M icrobiology Chemotherapy 1992;38:99-106
S.M. Hussain Qadri Yoshio Ueno J. Joyce Bums Edna Almodovar Nada Rabea
In vitro Activity of Sparfloxacin (CI-978), a New Broad-Spectrum Fluoroquinolone
King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
Abstract The in vitro activity of sparfloxacin (CI-978, AT-4140), a new fluoroquinolone, was compared with ciprofloxacin, norfloxa cin and other commonly used antimicrobial agents against 650 strains of Enterobacteriaceae, 237 isolates of other gram-nega tive bacilli and 318 strains of gram-positive cocci. The MICs of sparfloxacin against 90% of the members of Enterobacteriaceac were between 0.12 and 0.5 pg/ml. All the 48 isolates of no toriously drug-resistant Serrada marcescens were inhibited by < 0.03-4.0 (ig/ml of sparfloxacin. All the 90 isolates of Acinetobacter, 80 of the 88 strains of Pseudomonas aeruginosa and all the 28 isolates of Xanthomonas maltophilia were susceptible to sparfloxacin. The MIC90 f°r the cocci tested ranged be tween 0.5 and 4.0 pg/ml of sparfloxacin. It inhibited 92% of en terococci as compared with 27% for ciprofloxacin and 22% for norfloxacin. It was better or comparable in activity to other flu oroquinolones and superior to penicillins, cephalosporins and aminoglycosides tested. There was cross-resistance between ci profloxacin, norfloxacin and sparfloxacin.
Introduction Bacterial isolates from clinical specimens in the developing countries of Asia, Africa and Latin America are known to be more resistant to commonly used antimicrobial agents than
those in Western Europe, USA and Canada [4,5,8,10]. It has been shown that clinical iso lates in Saudi Arabia are no exceptions and tend to be significantly less susceptible to vari ous antibiotics [13,14], Using these isolates we determined the in vitro activity of the new flu-
Dr.S.M.H. Qadri Microbiology Laboratory King Faisal Specialist Hospital and Research Centre, MBC-10, PO Box 3354 Riyadh 11211 (Kingdom of Saudi Arabia)
© 1992 S. Kargcr AG, Basel 0009-3157/92/ 0382-0099 $ 2.75/0
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Key Words Sparfloxacin CI-978 AT-4140 Fluoroquinolones In vitro activity
oroquinolone sparfloxacin and compared it with those of other agents. Our findings are presented in this paper.
Materials and Methods A total of 1,205 strains of recent clinical isolates were studied. These bacteria were isolated from pa tient specimens at the King Faisal Specialist Hospital and Research Centre which is a 550-bed tertiary care facility in Riyadh and serves as a referral center for the Kingdom of Saudi Arabia and the Middle East. Mi croorganisms were identified by a standard procedure [1] and susceptibility testing was performed by the agar dilution method as recommended by the National Committee for Clinical Laboratory Standards [12]. Muller-Hinton agar (Difco Laboratories, Detroit, Mich., USA) with a pH between 7.2 and 7.4 was used throughout the study. Standard bacterial suspensions were inoculated onto the agar surface with a multi point inoculator. All incubations were at 35 °C for 18-24 h. Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 29213 were used as quality control organisms. The quality control results were found to be within ex pected ranges during the period of this investigation. Sparfloxacin was provided by Parkc-Davis Pharmaceu tical Research, Division of Warner-Lambert (Ann Ar bor, Mich., USA). Other drugs were purchased from commercial sources. Bacteria were considered resis tant when the MIC for fluoroquinolones exceeded 4.0 pg/ml. Other interpretation were those recommended by the National Committee for Clinical Laboratory Standards [12].
cin was similar or superior to that of ciproflox acin and norfloxacin (table 1). Although spar floxacin was inhibitory to all the 48 isolates of Serratia marcescens, the MIC values were 2- to 4-fold higher than that of ciprofloxacin. Its bacterial activity towards Enterobacter species was superior to that of ciprofloxacin and nor floxacin. Of the 24 strains of Citrobacter freundii tested 4 were found to be resistant to all the 3 fluoroquinolones tested. The MIC90 for sparfloxacin for Enterobacteriaceae ranged between 0.12 and 0.5 pg/ml. Of the 88 isolates of P. aeruginosa tested, 80 (91%) were susceptible to sparfloxacin as compared to 96% for ciprofloxacin and 92% for norfloxacin. However, sparfloxacin was significantly more active against Xanthomonas maltophilia, Acinetobacter and Aeromonas hydrophila than other fluoroquinolones. Both methicillin-susccptible as well as methicillin-resistant isolates of S. aureus were susceptible to sparfloxacin, ciprofloxacin and norfloxacin. However, the MIC90 of sparfloxa cin for these isolates was 0.5 pg/ml compared with 1.0 pg/ml for other fluoroquinolones. Sparfloxacin also exhibited superior activity against coagulase-negative staphylococci and enterococci. Of the 3 fluoroquinolones tested sparfloxacin inhibited 92% of enterococci as compared with 22 and 27% for norfloxacin and ciprofloxacin, respectively.
