC. However, within the window, 1-step mutants can be selected, which will increase the likelihood of a second mutation. Fluoroquinolones that maintain a drug concentration above the MPC are more likely to protect against the emergence of resistance. Blondeau et al. (2001) demonstrated that moxifloxacin and gatifloxacin can achieve serum levels above the MPC. They suggested the same for levofloxacin if more frequent administration or higher doses are used. However, organisms can have higher MPCs if they already have first step mutations. Croisier et al. (2004) showed in a rabbit model that pneumococcal strains with preexisting single mutations (particularly parC) yielded a high rate of new mutations in the presence of levofloxacin or moxifloxacin, resulting in a failure to decrease the bacterial load in the lungs. These strains had high MPCs that enabled the growth of mutants within the mutant selection window. In conclusion, in this ex vivo study, the SBA of moxifloxacin was approximately 4-fold greater than that of levofloxacin versus isolates of pen-S and pen-R S. pneumoniae, confirming the known greater in vitro potency of moxifloxacin. Whether this potency will
377
translate into better clinical outcome or delay emergence of resistance remains to be proven. Acknowledgments The authors thank Judy Rothberg for her technical work, Eileen Lindsey for her secretarial support, and the staff of the Clinical Research Center of Robert Wood Johnson Medical School and University Hospital, New Brunswick, NJ, for their help with patient recruitment and nursing care. This study was supported in part by a grant from Bayer (Pittsburgh, PA). References Alkorta M, Gimenez MJ, Vicente D, Aguilar L, Perez-Trallero E (2005) In vivo activity of gemifloxacin, moxifloxacin, and levofloxacin against pneumococci with gyrA and parC point mutations in a sepsis mouse model measured with the all or nothing mortality end-point. Int J Antimicrob Agents 25:163 – 167. Anzueto A, Niederman MS, Pearle J, Restrepo MI, Heyder A, Choudhri SH (2006) Community-acquired pneumonia recovery in the elderly (CAPRIE): efficacy and safety of moxifloxacin therapy versus that of levofloxacin therapy. Clin Infect Dis 42:73 – 81. Blondeau JM, Zhao X, Hansen G, Drlica K (2001) Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 45:433 – 438. Chen DK, McGeer A, de Azavedo JC, Low DE (1999) Decreased susceptibility of Streptococcus pneumoniae. N Engl J Med 341: 233 – 239. Croisier D, Etienne M, Bergoin E, Charles PE, Lequeu C, Piroth L, Portier H, Chavanet P (2004) Mutant selection window in levofloxacin and moxifloxacin treatments of experimental pneumococcal pneumonia in a rabbit model of human therapy. Antimicrob Agents Chemother 48:1699 – 1707. Davidson R, Cavalcanti R, Brunton JL, Bast DJ, de Azavedo JCS, Kibsey P, Fleming C, Low DE (2002) Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 346: 747 – 750. Doern GV, Richter SS, Miller A, Miller N, Rice C, Heilmann K, Beekmann S (2005) Antimicrobial resistance among Streptococcus pneumoniae in the United States: have we begun to turn the corner on resistance to certain antimicrobial classes? Clin Infect Dis 41:139 – 148. Drlica K (2003) The mutant selection window and antimicrobial resistance. J Antimicrob Chemother 52:11 – 17. Empey PE, Jennings HR, Thornton AC, Rapp RP, Evans ME (2001) Levofloxacin failure in a patient with pneumococcal pneumonia. Ann Pharmacother 35:687 – 690. Fuller JD, Low DE (2005) A review of Streptococcus pneumoniae infection treatment failures associated with fluoroquinolone resistance. Clin Infect Dis 41:118 – 121. Kays MB, Smith DW, Wack MF, Denys GA (2002) Levofloxacin treatment failure in a patient with fluoroquinolone-resistant Streptococcus pneumoniae pneumonia. Pharmacotherapy 22:395 – 399. National Committee for Clinical Laboratory Standards (1999) Methodology for the Serum Bactericidal Test; Approved Guideline (Document M21A, Vol. 19, No. 17). Wayne (PA)7 NCCLS. Perez-Trallero E, Marimon JM, Gonzalez A, Ercibengoa M, Larruskain J (2005) In vivo development of high-level fluoroquinolone resistance in Streptococcus pneumoniae in chronic obstructive pulmonary disease. Clin Infect Dis 41:560 – 564. Reinert RR, Schlaeger JJ, Lutticken R (1998) Moxifloxacin: a comparison with other antimicrobial agents of in-vitro activity against Streptococcus pneumoniae. J Antimicrob Chemother 42:803 – 806.
