ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1992,
p.
Vol. 36, No. 2
255-261
0066-4804/92/020255-07$02.00/0 Copyright C 1992, American Society for Microbiology
In Vitro Activity of Sparfloxacin (AT-4140), a New Quinolone Agent, against Invasive Isolates from Pediatric Patients JOSEPH C. AKANIRO,1 HARRIS R. STUTMAN, 2* ADRIANO G. ARGUEDAS,"2 AND OFELIA M. VARGAS' Department of Pediatrics, Memorial Miller Children's Hospital, Long Beach, California 90801-1428,1 and College of Medicine, University of California, Irvine, California 92668-99692 Received 5 June 1991/Accepted 14 November 1991
Sparfloxacin is a new oral fluoroquinolone agent with putative activity against common pediatric pathogens. Using the broth microdilution method, we evaluated sparfloxacin activity in comparison with those of other antimicrobial agents against 383 pediatric isolates derived from cultures of blood and other normally sterile body fluids. MICs were assessed in Mueller-Hinton broth, serum, and urine, as well as at inoculum sizes of i04 to 108 CFU/ml. The emergence and stability of resistance and cross-resistance of Pseudomonas aeruginosa (mucoid and nonmucoid) and Staphylococcus aureus to sparfloxacin and ciprofloxacin were evaluated. Inhibitory activity of sparfloxacin against most test organisms was within achievable serum levels. Sparfloxacin was -2- to 4-fold more active than other quinolones against gram-positive pathogens and 2- to 4-fold less active than ciprofloxacin against P. aeruginosa. Sparfloxacin activity was unaffected by urine and was enhanced by two- to eightfold in human serum. Its potency was not affected by inocula of -107 CFU/ml. The frequency of development of spontaneous resistance was similar to that found for other new quinolone agents, and stable resistance emerged only in P. aeruginosa. Sparfloxacin merits additional study against invasive pediatric pathogens.
activities of sparfloxacin and other quinolone derivatives as well as standard antimicrobial agents routinely used in treating pediatric infections. Additionally, we examined the ability of sparfloxacin to select for rapid single-step resistance, as well as the frequency of emergence of resistant bacterial clones following prolonged drug exposure. The effects of various medium conditions on the in vitro activity of this quinolone compound were also investigated.
Sparfloxacin is a new synthetic, orally administered member of the quinolonecarboxylic class of antimicrobial agents. Like other quinolone derivatives, its antimicrobial effect is mediated via the inhibition of DNA gyrase (5, 16, 31, 32), which controls various DNA-mediated functions in bacterial cells. Although the new quinolones are generally characterized by a broad antimicrobial spectrum, their activities against gram-positive organisms are limited (31), with diminished activity generally demonstrated against staphylococci (19), streptococci, and enterococci (21). Preliminary data (6, 14, 15, 17) indicate that sparfloxacin may have enhanced activity against enterococci, methicillin-resistant and methicillin-susceptible staphylococci, and other gram-positive organisms in addition to pathogenic anaerobes, Chlamydia trachomatis, Mycoplasma pneumoniae, and some mycobacteria. Because of their potency, favorable pharmacokinetic profile, and bioavailability, agents from the fluoroquinolone class play an important role in the management of systemic and other serious infections. Although these compounds are currently contraindicated for routine use in the pediatric population because of arthropathy-related side effects in experimental juvenile animals (3, 10, 27, 30), several workers (20, 22, 26, 28) have been unable to detect joint toxicities in children receiving quinolones. A review of worldwide clinical experience with children receiving ciprofloxacin on a compassionate basis (12) did not reveal any substantial difference in side effects between pediatric and adult populations. Transitory arthralgia was reported in only 1.3% of the study population. In another pediatric study, investigators (25) using magnetic resonance imaging did not detect evidence of ciprofloxacin-related arthropathogenic effects. With confirmation of these data, it appears that the use of quinolones in certain pediatric patients may be medically warranted. This study was undertaken to investigate and compare the *
MATERIALS AND METHODS
Organisms. A total of 383 pediatric isolates representing 13 bacterial genera were tested. Bacterial identification was performed in our clinical microbiology department with the Gram Negative and Gram Positive Identification Cards (Vitek Systems Inc., Hazelwood, Mo.) as well as conventional methodologies (7-9, 13). All organisms were invasive isolates recently obtained from blood or other normally sterile body fluids of patients hospitalized in our institution. All organisms were stored by ultrafreezing methods at -70°C and, and prior to use, were thawed and subcultured at least twice onto an appropriate solid medium. Antimicrobial agents. Sparfloxacin powder was kindly supplied by Parke-Davis Pharmaceutical Research Division, Ann Arbor, Mich. All comparative antimicrobial agents were obtained from the respective manufacturers in the form of standard powders of known potency. All antimicrobial agents were initially solubilized in the appropriate solvents, as recommended by the manufacturers, and diluted to a stock concentration of 2,560 ,ug/ml. Working antimicrobial agent solutions were stored at -70°C and used within 4 weeks of preparation. In all experiments, drug stability was strictly monitored by testing of newly prepared panels with reference organisms. Subsequent testing of the same test panels did not show a diminution in antimicrobial potency. Susceptibility determinations. Testing of susceptibility of bacterial isolates was performed by the twofold broth microdilution method as previously described (1, 18, 29). For testing of streptococci, the broth was supplemented to
Corresponding author. 255
256
AKANIRO ET AL.