Results
100
Sparfloxacin (CI-978, AT-4140) is a new synthetic fluoroquinolone with a chemical for mula of 5-amino-l-cyclopropyl-6,8-difluoro1,4- dihydro -7- (cis -3,5-dimethyl -1-piperazinyl)-4-oxoquinolone-3-carboxylic acid [11]. Its broad-spectral activity against both gram-pos itive and gram-negative bacteria along with excellent pharmacokinetic properties has gen erated much interest in its development [2, 3,
Qadri/Ueno/Burns/Almodovar/Rabca
In vitro Activity of Sparfloxacin
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Discussion A total of 1,205 isolates, consisting of 650 Enterobacteriaccae, 237 Pseudomonas, Acinetobacter and Aeromonas and 318 isolates of gram-positive cocci were used to determine their MICs to sparfloxacin, ciprofloxacin, nor floxacin, imipenem, ampicillin, piperacillin, oxacillin, vancomycin, cephalothin, cefoxitin, ceftazidime, gentamicin and amikacin. Against members of the family Enterobacteriaceae the antibacterial activity of sparfloxa-
Table 1. In vitro activity of sparfloxacin and other antimicrobial agents Bacterium
Drug
MIC, pg/ml MIC»
MIC*
range
Resistant %
Citrobacter (24)
sparfloxacin ciprofloxacin norfloxacin imipcncm ampicillin ccphalothin cefoxitin ceftazidime gentamicin amikacin
32.0 >32.0 0.5 0.12 0.5
>4.0 >4.0 >4.0 2.0 > 32.0 > 32.0 >32.0 >16.0 0.5 4.0
< 0.03-> 4.0 < 0.03-> 4.0 0.12—> 4.0 0.25-2.0 2.0-> 32 2.0-> 32 2.0-> 32 0.5-> 16 0.12-> 32 0.25-> 32
17 17 17 0 92 92 86 15 23 8
Enterobacter sp. (101)
sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin ccphalothin cefoxitin ceftazidime gentamicin amikacin
0.03 32 >32 >32 0.5 0.25 1.0
0.12 2.0 4.0 0.2 >32 >32 >32 16.0 >32 >32
32 8-> 32 0.5-> 16.0 0.25-> 32 0.5-> 32
0 1 2 2 97 97 95 20 14 13
Escherichia coli (193)
sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin ccphalothin cefoxitin ceftazidime gentamicin amikacin
4.0 < 0.03-> 4.0 0.12->4.0 0.06-1.0 8.0-> 32 4.0-> 32 2.0-> 32 0.12-1.0 0.12—> 32 0.12—> 32
1 1 1 0 58 43 7 2 9 4
Klebsiella oxytoca (32)
sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin cephalothin cefoxitin ceftazidime gentamicin amikacin
0.03 32 4.0 8.0 0.15 0.25 0.5
0.5 0.12 0.5 0.5 >32 >32 16 4.0 1.0 8.0
32 4-16 0.25-> 32 0.12—> 32 0.25-16.0
0 0 0 0 94 37 0 6 16 6
101
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Numbers of strains are given in parentheses.
Table 1 (c o n tin u e d )
Drug
MIC, pg/ml MIC jo
Klebsiella pneumoniae (65)
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin cephalothin cefoxitin ceftazidime gentamicin amikacin
0.06 32 8.0 8.0 0.25 0.25 0.5
Proteus mirabilis (42)
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin cephalothin cefoxitin ceftazidime gentamicin amikacin
0.12 0.03 0.12 0.25 >32 >32 >32 0.12 0.25 0.5
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin cephalothin gentamicin amikacin
0.06 4 0.06-> 4 0.12-> 32 0.12-1.0 16-> 32 4.0-> 32 4.0-> 32 0.25-> 16.0 0.12-> 32 0.5-> 32
2 2 3 0 99 30 8 13 25 19
0.03-4.0 28 0.12-2 0.5-> 32 1.0-> 32 1.0-> 32 0.12-16 0.12->32 0.25-8
0 0 3 0 39 34 4 1 11 0
2.0 >32 >32 >32 2.0 >32 4.0
0.06-0.5 32 8-> 32 4-> 32 0.12—> 16 0.25-> 32 0.25-16
0 0 0 0 94 97 83 6 12 0
0.12 0.12 0.5 0.5 >32 >32 0.5 2.0
0.03-0.12 32 1.0-> 32 0.12-> 32 0.12-4.0
0 0 0 0 26 15 2 0
0.5 0.25 2.0 0.5 >32 >32 >32 8.0 >32 16 1.0
0.5 2.0 1.0
2.0 8.0 8.0 1.0
>32 4.0 0.5 0.5 1.0
Qadri/Ueno/Burns/Almodovar/Rabea
In vitro Activity of Sparfloxacin
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Bacterium
Table 1 (co n tin u ed )
Drug
MIC, pg/ml MIC*
Serratia marcescens (48)
Shigella (29)
Pseudomonas aeruginosa (88)
Xanthomonas maltophilia (28)
Aeromonas hydrophilia (31)
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin piperacillin ccphalothin cefoxitin ceftazidime gentamicin amikacin
0.12 < 0.03 0.5 0.5 >32 2.0 >32 >32
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin ccphalothin gentamicin amikacin
0.06 < 0.03 0.12 0.12 4.0 2.0
Sparfloxacin ciprofloxacin norfloxacin imipenem cefoxitin ceftazidime piperacillin gentamicin amikacin Sparfloxacin ciprofloxacin norfloxacin imipenem cefoxitin ceftazidime piperacillin gentamicin amikacin sparfloxacin ciprofloxacin norfloxacin