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D. Hart, M.P. Weinstein / Diagnostic Microbiology and Infectious Disease 58 (2007) 375 – 378
Reller LB, Stratton CW (1977) Serum dilution test for bactericidal activity. II. Standardization and correlation with antimicrobial assays. J Infect Dis 136:196 – 204. Saravolatz L, Manzor O, Check C, Pawlak J, Belian B (2001) Antimicrobial activity of moxifloxacin, gatifloxacin, and six fluoroquinolones against Streptococcus pneumonia. J Antimicrob Chemother 47:875 – 877. Schlichter JG, MacLean H (1947) A method of determining the effective therapeutic level in the treatment of subacute bacterial endocarditis with penicillin: a preliminary report. Am Heart J 34:209 – 211. Schlichter JG, MacLean H, Milzer A (1949) Effective penicillin therapy in subacute bacterial endocarditis and other chronic infections. Am J Med Sci 217:600 – 608. Shah PM (1999) Serum bactericidal activity of levofloxacin against Streptococcus pneumoniae. J Antimicrob Chemother 43(Suppl. C): 61 – 65.
Stratton CW, Reller LB (1977) Serum dilution test for bactericidal activity. I. Selection of physiologic diluent. J Infect Dis 136:187 – 195. Urban C, Rahman N, Zhao X, Mariano N, Segal-Maurer S, Drlica K, Rahal JJ (2001) Fluoroquinolone-resistant Streptococcus pneumoniae associated with levofloxacin therapy. J Infect Dis 184:794 – 798. Weinstein MP, Stratton CW, Ackley A, Hawley HB, Robinson PA, Fisher BD, Alcid DV, Stephens DS, Reller LB (1985) Multicenter collaborative evaluation of a standardized serum bactericidal test as a prognostic indicator in infective endocarditis. Am J Med 78:262 – 269. Weinstein MP, Stratton CW, Hawley HB, Ackley A, Reller LB (1987) Multicenter collaborative evaluation of a standardized serum bactericidal test as a predictor of therapeutic efficacy in acute and chronic osteomyelitis. Am J Med 83:218 – 222. Zhao X, Drlica K (2001) Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin Infect Dis 33(Suppl. 3):S147 – S156.
Cross-over assessment of serum bactericidal activity of moxifloxacin and levofloxacin versus penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae in healthy volunteers Daniel Hart4, Melvin P. Weinstein Division of Allergy, Immunology, and Infectious Diseases, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA Received 1 November 2006; accepted 6 February 2007
Abstract We compared the serum bactericidal activity (SBA) of moxifloxacin and levofloxacin against penicillin-susceptible and penicillinresistant Streptococcus pneumoniae in 12 healthy volunteers. Each subject received 3 days of oral moxifloxacin 400 mg daily and levofloxacin 750 mg daily, respectively, with a 2- to 4-week washout period between regimens. Blood was drawn at 6 time points after the third dose of each antibiotic. Mean serum bactericidal titers (MSBTRs) for moxifloxacin were 4-fold higher than the mean titers for levofloxacin at each time point. For each drug, MSBTRs at each time point were the same or within one 2-fold dilution when analyzed according to the penicillin susceptibility of the strains or the sex of the subjects. The difference in SBA of the 2 drugs may have implications for the emergence of resistance and clinical outcome. D 2007 Elsevier Inc. All rights reserved. Keywords: Serum bactericidal activity; Moxifloxacin; Levofloxacin; Streptococcus pneumoniae
A continuing lesson of the antibiotic era is that the longer an agent or class of agents is used, the more likely it is that microbial resistance will develop. The fluoroquinolone class of antibiotics is no exception. Quinolone prescriptions in Canada increased from 0.8 to 5.5 per 100 persons per year from 1988 to 1997 (Chen et al., 1999). Concordantly, the percentage of pneumococci with reduced susceptibility to quinolones increased from 0 in 1993 to 1.7 in 1997 and 1998 (Chen et al., 1999). In the United States, pneumococcal resistance to quinolones has increased, whereas resistance to other drug classes has decreased or plateaued (Doern et al., 2005). Not surprisingly, there are reports of fluoroquinolone failure clinically, including levofloxacin
This research was presented in part as a poster at the 43rd Annual Meeting of the IDSA, San Francisco, CA, October 2005 (Abstract #476). 4 Corresponding author. Division of Allergy, Immunology, and Infectious Diseases, UMDNJ—Robert Wood Johnson Medical School, One Robert Wood Johnson Place, New Brunswick, NJ 08903-0019, USA. Tel.: +1-732-235-8012; fax: +1-732-235-7951. E-mail address: [email protected] (D. Hart). 0732-8893/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2007.02.006