contain 5% sheep blood, and for all studies involving Haemophilus species, haemophilus test medium (11) was used. The MIC-2000 Plus System (Dynatech Laboratories, Inc., Chantilly, Va.) was used to prepare the test panels in 96-well microtiter plates containing graded concentrations of antimicrobial agents in 0.1-ml aliquots of cation-supplemented Mueller-Hinton broth. Inocula for in vitro tests were prepared by adjusting overnight broth cultures to match a density of 0.5 on the McFarland scale. For testing Haemophilus influenzae, exponentially growing cultures from chocolate agar were suspended in saline and similarly adjusted. Antimicrobial agent panels were inoculated with each test organism to yield a final inoculum of 2 x 105 CFU/ml. This inoculum size was verified by standard bacterial quantitation. The test panels were incubated aerobically at 37°C for 18 h. For streptococci, H. influenzae, and Moraxella catarrhalis, incubation was carried out in an atmosphere of 5% Co2. The MIC was defined as the lowest concentration of antimicrobial agent that inhibited the development of visible growth in the microtiter plate wells. All tests were performed with the inclusion of the following American Type Culture Collection quality assurance bacterial strains: Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, and Staphylococcus aureus ATCC 29213. In all cases, susceptibility endpoints were consistent with established values (18). Factors affecting in vitro activity. Using 10 bacterial isolates, we evaluated the effect of pooled human serum in 50% (vol/vol) Mueller-Hinton broth. Serum-supplemented wells without antimicrobial agents were used as controls. Additionally, five isolates of P. aeruginosa, each at final inoculum sizes of 104, 105, 106, 107, and 108 CFU/ml, were exposed to microtiter plate wells containing sparfloxacin at graded concentrations. Similarly, MICs were determined in urine with earlymorning pooled urine samples from normal male volunteers. Prior to being tested, the urine was sterilized by membrane filtration with 0.22 ,um-pore-size filters (Millipore Corp). In these susceptibility determinations, standard incubation conditions and endpoint criteria (1, 18) were used. Selection for progressive multiple-step resistance. Four isolates of P. aeruginosa (two mucoid and two nonmucoid) and two isolates of oxacillin-susceptible S. aureus obtained from both pediatric patients and cystic fibrosis (CF) sputum samples were used to study the gradual emergence and stability of resistance and cross-resistance to sparfloxacin and ciprofloxacin. As previously described, the MICs were determined, and isolates from microtiter wells containing the highest drug concentration that permitted visible growth were subcultured on antibiotic-free medium and incubated for 24 h in ambient air at 37°C. In these experiments, mucoid maintenance agar (1) was used to culture P. aeruginosa, and blood agar was used to culture S. aureus. Following incubation on the appropriate solid medium, new MICs were determined with five randomly selected colonies. This process was repeated 10 times. Terminal MICs were compared with initial MICs. Acquired resistance was arbitrarily defined as an eightfold increase over the initial MIC. To assess whether resistance was a stable mutation or a transitory event, we subcultured organisms from passage 10 five successive times on antibiotic-free medium and retested them by the broth microdilution method. A stable mutation was defined as a terminal MIC within one dilution of the MIC obtained in passage 10. Adaptation was defined as a .4-fold decrease (after five passages on antibiotic-free medium) in the MIC obtained in passage 10.