1.0
>32 2.0
1.0 1.0 1.0
0.12 0.5 1.0
>32 2.0 8.0 2.0 2.0 0.06 0.12 1.0
>16 >32 > 16 >128 >32 >32 0.03 0.06 0.12
MIC* 1.0
0.5 2.0 2.0 >32 >256 >32 >32 8.0 >32 >32
range 256 >32 8-> 32 0.5-16 0.25-> 32 1.0->32
Resistant % 0 0 5 0 96 71 100 71 6 40 27 0 0
>32 16.0 8.0 8.0
0.03-0.12 32 2-16.0 0.12-> 32 0.25-16
4.0 2.0 2.0 2.0 >32 8.0 >128 >32 >32
< 0.03-> 4.0 0.12-8.0 0.5-16 1.5-> 16.0 >32 1.0-> 16.0 8.0-> 128 0.5-> 32 0.5-> 32
9 4 8 9 100 8 12 28 14
0.5 8.0 16 >16 >32 > 16 >128 >32 >32
0.03-1.0 0.12-8.0 1.0-> 32 >16 >32 4.0-> 16.0 8-> 128 4->32 4->32
12 29 1«) 100 36 91 50 50
0.12 0.12 1.0 1.0
0.12 0.12 0.5
32 >32 >32 2.0 0.25 0.25
0.25 >32 >32 >32 >32 0.5 1.0
0.12-0.25 >32 >32 >32 2.0-> 32 0.12-1.0 0.12-1.0
Sparfloxacin ciprofloxacin norfloxacin imipencm ampicillin cephalothin cefoxitin ceftazidime gentamicin amikacin
32 >32 >32 2.0 0.5 0.5
0.12 0.5 16 8.0 >32 >32 >32 16.0 >32 >32
32 1.0-8.0 4-> 32 8-> 32 8-> 32 2.0-> 16.0 0.25-> 32 0.5-> 32
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin oxacillin cephalothin vancomycin
0.12 0.12 0.5 0.12 >32 0.5 2.0 0.25
0.5
0.25 >32
0.12-0.5 0.12-1.0 0.25-1.0 0.12-0.5 2.0-> 32 0.25->4 2.0-> 32 0.25-2
Coagulasc-negative staphylococci (131)
Sparfloxacin ciprofloxacin norfloxacin imipencm ampicillin oxacillin cephalothin vancomycin
0.25 0.5 0.5 0.12 >32 >4.0 >32 0.5
4.0 2.0 4.0 0.5 >32 >4.0 >32 2.0
Enterococcus
Sparfloxacin
4.0
4.0
0.5-8.0
8
(59)
ciprofloxacin norfloxacin imipencm ampicillin cephalothin vancomycin
8.0 8.0 0.25 4.0 >32 0.5
16.0 16.0 4.0 16.0 >32 2.0
2.0-16 2.0-> 32 0.12-8.0 4.0-> 32 16-> 32 0.5-4.0
73 78
Acinetobacter (90)
Staphylococcus aureus (128)
1.0
1.0 1.0
1.0
16 2.0
0.12-8.0 0.5-8.0 0.5-16 0.12-> 16.0 4.0-> 32.0 0.5-> 4 4.0-> 32 0.25-4.0
0
100 69 67 33 8 37 0 0 33 0
80 100 88 3 15 19 0 0
0 0
97 10 10 0
3 3 6 10 91 66 66 0
0
3 94 0
Numbers of strains are given in parentheses.
104
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In vitro Activity of Sparfloxacin
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Bacterium
6, 7, 11, 16]. Nakamura ct al. [11] reported its bioavailability to be 77% in dogs following oral or intravenous administration, and its lev els in tissues and plasma of experimental ani mals were 1-11 times higher than those of ci profloxacin. In vitro activities in developed and indus trialized countries have shown that Sparfloxa cin has excellent broad-spectrum antibacterial activity [2,3, 6, 7,11,16]. However, the clinical isolates in these countries tend generally to be more susceptible to various antimicrobials as compared to those in developing countries. Previous studies have shown that gram-nega tive bacteria, especially E. coli, Proteus mirabilis, Enterobacter, Serratia and Pseudomo nas were more resistant to penicillins, cepha losporins and aminoglycosides in Saudi Arabia than in the USA [13-15], Therefore, this study was undertaken for comparative in vitro activity of Sparfloxacin against these rela tively resistant clinical isolates. Against most Enterobacteriaceae Sparfloxacin was found to have comparable or superior antiactcrial ac tivity than ciprofloxacin or norfloxacin and to be better than any other drug tested except imipenem. These findings are consistent with
those reported for sparfloxacin elsewhere [6, 9,11,16], Previous reports have shown that sparflox acin was more active against both methicillinsusceptible and mcthicillin-resistant 5. aureus and coagulase-negative staphylococci [2, 77]. We found this to be true with our isolates of staphylococci, especially with S. aureus. Un like other fluoroquinolones which have little activity against enterococci, sparfloxacin ex hibited excellent activity inhibiting 92% of the 59 isolates at an MIC of 4.0 pg/ml. Excellent in vitro activity, improved phar macokinetic properties, the possibility of sin gle daily dosing [9,11] and the increased halflife of sparfloxacin as compared with presently available fluoroquinolones makes it a suitable candidate for clinical trials.
