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Chemotherapy 1991;37:420-425

Postantibiotic Effect of Ciprofloxacin Compared with that of Five Other Quinolones F. Minguez, C. Ramos, S. Barrientos, A. Loscos, J. Prieto Department of Microbiology, Faculty of Medicine, Complutcnse University, Madrid, Spain

Key Words. Postantibiotic effect • Ciprofloxacin • Quinolones

Introduction

The fluoroquinolones display high ac­ tivity against Enterobacteriaccae and good activity against other gram-negative bacilli and gram-positive cocci [1-5]. Their phar­ macokinetic properties are highly accept­ able: excellent oral absorption, good dis­ tribution and slight metabolization [6, 7]. Numerous studies of the in vitro anti­

microbial activity, with regard to minimal inhibitory concentrations (MICs) and min­ imal bactericidal concentrations, have been performed. We, in company with oth­ er authors [8], are of the opinion that these data arc insufficient unless accom­ panied by studies of subinhibitory effects, concentration effects, killing kinetics and the postantibiotic effect (PAE). The postantibiotic effect is defined as

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Abstract. The antimicrobial activity (minimal inhibitory concentration, MIC, and kill­ ing kinetics) and postantibiotic effect (PAE) of different concentrations (MIC and 6 mg/ 1) of ciprofloxacin, norfloxacin, ofloxacin, pefloxacin, fleroxacin and lomcfloxacin on pure cultures of Staphylococcus aureus and Escherichia coli were compared in vitro. The MIC, killing kinetics and PAE were determined by standard methods. Ciprofloxacin dis­ played the lowest MICs, while the highest were those of norfloxacin against S. aureus and lomefloxacin against E. coli. The killing curves showed ciprofloxacin to be the most and norfloxacin the least active. The bactericidal power was dependent on the concen­ tration. At MIC, the fluoroquinolones, with the exception of norfloxacin, induced PAEs of 1-2 h. The effect was, in all cases, greater against E. coli. When assayed at 6 mg/1 the PAEs were increased to 2-5 h, the best results being obtained by ciprofloxacin followed by ofloxacin. Norfloxacin produced no PAE on S. aureus and scarcely reached 1.3 h against E. coli. There was a close relationship between bactericidal power and PAE.

421

Postantibiotic Effect of Six Quinoloncs

the suppression of bacterial growth, per­ sisting after brief exposure of bacterial cultures to antimicrobial concentrations equal to, or greater than, the MIC [9, 10]. An ample PAE permits a more widely spaced dosis interval without loss of effi­ cacy, resulting in reduced toxicity and a fi­ nancial saving for the patient. This work describes a comparative in vitro study of the antimicrobial activity (MIC and killing curves) and the PAE of different concentrations (MIC and 6 mg/1) of ciprofloxacin, norfloxacin, ofloxacin, pefloxacin, fleroxacin and lomefloxacin on pure cultures of Staphylococcus aureus and Escherichia coli.

determined at 37 °C in a shaking bath, and colony counts were performed on Mueller-Hinton agar at hourly intervals. Postantibiotic Effect Pure bacterial cultures in Mueller-Hinton broth, with 107 CFU/ml, in logarithmic growth phase, were exposed for 1 h to different concentrations (MIC and 6 mg/l) of the drugs. Exposure was carried out in a shaking bath at 37 °C. The antimicrobial agent was removed by diluting the culture 1,000-fold with fresh Mueller-Hinton broth [9]. Then bacterial growth kinetics were deter­ mined at 37°C in a shaking bath. Each hour bacte­ rial countings on Mueller-Hinton agar were made. The PAE was measured as the difference in time required by cultures and controls, after elimination of the antimicrobial, to increase the bacterial pop­ ulation by 1 log10. A PAE greater than 0.5 h was con­ sidered significant [9. 10]. All assays were performed at least 3 times.