ANTIMICROB. AGENTS CHEMOTHER.
During the 10 passages, test organisms were exposed only to an individual antimicrobial agent. To determine whether cross-resistance occurred, we exposed all sparfloxacin-resistant isolates to ciprofloxacin. Following selection, new MICs were determined. Cross-resistance was defined as an eightfold increase in the MIC over the preselection (passage 1) MIC. Determination of spontaneous mutation frequencies. Eleven randomly selected isolates of P. aeruginosa (5 mucoid and 6 nonmucoid) were studied. One milliliter each of an exponentially growing culture, concentrated to yield 2109 CFU/ml as the final inoculum, was subcultured on Mueller-Hinton agar containing either sparfloxacin or ciprofloxacin at four and eight times the original MIC. After 72 h of incubation at 37°C in a C02-free atmosphere, bacterial colonies were counted. These mutants were subcultured on antibiotic-free medium and the MIC was reassessed. By comparing the original inoculum size with the number of resistant mutants, the frequency of mutation was determined. RESULTS Susceptibility testing. The results obtained from testing of 357 bacterial isolates are summarized in Table 1. The range of concentrations of sparfloxacin which inhibited members of the family Enterobacteriaceae (MICs for 50 and 90% of isolates [MIC50 and MICg, respectively]) were 0.016 to 0.125 and 0.016 to 0.5 ,ug/ml, respectively, with the exception of Serratia marcescens for which the MIC50 was 0.25 ,ug/ml and the MIC90 was 4 jig/ml. The MIC90 of sparfloxacin for M. catarrhalis and H. influenzae was 16.0 1.0->16.0 4.0->16.0 2.0-32.0 2.0-64.0 0.063->64.0 0.25-8.0
0.032-0.5 0.125-1.0 0.5-4.0 0.063-1.0 C0.032-64.0 0.125-4.0 C0.063-32.0
0.016/0.30-0.125/2.37 0.5-4.0
0.125-8.0 0.5->16.0 1.0->16.0 0.5-> 16.0
Sparfloxacin Ciprofloxacin Enoxacin
Sparfloxacin Ciprofloxacin Enoxacin
Range
90%
Ofloxacin Penicillin G Nafcillin Cephalothin TMP/SMX Vancomycin
Staphylococcus epidermidis Oxacillin susceptible (15)
(>±g/ml)
50%
32.0-64.0 0.5-8.0 0.5-1.0
0.032/0.60-0.063/1.19 1.0
0.125 0.25
1.0
8.0 8.0 >16.0
0.125-8.0 0.125-8.0 0.5->16.0 0.5->16.0
Continued on following page
ACTIVITY OF SPARFLOXACIN AGAINST INVASIVE ISOLATES
VOL. 36, 1992
259
TABLE 1-Continued Organism (no. of isolates tested)
Antimicrobial agent Ofloxacin Penicillin G Nafcillin Cephalothin TMP/SMX Vancomycin
Oxacillin resistant (8)
Group A streptococci (13)
Group B streptococci (23)
Streptococcus pneumoniae (48)
0.5 0.5 0.25 0.125 0.125/2.375 2.0
MIC (ug/ml) 9P0%
16.0 4.0 0.5 0.5 8.0/152.0 4.0
Sparfloxacin Ciprofloxacin Enoxacin Penicillin G Cephalothin Erythromycin Vancomycin
Sparfloxacin Ciprofloxacin Enoxacin Penicillin G Cephalothin Erythromycin Vancomycin Sparfloxacin Ciprofloxacin Enoxacin
Cephalothin Chloramphenicol Erythromycin
Range 0.25-16.0 C0.032-4.0 0.063-0.5 0.125-0.5 0.016/0.30-16.0/304 1.0-32.0 0.5-16.0 2.0-16.0 16.0->16.0 4.0-16.0 8.0->64.0 0.25->64.0 0.5->64.0
Sparfloxacin Ciprofloxacin Enoxacin Ofloxacin Penicillin G Nafcillin Cephalothin TMP/SMX Vancomycin
Ofloxacin Penicillin G
a
50%l
0.063/1.19-16/304
1.0-2.0
0.5 0.5 8.0 0.03 0.03
1.0 1.0 16.0 0.12 0.25
0.25
C0.032 0.5
0.5 1.0 16.0 0.063 0.125
0.5 1.0 >16.0 0.063 0.125
C
p.