Acknowledgement We wish to thank Parkc-Davis Pharmaceutical Re search Division (Ann Arbor, Mich., USA) for a gener ous supply of sparfloxacin, Ms. Amy Pering for secre tarial assistance and Mrs. Marilyn Smith for computer search of literature.
References 3 Docbbling, B.N.; Pfaller, M.A.; Vale, M.J.; Wenzel, R.P.: Compara tive in-vitro activity of the new quinolone sparfloxacin (CI-978, AT-4140) against nosocomial Gram negative bloodstream isolates. Eur. J. clin. Microbiol, infect. Dis. 9:298301 (1990). 4 Farrar, W.E.: Antibiotic resistance in developing countries. J. infect. Dis. 152: 1103(1985).
5 Frost, J.A.; Rowe, B.; Vandepitte, J.: Acquisition of trimethoprim resis tance in epidemic strains of Shigella dysenteriae type I from Zaire. Lancet /: 963 (1982). 6 Kojima, T.; Inoue, M.; Mitsuhashi, S.: In-vitro activity of AT-4140 against clinical bacterial isolates. Antimicrob. Agents Chemother. 33; 1980-1988 (1989).
105
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1 Balows, A.; Hausier, W.J., Jr.; Her mann, K.L.; Isenberg, H.D.; Shadomy, H.J.: Manual of clinical micro biology (American Society for Mi crobiology, Washington 1991). 2 Chaudhry, A.Z.; Knapp, C.C.; Sierra-Madero, J.; Washington, J.A.: Antistaphylococcal activities of sparfloxacin (CI-978; AT-4140), ofloxacin and ciprofloxacin. Antimicrob. Agents Chemother. 34: 18431845 (1990).
106
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14 Qadri, S.M.H.; Rizvi, W.H.: Rah man, S.A.; et al.: Antimicrobial re sistance of Escherichia, Klebsiella, and Pseudomonas in a large metro politan hospital in Saudi Arabia. Comparison with those in USA. J. natn. med. Ass. 81: 1061-1064 (1989). 15 Qadri, S.M.H.; Kroschinsky, R.M.; Cunha, B.A.: Similarities and differ ences in the antimicrobial resistance of clinical isolates in Saudi Arabia and the United States. Curr. ther. Res. 47: 130-135(1990). 16 Rolston. K.V.I.; Messer, M.; Ho, D.H.: Comparative in-vitro activ ities of newer quinolones against Pseudomonas species and Xanlhomonas maltophilia isolated from patients with cancer. Antimicrob. Agents Chemother. 34: 1812-1813 ( 1990).
In vitro Activity of Sparfloxacin
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7 Kojima, T.; Inoue, M.; Mitsuhashi, 11 Nakamura, S.; Minami, A.; Nakata, S.: In-vitro activity of AT-4140 K.; Kurobc, N.; Kouno, K.; Sakaguchi. Y.; Kashimoto, S.; Yoshida, H.; against quinolone and methicillinresistant Staphylococcus aureus. AnKojima, T.; Ohou. T ; Fujimoto, K.; Nakamura, M.; Hashimoto, M.; Shi timicrob. Agents Chemother. 34: mizu, H.: In-vitro and in vivo anti 1123-1127(1990). bacterial activities of AT-4140. a new 8 Mhalu, F.S.; Mmari, P.W.; Ljumba, broad spectrum quinolone. AntimiJ. : Rapid emergence of El Tor Vibrio crob. Agents Chemother. 33: 1167cholerae resistant to antimicrobial 1173(1989). agents during the first six months of the fourth cholera epidemic in Tan 12 National Committee for Clinical Laboratory Standards: Methods for zania. Lancet 345 (1979). dilution antimicrobial susceptibility 9 Miyamoto, R.; Matsumoto, J.; tests for bacteria that grow aerobi Chiba, K.; F.gawa, H.; Shibamori, K.; cally (tentative standard). Publica Minamida, A.; Nishimura, Y.; tion M7-T2 (NCCLS, Villanova Okada, H.; Kataoka, M.; Fujita, M.; 1988). Hirosc.T.; Nakano, J.: Synthesis and structure activity relationships of 513 Qadri, S.M.H.; Ostrawski, S.; John son, S.; Fluornoy, D.J.: Differences substituted 6,8-difluoroquinolones, including Sparfloxacin, a new quino in antimicrobial susceptibilities of lone antibacterial agent with im clinical isolates in Saudi Arabia and proved potency. J. mcd. Chcm. 33: the United States. J. natn. med. Ass. 79:433-437 (1987). 1645-1656(1990). 10 Murray, B.E.; Alvarado, T.; Kim, K. H.; et al.: Increasing resistance to trimethoprim-sulfamethoxazole among isolates of Escherichia coli in developing countries. J. infect. Dis. 152:1107-1113(1985).