failure in pneumococcal pneumonia (Davidson et al., 2002; Empey et al., 2001; Kays et al., 2002; Urban et al., 2001) and acute exacerbation of chronic obstructive pulmonary disease (Perez-Trallero et al., 2005). Fuller and Low (2005) recently reviewed published cases of fluoroquinolone treatment failures in respiratory infections with quinoloneresistant pneumococci. All failures involved ciprofloxacin or levofloxacin. Moxifloxacin was cleared for use by the Food and Drug Administration in 1999 and has demonstrated greater in vitro activity against pneumococci in comparison with other fluoroquinolones including levofloxacin (Reinert et al., 1998; Saravolatz et al., 2001). Conventional in vitro susceptibility testing does not fully consider the pharmacokinetic properties of an antimicrobial agent. By contrast, the serum bactericidal test (SBT) accounts more completely for the pharmacokinetic properties of the antimicrobial agents being administered (Schlichter and MacLean, 1947; Schlichter et al., 1949), measuring the inhibitory activity of serum, from a patient receiving antibiotic therapy, against the bacterial pathogen isolated from the patient’s blood. Over the years, the SBT
376
D. Hart, M.P. Weinstein / Diagnostic Microbiology and Infectious Disease 58 (2007) 375 – 378
After administration of the third dose of each antibiotic, subjects stayed at the Clinical Research Center at Robert Wood Johnson University Hospital (RWJUH, New Brunswick, NJ) and had blood drawn at 1, 2, 4, 8, 12, and 24 h after dosing. Three isolates of pen-S (MICs: 0.016, 0.012, and 0.023 Ag/mL) and 3 isolates of pen-R (MICs: 8, 2, and 2 Ag/mL) S. pneumoniae were used in the study. All isolates were susceptible to levofloxacin (MICs: 0.38, 0.75, 0.38, 0.25, 0.5, and 0.38 Ag/mL) and moxifloxacin (MICs: 0.064, 0.125, 0.047, 0.047, 0.094, and 0.047 Ag/mL). All isolates were from bacteremic patients at RWJUH. SBTs were performed by the standardized microdilution method according to the CLSI/NCCLS guidelines (NCCLS, 1999). Twelve subjects who met the enrollment criteria completed the study. Mean serum bactericidal titers (MSBTRs) for levofloxacin and moxifloxacin are categorized by subject’s sex and by penicillin susceptibility of the tested isolates in Table 1. Maximal MSBTRs were 1:16 for levofloxacin and 1:64 for moxifloxacin. Twenty-four hours after drug administration, mean titers were b1:2 for levofloxacin and 1:8 for moxifloxacin. MSBTRs for all subjects combined were at least 4-fold higher for moxifloxacin compared with levofloxacin at each time point over a 24-h period. For each drug at each time point, mean titers were either identical or within one 2-fold dilution regardless of subject’s sex or penicillin susceptibility of the isolates. In a previous study of 12 healthy volunteers dosed with 500 mg of levofloxacin, there was no difference in the level or duration of SBA based on penicillin susceptibility (Shah, 1999). Not surprisingly, in our study, MSBTRs for either moxifloxacin or levofloxacin were not affected by the penicillin susceptibility status of the pneumococci. A sex difference was noted for both drugs with regard to the time of peak SBA. In males, maximal MSBTRs were observed at 1 h after either drug was administered; however, for females, maximal titers were observed at 2 or 4 h postdosing. Subjects were allowed to take the antibiotic with or without food; the option chosen was not recorded. This difference has not been observed
has undergone modifications (Reller and Stratton, 1977; Stratton and Reller, 1977), eventually resulting in guidelines from the Clinical and Laboratory Standards Institute (CLSI—formerly National Committee for Clinical Laboratory Standards, NCCLS, 1999). By factoring in absorption, distribution, protein binding, and elimination of a drug, the SBT has the potential to be a more reliable predictor of clinical and microbiologic outcome than conventional in vitro susceptibility testing. The SBT has been evaluated as an adjunct in the management of infective endocarditis (Weinstein et al., 1985) and acute and chronic osteomyelitis (Weinstein et al., 1987). Furthermore, serum from healthy volunteers to whom antibiotics have been administered can be used ex vivo to compare bactericidal activity of drugs against potential pathogens. In this study, we compare the serum bactericidal activity (SBA) of moxifloxacin and levofloxacin against both penicillin-susceptible (pen-S) and penicillin-resistant (penR) Streptococcus pneumoniae in 12 healthy volunteers (6 males and 6 females). Subjects were required to be 18 to 40 years old and within 10% of ideal body weight. Health was assessed by the investigators based on history, physical examination, routine laboratory screening, and electrocardiogram. Subjects were required to discontinue any medications for 24 h before starting either study drug. Exclusion criteria consisted of known hypersensitivity to quinolones, history of alcohol/substance abuse, pregnancy, or use of an investigational drug within the preceding 30 days. Patients could also be excluded for a history of cardiopulmonary, renal, gastrointestinal, or hepatic disease or any current or chronic infection. Each subject received 3 days of oral moxifloxacin 400 mg daily and levofloxacin 750 mg daily; the 2 regimens were separated by a 2- to 4-week period to allow sufficient time for washout of the first study drug. The order in which each antibiotic series was administered was random, resulting in 6 patients starting with moxifloxacin and 6 with levofloxacin.