Vol. 36, No. 2
255-261
0066-4804/92/020255-07$02.00/0 Copyright C 1992, American Society for Microbiology
In Vitro Activity of Sparfloxacin (AT-4140), a New Quinolone Agent, against Invasive Isolates from Pediatric Patients JOSEPH C. AKANIRO,1 HARRIS R. STUTMAN, 2* ADRIANO G. ARGUEDAS,"2 AND OFELIA M. VARGAS' Department of Pediatrics, Memorial Miller Children's Hospital, Long Beach, California 90801-1428,1 and College of Medicine, University of California, Irvine, California 92668-99692 Received 5 June 1991/Accepted 14 November 1991
Sparfloxacin is a new oral fluoroquinolone agent with putative activity against common pediatric pathogens. Using the broth microdilution method, we evaluated sparfloxacin activity in comparison with those of other antimicrobial agents against 383 pediatric isolates derived from cultures of blood and other normally sterile body fluids. MICs were assessed in Mueller-Hinton broth, serum, and urine, as well as at inoculum sizes of i04 to 108 CFU/ml. The emergence and stability of resistance and cross-resistance of Pseudomonas aeruginosa (mucoid and nonmucoid) and Staphylococcus aureus to sparfloxacin and ciprofloxacin were evaluated. Inhibitory activity of sparfloxacin against most test organisms was within achievable serum levels. Sparfloxacin was -2- to 4-fold more active than other quinolones against gram-positive pathogens and 2- to 4-fold less active than ciprofloxacin against P. aeruginosa. Sparfloxacin activity was unaffected by urine and was enhanced by two- to eightfold in human serum. Its potency was not affected by inocula of -107 CFU/ml. The frequency of development of spontaneous resistance was similar to that found for other new quinolone agents, and stable resistance emerged only in P. aeruginosa. Sparfloxacin merits additional study against invasive pediatric pathogens.
activities of sparfloxacin and other quinolone derivatives as well as standard antimicrobial agents routinely used in treating pediatric infections. Additionally, we examined the ability of sparfloxacin to select for rapid single-step resistance, as well as the frequency of emergence of resistant bacterial clones following prolonged drug exposure. The effects of various medium conditions on the in vitro activity of this quinolone compound were also investigated.
Sparfloxacin is a new synthetic, orally administered member of the quinolonecarboxylic class of antimicrobial agents. Like other quinolone derivatives, its antimicrobial effect is mediated via the inhibition of DNA gyrase (5, 16, 31, 32), which controls various DNA-mediated functions in bacterial cells. Although the new quinolones are generally characterized by a broad antimicrobial spectrum, their activities against gram-positive organisms are limited (31), with diminished activity generally demonstrated against staphylococci (19), streptococci, and enterococci (21). Preliminary data (6, 14, 15, 17) indicate that sparfloxacin may have enhanced activity against enterococci, methicillin-resistant and methicillin-susceptible staphylococci, and other gram-positive organisms in addition to pathogenic anaerobes, Chlamydia trachomatis, Mycoplasma pneumoniae, and some mycobacteria. Because of their potency, favorable pharmacokinetic profile, and bioavailability, agents from the fluoroquinolone class play an important role in the management of systemic and other serious infections. Although these compounds are currently contraindicated for routine use in the pediatric population because of arthropathy-related side effects in experimental juvenile animals (3, 10, 27, 30), several workers (20, 22, 26, 28) have been unable to detect joint toxicities in children receiving quinolones. A review of worldwide clinical experience with children receiving ciprofloxacin on a compassionate basis (12) did not reveal any substantial difference in side effects between pediatric and adult populations. Transitory arthralgia was reported in only 1.3% of the study population. In another pediatric study, investigators (25) using magnetic resonance imaging did not detect evidence of ciprofloxacin-related arthropathogenic effects. With confirmation of these data, it appears that the use of quinolones in certain pediatric patients may be medically warranted. This study was undertaken to investigate and compare the *
MATERIALS AND METHODS
Organisms. A total of 383 pediatric isolates representing 13 bacterial genera were tested. Bacterial identification was performed in our clinical microbiology department with the Gram Negative and Gram Positive Identification Cards (Vitek Systems Inc., Hazelwood, Mo.) as well as conventional methodologies (7-9, 13). All organisms were invasive isolates recently obtained from blood or other normally sterile body fluids of patients hospitalized in our institution. All organisms were stored by ultrafreezing methods at -70°C and, and prior to use, were thawed and subcultured at least twice onto an appropriate solid medium. Antimicrobial agents. Sparfloxacin powder was kindly supplied by Parke-Davis Pharmaceutical Research Division, Ann Arbor, Mich. All comparative antimicrobial agents were obtained from the respective manufacturers in the form of standard powders of known potency. All antimicrobial agents were initially solubilized in the appropriate solvents, as recommended by the manufacturers, and diluted to a stock concentration of 2,560 ,ug/ml. Working antimicrobial agent solutions were stored at -70°C and used within 4 weeks of preparation. In all experiments, drug stability was strictly monitored by testing of newly prepared panels with reference organisms. Subsequent testing of the same test panels did not show a diminution in antimicrobial potency. Susceptibility determinations. Testing of susceptibility of bacterial isolates was performed by the twofold broth microdilution method as previously described (1, 18, 29). For testing of streptococci, the broth was supplemented to
Corresponding author. 255
256
AKANIRO ET AL.