S.M. Hussain Qadri Yoshio Ueno J. Joyce Bums Edna Almodovar Nada Rabea
In vitro Activity of Sparfloxacin (CI-978), a New Broad-Spectrum Fluoroquinolone
King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
Abstract The in vitro activity of sparfloxacin (CI-978, AT-4140), a new fluoroquinolone, was compared with ciprofloxacin, norfloxa cin and other commonly used antimicrobial agents against 650 strains of Enterobacteriaceae, 237 isolates of other gram-nega tive bacilli and 318 strains of gram-positive cocci. The MICs of sparfloxacin against 90% of the members of Enterobacteriaceac were between 0.12 and 0.5 pg/ml. All the 48 isolates of no toriously drug-resistant Serrada marcescens were inhibited by < 0.03-4.0 (ig/ml of sparfloxacin. All the 90 isolates of Acinetobacter, 80 of the 88 strains of Pseudomonas aeruginosa and all the 28 isolates of Xanthomonas maltophilia were susceptible to sparfloxacin. The MIC90 f°r the cocci tested ranged be tween 0.5 and 4.0 pg/ml of sparfloxacin. It inhibited 92% of en terococci as compared with 27% for ciprofloxacin and 22% for norfloxacin. It was better or comparable in activity to other flu oroquinolones and superior to penicillins, cephalosporins and aminoglycosides tested. There was cross-resistance between ci profloxacin, norfloxacin and sparfloxacin.
Introduction Bacterial isolates from clinical specimens in the developing countries of Asia, Africa and Latin America are known to be more resistant to commonly used antimicrobial agents than
those in Western Europe, USA and Canada [4,5,8,10]. It has been shown that clinical iso lates in Saudi Arabia are no exceptions and tend to be significantly less susceptible to vari ous antibiotics [13,14], Using these isolates we determined the in vitro activity of the new flu-
Dr.S.M.H. Qadri Microbiology Laboratory King Faisal Specialist Hospital and Research Centre, MBC-10, PO Box 3354 Riyadh 11211 (Kingdom of Saudi Arabia)
© 1992 S. Kargcr AG, Basel 0009-3157/92/ 0382-0099 $ 2.75/0
Downloaded by: Stockholm University Library 130.237.165.40 - 12/9/2018 11:50:13 PM
Key Words Sparfloxacin CI-978 AT-4140 Fluoroquinolones In vitro activity
oroquinolone sparfloxacin and compared it with those of other agents. Our findings are presented in this paper.
Materials and Methods A total of 1,205 strains of recent clinical isolates were studied. These bacteria were isolated from pa tient specimens at the King Faisal Specialist Hospital and Research Centre which is a 550-bed tertiary care facility in Riyadh and serves as a referral center for the Kingdom of Saudi Arabia and the Middle East. Mi croorganisms were identified by a standard procedure [1] and susceptibility testing was performed by the agar dilution method as recommended by the National Committee for Clinical Laboratory Standards [12]. Muller-Hinton agar (Difco Laboratories, Detroit, Mich., USA) with a pH between 7.2 and 7.4 was used throughout the study. Standard bacterial suspensions were inoculated onto the agar surface with a multi point inoculator. All incubations were at 35 °C for 18-24 h. Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 29213 were used as quality control organisms. The quality control results were found to be within ex pected ranges during the period of this investigation. Sparfloxacin was provided by Parkc-Davis Pharmaceu tical Research, Division of Warner-Lambert (Ann Ar bor, Mich., USA). Other drugs were purchased from commercial sources. Bacteria were considered resis tant when the MIC for fluoroquinolones exceeded 4.0 pg/ml. Other interpretation were those recommended by the National Committee for Clinical Laboratory Standards [12].
cin was similar or superior to that of ciproflox acin and norfloxacin (table 1). Although spar floxacin was inhibitory to all the 48 isolates of Serratia marcescens, the MIC values were 2- to 4-fold higher than that of ciprofloxacin. Its bacterial activity towards Enterobacter species was superior to that of ciprofloxacin and nor floxacin. Of the 24 strains of Citrobacter freundii tested 4 were found to be resistant to all the 3 fluoroquinolones tested. The MIC90 for sparfloxacin for Enterobacteriaceae ranged between 0.12 and 0.5 pg/ml. Of the 88 isolates of P. aeruginosa tested, 80 (91%) were susceptible to sparfloxacin as compared to 96% for ciprofloxacin and 92% for norfloxacin. However, sparfloxacin was significantly more active against Xanthomonas maltophilia, Acinetobacter and Aeromonas hydrophila than other fluoroquinolones. Both methicillin-susccptible as well as methicillin-resistant isolates of S. aureus were susceptible to sparfloxacin, ciprofloxacin and norfloxacin. However, the MIC90 of sparfloxa cin for these isolates was 0.5 pg/ml compared with 1.0 pg/ml for other fluoroquinolones. Sparfloxacin also exhibited superior activity against coagulase-negative staphylococci and enterococci. Of the 3 fluoroquinolones tested sparfloxacin inhibited 92% of enterococci as compared with 22 and 27% for norfloxacin and ciprofloxacin, respectively.