Material and Methods

Antimicrobial Agents The antimicrobial agents used in this study were: ciprofloxacin (Bayer SA), norfloxacin (Merck Sharp and Dohmc). ofloxacin (Hocchst Ibérica SA), pe­ floxacin (Rhône Poulenc Farma, SAE), fleroxacin (Roche SA) and lomefloxacin (Searle Ibérica SA). Susceptibility Test The MIC of each antimicrobial agent was deter­ mined by the broth macrodilution method (II). Killing Kinetics Pure bacterial cultures in Mueller-Hinton broth, with 107 colony-forming units per milliliter (CFU/ ml), in logarithmic growth phase, were exposed to each antimicrobial at concentrations corresponding to MICs, as well as at higher concentrations (6 mg/ I), for a period of 8 h. Bacterial growth kinetics were

Statistical Analysis The arithmetic average and standard error were employed as statistical parameters.

Results

The MICs of the different antimicro­ bials assayed are shown in table 1. Cipro­ floxacin was the most active of the fluoro­ quinolones used against E. coli, while lomefloxacin displayed the least activity. S. aureus was less sensitive (2-33 times) than E. coli, particularly with respect to norfloxacin. The killing kinetics, at the antimicro­ bial MICs, against S. aureus and E. coli are shown in figures 1 and 2, respectively. The most active antimicrobial agent was cipro­ floxacin, while the least active was norflox­ acin. At concentrations of 6 mg/1 (fig. 3, 4) greater reductions in bacterial growth were obtained. Ciprofloxacin once again displayed the greatest bactericidal capac-

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Microorganisms In this work were employed the S. aureus strain 29213 of the American Type Culture Collection (ATCC 29213) and E. coli (ATCC 25922). Both strains had recently been recuperated from skim milk at -2 0 °C and were then maintained by serial passage in Mueller-Hinton agar during the experi­ ment.

422______________________________________________________Mingucz/Ramos/Barrientos/Loscos/Prieto Table 1. MIC (first of the two concentrations) and PAE (means ±SE ) of six fluoroquinolones on S. aureus and E. coli

Ciprofloxacin Norfloxacin Ofloxacin Pefloxacin Fleroxacin Lomefloxacin

Concentration (mg/l) against

PAE, h

S. aureus

E. coli

5. aureus

E. coli

0.5 6 4 6 0.5 6 2 6 0.5 6 1 6

0.015 6 0.12 6 0.12 6 0.06 6 0.12 6 0.5 6

1.6 ±0.2 3.3 ±0.6 0.4 ±0.3 0.6 ±0.3 1.4 ±0.3 3.1 ±0.5 1.1 ±0.4 1.7 ±0.5 0.8 ±0.3 2.0 ±0.4 0.9 ±0.5 2.1 ±0.8

2.2 ±0.6 4.9 ±1.0 0.5 ±0.2 1.0 ±0.3 2.4 ±0.7 4.3 ±0.9 1.8 ±0.6 3.4 ±0.7 0.9 ±0.2 2.1 ±0.4 1.5 ±0.4 2.4 ±0.3

Fig. 1. Killing kinetics of six fluoroquinolones against S. aureus at MICs: • = control; A = 0.5 mg/l of ciprofloxacin; ■ = 4 mg/l of norfloxacin; O = 0.5 mg/l of ofloxacin; ☆ = 2 mg/l of pefloxacin; □ = 0.5 mg/l of feroxacin; A = 1 mg/l of lomefloxacin.

Fig. 2. Killing kinetics of six fluoroquinolones against E. coli at MICs; • = control; A = 0.015 mg/l of ciprofloxacin; ■ = 0.12 mg/l of norfloxacin; O = 0.12 mg/l of ofloxacin; ☆ = 0.06 mg/l of pefloxacin; □ = 0.12 mg/l of fleroxacin; ▲ = 0.5 mg/l of lo­ mefloxacin.

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Antimicrobial agent

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Postantibiotic Effect of Six Quinolones

ity against E. coli and at 2 h had produced a reduction in growth of 3 log,,, (99.9%) of the initial inoculum. Norfloxacin again displayed the lowest activity. None of the cultures, with the exception of those treat­ ed with norfloxacin, regained a normal growth rate after 8 h of exposure to the antimicrobial agent. Table 1 lists the results of the PAE study. The MIC of fluoroquinolones, ex­ cept norfloxacin, induced PAEs generally of between 1 and 2 h. The PAEs on E. coli were greater than these on S. aureus, with ciprofloxacin and ofloxacin producing the greatest PAEs. At concentrations of 6 mg/l, the PAEs reached 2-5 h, which were maximal with ciprofloxacin and

ofloxacin, principally on E. coli. Against S. aureus, norfloxacin scarcely produced a PAE, while the PAE on E. coli at 6 mg/l, 50 times the MIC, lasted less than 1 h.