contain 5% sheep blood, and for all studies involving Haemophilus species, haemophilus test medium (11) was used. The MIC-2000 Plus System (Dynatech Laboratories, Inc., Chantilly, Va.) was used to prepare the test panels in 96-well microtiter plates containing graded concentrations of antimicrobial agents in 0.1-ml aliquots of cation-supplemented Mueller-Hinton broth. Inocula for in vitro tests were prepared by adjusting overnight broth cultures to match a density of 0.5 on the McFarland scale. For testing Haemophilus influenzae, exponentially growing cultures from chocolate agar were suspended in saline and similarly adjusted. Antimicrobial agent panels were inoculated with each test organism to yield a final inoculum of 2 x 105 CFU/ml. This inoculum size was verified by standard bacterial quantitation. The test panels were incubated aerobically at 37°C for 18 h. For streptococci, H. influenzae, and Moraxella catarrhalis, incubation was carried out in an atmosphere of 5% Co2. The MIC was defined as the lowest concentration of antimicrobial agent that inhibited the development of visible growth in the microtiter plate wells. All tests were performed with the inclusion of the following American Type Culture Collection quality assurance bacterial strains: Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922, and Staphylococcus aureus ATCC 29213. In all cases, susceptibility endpoints were consistent with established values (18). Factors affecting in vitro activity. Using 10 bacterial isolates, we evaluated the effect of pooled human serum in 50% (vol/vol) Mueller-Hinton broth. Serum-supplemented wells without antimicrobial agents were used as controls. Additionally, five isolates of P. aeruginosa, each at final inoculum sizes of 104, 105, 106, 107, and 108 CFU/ml, were exposed to microtiter plate wells containing sparfloxacin at graded concentrations. Similarly, MICs were determined in urine with earlymorning pooled urine samples from normal male volunteers. Prior to being tested, the urine was sterilized by membrane filtration with 0.22 ,um-pore-size filters (Millipore Corp). In these susceptibility determinations, standard incubation conditions and endpoint criteria (1, 18) were used. Selection for progressive multiple-step resistance. Four isolates of P. aeruginosa (two mucoid and two nonmucoid) and two isolates of oxacillin-susceptible S. aureus obtained from both pediatric patients and cystic fibrosis (CF) sputum samples were used to study the gradual emergence and stability of resistance and cross-resistance to sparfloxacin and ciprofloxacin. As previously described, the MICs were determined, and isolates from microtiter wells containing the highest drug concentration that permitted visible growth were subcultured on antibiotic-free medium and incubated for 24 h in ambient air at 37°C. In these experiments, mucoid maintenance agar (1) was used to culture P. aeruginosa, and blood agar was used to culture S. aureus. Following incubation on the appropriate solid medium, new MICs were determined with five randomly selected colonies. This process was repeated 10 times. Terminal MICs were compared with initial MICs. Acquired resistance was arbitrarily defined as an eightfold increase over the initial MIC. To assess whether resistance was a stable mutation or a transitory event, we subcultured organisms from passage 10 five successive times on antibiotic-free medium and retested them by the broth microdilution method. A stable mutation was defined as a terminal MIC within one dilution of the MIC obtained in passage 10. Adaptation was defined as a .4-fold decrease (after five passages on antibiotic-free medium) in the MIC obtained in passage 10.