Results
100
Sparfloxacin (CI-978, AT-4140) is a new synthetic fluoroquinolone with a chemical for mula of 5-amino-l-cyclopropyl-6,8-difluoro1,4- dihydro -7- (cis -3,5-dimethyl -1-piperazinyl)-4-oxoquinolone-3-carboxylic acid [11]. Its broad-spectral activity against both gram-pos itive and gram-negative bacteria along with excellent pharmacokinetic properties has gen erated much interest in its development [2, 3,
Qadri/Ueno/Burns/Almodovar/Rabca
In vitro Activity of Sparfloxacin
Downloaded by: Stockholm University Library 130.237.165.40 - 12/9/2018 11:50:13 PM
Discussion A total of 1,205 isolates, consisting of 650 Enterobacteriaccae, 237 Pseudomonas, Acinetobacter and Aeromonas and 318 isolates of gram-positive cocci were used to determine their MICs to sparfloxacin, ciprofloxacin, nor floxacin, imipenem, ampicillin, piperacillin, oxacillin, vancomycin, cephalothin, cefoxitin, ceftazidime, gentamicin and amikacin. Against members of the family Enterobacteriaceae the antibacterial activity of sparfloxa-
Table 1. In vitro activity of sparfloxacin and other antimicrobial agents Bacterium
Drug
MIC, pg/ml MIC»
MIC*
range
Resistant %
Citrobacter (24)
sparfloxacin ciprofloxacin norfloxacin imipcncm ampicillin ccphalothin cefoxitin ceftazidime gentamicin amikacin
32.0 >32.0 0.5 0.12 0.5
>4.0 >4.0 >4.0 2.0 > 32.0 > 32.0 >32.0 >16.0 0.5 4.0
< 0.03-> 4.0 < 0.03-> 4.0 0.12—> 4.0 0.25-2.0 2.0-> 32 2.0-> 32 2.0-> 32 0.5-> 16 0.12-> 32 0.25-> 32
17 17 17 0 92 92 86 15 23 8
Enterobacter sp. (101)
sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin ccphalothin cefoxitin ceftazidime gentamicin amikacin
0.03 32 >32 >32 0.5 0.25 1.0
0.12 2.0 4.0 0.2 >32 >32 >32 16.0 >32 >32
32 8-> 32 0.5-> 16.0 0.25-> 32 0.5-> 32
0 1 2 2 97 97 95 20 14 13
Escherichia coli (193)
sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin ccphalothin cefoxitin ceftazidime gentamicin amikacin
4.0 < 0.03-> 4.0 0.12->4.0 0.06-1.0 8.0-> 32 4.0-> 32 2.0-> 32 0.12-1.0 0.12—> 32 0.12—> 32
1 1 1 0 58 43 7 2 9 4
Klebsiella oxytoca (32)
sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin cephalothin cefoxitin ceftazidime gentamicin amikacin
0.03 32 4.0 8.0 0.15 0.25 0.5
0.5 0.12 0.5 0.5 >32 >32 16 4.0 1.0 8.0
32 4-16 0.25-> 32 0.12—> 32 0.25-16.0
0 0 0 0 94 37 0 6 16 6
101
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Numbers of strains are given in parentheses.
Table 1 (c o n tin u e d )
Drug
MIC, pg/ml MIC jo
Klebsiella pneumoniae (65)
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin cephalothin cefoxitin ceftazidime gentamicin amikacin
0.06 32 8.0 8.0 0.25 0.25 0.5
Proteus mirabilis (42)
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin cephalothin cefoxitin ceftazidime gentamicin amikacin
0.12 0.03 0.12 0.25 >32 >32 >32 0.12 0.25 0.5
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin cephalothin gentamicin amikacin
0.06 4 0.06-> 4 0.12-> 32 0.12-1.0 16-> 32 4.0-> 32 4.0-> 32 0.25-> 16.0 0.12-> 32 0.5-> 32
2 2 3 0 99 30 8 13 25 19
0.03-4.0 28 0.12-2 0.5-> 32 1.0-> 32 1.0-> 32 0.12-16 0.12->32 0.25-8
0 0 3 0 39 34 4 1 11 0
2.0 >32 >32 >32 2.0 >32 4.0
0.06-0.5 32 8-> 32 4-> 32 0.12—> 16 0.25-> 32 0.25-16
0 0 0 0 94 97 83 6 12 0
0.12 0.12 0.5 0.5 >32 >32 0.5 2.0
0.03-0.12 32 1.0-> 32 0.12-> 32 0.12-4.0
0 0 0 0 26 15 2 0
0.5 0.25 2.0 0.5 >32 >32 >32 8.0 >32 16 1.0
0.5 2.0 1.0
2.0 8.0 8.0 1.0
>32 4.0 0.5 0.5 1.0
Qadri/Ueno/Burns/Almodovar/Rabea
In vitro Activity of Sparfloxacin
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Bacterium
Table 1 (co n tin u ed )
Drug
MIC, pg/ml MIC*
Serratia marcescens (48)
Shigella (29)
Pseudomonas aeruginosa (88)
Xanthomonas maltophilia (28)
Aeromonas hydrophilia (31)
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin piperacillin ccphalothin cefoxitin ceftazidime gentamicin amikacin
0.12 < 0.03 0.5 0.5 >32 2.0 >32 >32
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin ccphalothin gentamicin amikacin
0.06 < 0.03 0.12 0.12 4.0 2.0
Sparfloxacin ciprofloxacin norfloxacin imipenem cefoxitin ceftazidime piperacillin gentamicin amikacin Sparfloxacin ciprofloxacin norfloxacin imipenem cefoxitin ceftazidime piperacillin gentamicin amikacin sparfloxacin ciprofloxacin norfloxacin