Table 1 Mean reciprocal serum bactericidal titers of levofloxacin and moxifloxacin according to susceptibility of S. pneumoniae strains to penicillin and sex of study subjects Drug
Penicillin susceptibility
Levofloxacin
a
Susceptible Resistantb
Moxifloxacin
All isolates Susceptiblea Resistantb All isolates
a b
Penicillin susceptible: V 0.06 Ag/mL. Penicillin resistant: z 2.0 Ag/mL.
Sex
M F M F M F M F
Time postdose (h) 1
2
4
8
12
24
16 8 16 8 8 32 32 32 32 32
8 16 8 16 16 32 64 32 64 64
8 8 8 16 8 32 64 32 64 32
4 8 4 8 4 32 32 16 32 32
2 4 2 4 4 16 16 8 16 16
b2 b2 b2 b2 b2 8 8 8 8 8
D. Hart, M.P. Weinstein / Diagnostic Microbiology and Infectious Disease 58 (2007) 375 – 378
previously by the manufacturer of either antimicrobial agent (personal communication), and the significance of this finding is unclear. Moxifloxacin had superior SBA against S. pneumoniae compared with levofloxacin in this study. This difference may have implications for clinical outcome and for preventing the emergence of resistance. There is very little data comparing clinical efficacy of moxifloxacin and levofloxacin directly in humans with pneumonia. Both were well tolerated and efficacious in a study that focused on the safety and efficacy of moxifloxacin and levofloxacin in elderly patients hospitalized with community-acquired pneumonia (Anzueto et al., 2006). The 2 antibiotics have been compared in animal models, including an evaluation against quinoloneresistant strains of S. pneumoniae (Alkorta et al., 2005). In this study, gemifloxacin and moxifloxacin had better efficacy than levofloxacin in a mouse model. The authors suggested that the predicted in vivo efficacy of quinolones should be based on minimum bactericidal concentrations (MBCs) in addition to the presence of molecular mutations conferring quinolone resistance. Whether or not the greater SBA and in vitro activity of moxifloxacin compared with that of levofloxacin will be associated with delayed emergence of resistance is unknown. However, an in vitro microbial resistance hypothesis, the mutant selection window, has been proposed (Drlica, 2003; Zhao and Drlica, 2001). The mutant selection window is the concentration range between the point where growth inhibition begins (which correlates with the MIC) and the point at which no resistant isolates are detected when N 1010 cells are plated in the presence of drug (which correlates with the mutant prevention concentration [MPC]). Only bacterial isolates with 2-step fluoroquinolone mutations would grow above the MPC. However, within the window, 1-step mutants can be selected, which will increase the likelihood of a second mutation. Fluoroquinolones that maintain a drug concentration above the MPC are more likely to protect against the emergence of resistance. Blondeau et al. (2001) demonstrated that moxifloxacin and gatifloxacin can achieve serum levels above the MPC. They suggested the same for levofloxacin if more frequent administration or higher doses are used. However, organisms can have higher MPCs if they already have first step mutations. Croisier et al. (2004) showed in a rabbit model that pneumococcal strains with preexisting single mutations (particularly parC) yielded a high rate of new mutations in the presence of levofloxacin or moxifloxacin, resulting in a failure to decrease the bacterial load in the lungs. These strains had high MPCs that enabled the growth of mutants within the mutant selection window. In conclusion, in this ex vivo study, the SBA of moxifloxacin was approximately 4-fold greater than that of levofloxacin versus isolates of pen-S and pen-R S. pneumoniae, confirming the known greater in vitro potency of moxifloxacin. Whether this potency will
377