ANTIMICROB. AGENTS CHEMOTHER.
During the 10 passages, test organisms were exposed only to an individual antimicrobial agent. To determine whether cross-resistance occurred, we exposed all sparfloxacin-resistant isolates to ciprofloxacin. Following selection, new MICs were determined. Cross-resistance was defined as an eightfold increase in the MIC over the preselection (passage 1) MIC. Determination of spontaneous mutation frequencies. Eleven randomly selected isolates of P. aeruginosa (5 mucoid and 6 nonmucoid) were studied. One milliliter each of an exponentially growing culture, concentrated to yield 2109 CFU/ml as the final inoculum, was subcultured on Mueller-Hinton agar containing either sparfloxacin or ciprofloxacin at four and eight times the original MIC. After 72 h of incubation at 37°C in a C02-free atmosphere, bacterial colonies were counted. These mutants were subcultured on antibiotic-free medium and the MIC was reassessed. By comparing the original inoculum size with the number of resistant mutants, the frequency of mutation was determined. RESULTS Susceptibility testing. The results obtained from testing of 357 bacterial isolates are summarized in Table 1. The range of concentrations of sparfloxacin which inhibited members of the family Enterobacteriaceae (MICs for 50 and 90% of isolates [MIC50 and MICg, respectively]) were 0.016 to 0.125 and 0.016 to 0.5 ,ug/ml, respectively, with the exception of Serratia marcescens for which the MIC50 was 0.25 ,ug/ml and the MIC90 was 4 jig/ml. The MIC90 of sparfloxacin for M. catarrhalis and H. influenzae was 16.0 1.0->16.0 4.0->16.0 2.0-32.0 2.0-64.0 0.063->64.0 0.25-8.0
0.032-0.5 0.125-1.0 0.5-4.0 0.063-1.0 C0.032-64.0 0.125-4.0 C0.063-32.0
0.016/0.30-0.125/2.37 0.5-4.0
0.125-8.0 0.5->16.0 1.0->16.0 0.5-> 16.0
Sparfloxacin Ciprofloxacin Enoxacin
Sparfloxacin Ciprofloxacin Enoxacin
Range
90%
Ofloxacin Penicillin G Nafcillin Cephalothin TMP/SMX Vancomycin
Staphylococcus epidermidis Oxacillin susceptible (15)
(>±g/ml)
50%
32.0-64.0 0.5-8.0 0.5-1.0
0.032/0.60-0.063/1.19 1.0
0.125 0.25
1.0
8.0 8.0 >16.0
0.125-8.0 0.125-8.0 0.5->16.0 0.5->16.0
Continued on following page
ACTIVITY OF SPARFLOXACIN AGAINST INVASIVE ISOLATES
VOL. 36, 1992
259
TABLE 1-Continued Organism (no. of isolates tested)
Antimicrobial agent Ofloxacin Penicillin G Nafcillin Cephalothin TMP/SMX Vancomycin
Oxacillin resistant (8)
Group A streptococci (13)
Group B streptococci (23)
Streptococcus pneumoniae (48)
0.5 0.5 0.25 0.125 0.125/2.375 2.0
MIC (ug/ml) 9P0%
16.0 4.0 0.5 0.5 8.0/152.0 4.0
Sparfloxacin Ciprofloxacin Enoxacin Penicillin G Cephalothin Erythromycin Vancomycin
Sparfloxacin Ciprofloxacin Enoxacin Penicillin G Cephalothin Erythromycin Vancomycin Sparfloxacin Ciprofloxacin Enoxacin
Cephalothin Chloramphenicol Erythromycin
Range 0.25-16.0 C0.032-4.0 0.063-0.5 0.125-0.5 0.016/0.30-16.0/304 1.0-32.0 0.5-16.0 2.0-16.0 16.0->16.0 4.0-16.0 8.0->64.0 0.25->64.0 0.5->64.0
Sparfloxacin Ciprofloxacin Enoxacin Ofloxacin Penicillin G Nafcillin Cephalothin TMP/SMX Vancomycin
Ofloxacin Penicillin G
a
50%l
0.063/1.19-16/304
1.0-2.0
0.5 0.5 8.0 0.03 0.03
1.0 1.0 16.0 0.12 0.25
0.25
C0.032 0.5
0.5 1.0 16.0 0.063 0.125
0.5 1.0 >16.0 0.063 0.125
C