1.0
>32 2.0
1.0 1.0 1.0
0.12 0.5 1.0
>32 2.0 8.0 2.0 2.0 0.06 0.12 1.0
>16 >32 > 16 >128 >32 >32 0.03 0.06 0.12
MIC* 1.0
0.5 2.0 2.0 >32 >256 >32 >32 8.0 >32 >32
range 256 >32 8-> 32 0.5-16 0.25-> 32 1.0->32
Resistant % 0 0 5 0 96 71 100 71 6 40 27 0 0
>32 16.0 8.0 8.0
0.03-0.12 32 2-16.0 0.12-> 32 0.25-16
4.0 2.0 2.0 2.0 >32 8.0 >128 >32 >32
< 0.03-> 4.0 0.12-8.0 0.5-16 1.5-> 16.0 >32 1.0-> 16.0 8.0-> 128 0.5-> 32 0.5-> 32
9 4 8 9 100 8 12 28 14
0.5 8.0 16 >16 >32 > 16 >128 >32 >32
0.03-1.0 0.12-8.0 1.0-> 32 >16 >32 4.0-> 16.0 8-> 128 4->32 4->32
12 29 1«) 100 36 91 50 50
0.12 0.12 1.0 1.0
0.12 0.12 0.5
32 >32 >32 2.0 0.25 0.25
0.25 >32 >32 >32 >32 0.5 1.0
0.12-0.25 >32 >32 >32 2.0-> 32 0.12-1.0 0.12-1.0
Sparfloxacin ciprofloxacin norfloxacin imipencm ampicillin cephalothin cefoxitin ceftazidime gentamicin amikacin
32 >32 >32 2.0 0.5 0.5
0.12 0.5 16 8.0 >32 >32 >32 16.0 >32 >32
32 1.0-8.0 4-> 32 8-> 32 8-> 32 2.0-> 16.0 0.25-> 32 0.5-> 32
Sparfloxacin ciprofloxacin norfloxacin imipenem ampicillin oxacillin cephalothin vancomycin
0.12 0.12 0.5 0.12 >32 0.5 2.0 0.25
0.5
0.25 >32
0.12-0.5 0.12-1.0 0.25-1.0 0.12-0.5 2.0-> 32 0.25->4 2.0-> 32 0.25-2
Coagulasc-negative staphylococci (131)
Sparfloxacin ciprofloxacin norfloxacin imipencm ampicillin oxacillin cephalothin vancomycin
0.25 0.5 0.5 0.12 >32 >4.0 >32 0.5
4.0 2.0 4.0 0.5 >32 >4.0 >32 2.0
Enterococcus
Sparfloxacin
4.0
4.0
0.5-8.0
8
(59)
ciprofloxacin norfloxacin imipencm ampicillin cephalothin vancomycin
8.0 8.0 0.25 4.0 >32 0.5
16.0 16.0 4.0 16.0 >32 2.0
2.0-16 2.0-> 32 0.12-8.0 4.0-> 32 16-> 32 0.5-4.0
73 78
Acinetobacter (90)
Staphylococcus aureus (128)
1.0
1.0 1.0
1.0
16 2.0
0.12-8.0 0.5-8.0 0.5-16 0.12-> 16.0 4.0-> 32.0 0.5-> 4 4.0-> 32 0.25-4.0
0
100 69 67 33 8 37 0 0 33 0
80 100 88 3 15 19 0 0
0 0
97 10 10 0
3 3 6 10 91 66 66 0
0
3 94 0
Numbers of strains are given in parentheses.
104
Qadri/Ueno/Burns/Almodovar/Rabea
In vitro Activity of Sparfloxacin
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Bacterium
6, 7, 11, 16]. Nakamura ct al. [11] reported its bioavailability to be 77% in dogs following oral or intravenous administration, and its lev els in tissues and plasma of experimental ani mals were 1-11 times higher than those of ci profloxacin. In vitro activities in developed and indus trialized countries have shown that Sparfloxa cin has excellent broad-spectrum antibacterial activity [2,3, 6, 7,11,16]. However, the clinical isolates in these countries tend generally to be more susceptible to various antimicrobials as compared to those in developing countries. Previous studies have shown that gram-nega tive bacteria, especially E. coli, Proteus mirabilis, Enterobacter, Serratia and Pseudomo nas were more resistant to penicillins, cepha losporins and aminoglycosides in Saudi Arabia than in the USA [13-15], Therefore, this study was undertaken for comparative in vitro activity of Sparfloxacin against these rela tively resistant clinical isolates. Against most Enterobacteriaceae Sparfloxacin was found to have comparable or superior antiactcrial ac tivity than ciprofloxacin or norfloxacin and to be better than any other drug tested except imipenem. These findings are consistent with
those reported for sparfloxacin elsewhere [6, 9,11,16], Previous reports have shown that sparflox acin was more active against both methicillinsusceptible and mcthicillin-resistant 5. aureus and coagulase-negative staphylococci [2, 77]. We found this to be true with our isolates of staphylococci, especially with S. aureus. Un like other fluoroquinolones which have little activity against enterococci, sparfloxacin ex hibited excellent activity inhibiting 92% of the 59 isolates at an MIC of 4.0 pg/ml. Excellent in vitro activity, improved phar macokinetic properties, the possibility of sin gle daily dosing [9,11] and the increased halflife of sparfloxacin as compared with presently available fluoroquinolones makes it a suitable candidate for clinical trials.