translate into better clinical outcome or delay emergence of resistance remains to be proven. Acknowledgments The authors thank Judy Rothberg for her technical work, Eileen Lindsey for her secretarial support, and the staff of the Clinical Research Center of Robert Wood Johnson Medical School and University Hospital, New Brunswick, NJ, for their help with patient recruitment and nursing care. This study was supported in part by a grant from Bayer (Pittsburgh, PA). References Alkorta M, Gimenez MJ, Vicente D, Aguilar L, Perez-Trallero E (2005) In vivo activity of gemifloxacin, moxifloxacin, and levofloxacin against pneumococci with gyrA and parC point mutations in a sepsis mouse model measured with the all or nothing mortality end-point. Int J Antimicrob Agents 25:163 – 167. Anzueto A, Niederman MS, Pearle J, Restrepo MI, Heyder A, Choudhri SH (2006) Community-acquired pneumonia recovery in the elderly (CAPRIE): efficacy and safety of moxifloxacin therapy versus that of levofloxacin therapy. Clin Infect Dis 42:73 – 81. Blondeau JM, Zhao X, Hansen G, Drlica K (2001) Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 45:433 – 438. Chen DK, McGeer A, de Azavedo JC, Low DE (1999) Decreased susceptibility of Streptococcus pneumoniae. N Engl J Med 341: 233 – 239. Croisier D, Etienne M, Bergoin E, Charles PE, Lequeu C, Piroth L, Portier H, Chavanet P (2004) Mutant selection window in levofloxacin and moxifloxacin treatments of experimental pneumococcal pneumonia in a rabbit model of human therapy. Antimicrob Agents Chemother 48:1699 – 1707. Davidson R, Cavalcanti R, Brunton JL, Bast DJ, de Azavedo JCS, Kibsey P, Fleming C, Low DE (2002) Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 346: 747 – 750. Doern GV, Richter SS, Miller A, Miller N, Rice C, Heilmann K, Beekmann S (2005) Antimicrobial resistance among Streptococcus pneumoniae in the United States: have we begun to turn the corner on resistance to certain antimicrobial classes? Clin Infect Dis 41:139 – 148. Drlica K (2003) The mutant selection window and antimicrobial resistance. J Antimicrob Chemother 52:11 – 17. Empey PE, Jennings HR, Thornton AC, Rapp RP, Evans ME (2001) Levofloxacin failure in a patient with pneumococcal pneumonia. Ann Pharmacother 35:687 – 690. Fuller JD, Low DE (2005) A review of Streptococcus pneumoniae infection treatment failures associated with fluoroquinolone resistance. Clin Infect Dis 41:118 – 121. Kays MB, Smith DW, Wack MF, Denys GA (2002) Levofloxacin treatment failure in a patient with fluoroquinolone-resistant Streptococcus pneumoniae pneumonia. Pharmacotherapy 22:395 – 399. National Committee for Clinical Laboratory Standards (1999) Methodology for the Serum Bactericidal Test; Approved Guideline (Document M21A, Vol. 19, No. 17). Wayne (PA)7 NCCLS. Perez-Trallero E, Marimon JM, Gonzalez A, Ercibengoa M, Larruskain J (2005) In vivo development of high-level fluoroquinolone resistance in Streptococcus pneumoniae in chronic obstructive pulmonary disease. Clin Infect Dis 41:560 – 564. Reinert RR, Schlaeger JJ, Lutticken R (1998) Moxifloxacin: a comparison with other antimicrobial agents of in-vitro activity against Streptococcus pneumoniae. J Antimicrob Chemother 42:803 – 806.
378
D. Hart, M.P. Weinstein / Diagnostic Microbiology and Infectious Disease 58 (2007) 375 – 378
Reller LB, Stratton CW (1977) Serum dilution test for bactericidal activity. II. Standardization and correlation with antimicrobial assays. J Infect Dis 136:196 – 204. Saravolatz L, Manzor O, Check C, Pawlak J, Belian B (2001) Antimicrobial activity of moxifloxacin, gatifloxacin, and six fluoroquinolones against Streptococcus pneumonia. J Antimicrob Chemother 47:875 – 877. Schlichter JG, MacLean H (1947) A method of determining the effective therapeutic level in the treatment of subacute bacterial endocarditis with penicillin: a preliminary report. Am Heart J 34:209 – 211. Schlichter JG, MacLean H, Milzer A (1949) Effective penicillin therapy in subacute bacterial endocarditis and other chronic infections. Am J Med Sci 217:600 – 608. Shah PM (1999) Serum bactericidal activity of levofloxacin against Streptococcus pneumoniae. J Antimicrob Chemother 43(Suppl. C): 61 – 65.
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