Acknowledgement We wish to thank Parkc-Davis Pharmaceutical Re search Division (Ann Arbor, Mich., USA) for a gener ous supply of sparfloxacin, Ms. Amy Pering for secre tarial assistance and Mrs. Marilyn Smith for computer search of literature.
References 3 Docbbling, B.N.; Pfaller, M.A.; Vale, M.J.; Wenzel, R.P.: Compara tive in-vitro activity of the new quinolone sparfloxacin (CI-978, AT-4140) against nosocomial Gram negative bloodstream isolates. Eur. J. clin. Microbiol, infect. Dis. 9:298301 (1990). 4 Farrar, W.E.: Antibiotic resistance in developing countries. J. infect. Dis. 152: 1103(1985).
5 Frost, J.A.; Rowe, B.; Vandepitte, J.: Acquisition of trimethoprim resis tance in epidemic strains of Shigella dysenteriae type I from Zaire. Lancet /: 963 (1982). 6 Kojima, T.; Inoue, M.; Mitsuhashi, S.: In-vitro activity of AT-4140 against clinical bacterial isolates. Antimicrob. Agents Chemother. 33; 1980-1988 (1989).
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1 Balows, A.; Hausier, W.J., Jr.; Her mann, K.L.; Isenberg, H.D.; Shadomy, H.J.: Manual of clinical micro biology (American Society for Mi crobiology, Washington 1991). 2 Chaudhry, A.Z.; Knapp, C.C.; Sierra-Madero, J.; Washington, J.A.: Antistaphylococcal activities of sparfloxacin (CI-978; AT-4140), ofloxacin and ciprofloxacin. Antimicrob. Agents Chemother. 34: 18431845 (1990).
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14 Qadri, S.M.H.; Rizvi, W.H.: Rah man, S.A.; et al.: Antimicrobial re sistance of Escherichia, Klebsiella, and Pseudomonas in a large metro politan hospital in Saudi Arabia. Comparison with those in USA. J. natn. med. Ass. 81: 1061-1064 (1989). 15 Qadri, S.M.H.; Kroschinsky, R.M.; Cunha, B.A.: Similarities and differ ences in the antimicrobial resistance of clinical isolates in Saudi Arabia and the United States. Curr. ther. Res. 47: 130-135(1990). 16 Rolston. K.V.I.; Messer, M.; Ho, D.H.: Comparative in-vitro activ ities of newer quinolones against Pseudomonas species and Xanlhomonas maltophilia isolated from patients with cancer. Antimicrob. Agents Chemother. 34: 1812-1813 ( 1990).
In vitro Activity of Sparfloxacin
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7 Kojima, T.; Inoue, M.; Mitsuhashi, 11 Nakamura, S.; Minami, A.; Nakata, S.: In-vitro activity of AT-4140 K.; Kurobc, N.; Kouno, K.; Sakaguchi. Y.; Kashimoto, S.; Yoshida, H.; against quinolone and methicillinresistant Staphylococcus aureus. AnKojima, T.; Ohou. T ; Fujimoto, K.; Nakamura, M.; Hashimoto, M.; Shi timicrob. Agents Chemother. 34: mizu, H.: In-vitro and in vivo anti 1123-1127(1990). bacterial activities of AT-4140. a new 8 Mhalu, F.S.; Mmari, P.W.; Ljumba, broad spectrum quinolone. AntimiJ. : Rapid emergence of El Tor Vibrio crob. Agents Chemother. 33: 1167cholerae resistant to antimicrobial 1173(1989). agents during the first six months of the fourth cholera epidemic in Tan 12 National Committee for Clinical Laboratory Standards: Methods for zania. Lancet 345 (1979). dilution antimicrobial susceptibility 9 Miyamoto, R.; Matsumoto, J.; tests for bacteria that grow aerobi Chiba, K.; F.gawa, H.; Shibamori, K.; cally (tentative standard). Publica Minamida, A.; Nishimura, Y.; tion M7-T2 (NCCLS, Villanova Okada, H.; Kataoka, M.; Fujita, M.; 1988). Hirosc.T.; Nakano, J.: Synthesis and structure activity relationships of 513 Qadri, S.M.H.; Ostrawski, S.; John son, S.; Fluornoy, D.J.: Differences substituted 6,8-difluoroquinolones, including Sparfloxacin, a new quino in antimicrobial susceptibilities of lone antibacterial agent with im clinical isolates in Saudi Arabia and proved potency. J. mcd. Chcm. 33: the United States. J. natn. med. Ass. 79:433-437 (1987). 1645-1656(1990). 10 Murray, B.E.; Alvarado, T.; Kim, K. H.; et al.: Increasing resistance to trimethoprim-sulfamethoxazole among isolates of Escherichia coli in developing countries. J. infect. Dis. 152:1107-1113(1985).