The results shown in table 1 bear out the reports of numerous authors [1-5], i.c. the fact that fluoroquinolones are more active against E. coli than against S. aureus and that ciprofloxacin is the most effective of these agents. This study of antimicro­ bial activity, taking into account the time factor, confirmed ciprofloxacin as the most active of the fluoroquinolones, espe-

Fig. 3. Killing kinetics of six fluoroquinolones against S. aureus at 6 mg/l: • = control; A = cipro­ floxacin; ■ = norfloxacin; O = ofloxacin; ■& = pefloxacin; □ = fleroxacin; A = lomcfloxacin.

Fig. 4. Killing kinetics of six fluoroquinolones against E. coli at 6 mg/I: • = control; A = ciproflox­ acin; ■ = norfloxacin; O = ofloxacin; = pefloxacin; □ = fleroxacin; ▲ = lomcfloxacin.

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Discussion

dally against E. coli. The activities dis­ played decreased as follows: ciprofloxacin > ofloxacin > pcfloxacin ^ fleroxacin ^ lomcfloxacin > norfloxacin. Pcrfloxacin against S. aureus, in spite of an MIC 2-4 times greater than those of fleroxacin and lomcfloxacin, showed greater activity in killing curves. The PAE of all the quinolones assayed, with the exception of norfloxacin, was pro­ found and greater against E. coli. There was a close relationship between PAE and bactericidal activity in killing curves. Ci­ profloxacin displayed the highest activity as well as the greatest PAEs, while nor­ floxacin, with much lower activity, scarcely produced a PAE. In general, an increase in the antimicrobial concentration was ac­ companied by an increase in the duration of the PAE. Various authors [8, 10] have reported that, although the PAE may be concentration dependent, it docs not in­ crease significantly above 10 times the MIC. Our study included a concentration of 6 mg/1 which for all the fluoroquino­ lones was considerably larger than their 10 times the MIC against E. coli. The exact mechanism for the produc­ tion of the PAE is not known, although the majority of authors [8, 10] believe the effect to be due to nonlethal damage pro­ duced and to the persistence of the drug at the site of action. The fluoroquinolones act fundamentally at the bacterial gyrase level [12] and by this means are able to achieve the ample PAEs recorded. Diverse in vivo studies [13-15] have raised the question, with regard to differ­ ent antimicrobial agents, of whether it is more effective to administer the drug in such a way as to obtain high scrum con­ centrations for short periods of time or to

Minguez/Ramos/Barrientos/Loscos/Prieto

aim for lower serum concentrations which may be maintained for longer periods. These same studies have demonstrated that the answer depends on the drug, on its activity and the PAE it produces. The fluoroquinolones assayed, with the ex­ ception of norfloxacin, which in addition reaches lower serum concentrations than the rest of the fluoroquinolones, should be administered in such a way as to reach high levels for short periods of time, since they have a long half-life (4-12 h) [7], high concentration-dependent bactericidal ca­ pacity and ample PAEs. As a result, under favorable conditions, a single high dose per day might constitute adequate antimi­ crobial therapy.

References 1 Barry AL, Jones RN, Thornsberry C, Ayers LW, Gerlach EH, Sommers HM: Antibacterial activ­ ities of ciprofloxacin, norfloxacin, oxolinic acid, cinoxacin, and nalidixic acid. Antimicrob Agents Chemothcr 1984;25:633-637. 2 King A, Phillips I: The comparative in vitro ac­ tivity of eight newer quinolones and nalidixic acid. J Antimicrob Chemother 1986;18(suppl D): 1- 20. 3 Chin NX, Brittain DC, Neu HC: In vitro ac­ tivity of RO 23-6240, a new fluorinated 4-quinolonc. Antimicrob Agents Chemother 1986;4675-680. 4 Barry AL, Gardiner RV, Packer RR: Bacterici­ dal activities of ten different fluoroquinolones against selected Enterobacteriaceac. Diagn Mi­ crobiol Infect Dis 1987;6:81-83. 5 Wise R. Andrews JM. Ashby JP, Metthews RS: In vitro activity of lomefloxacin, a new quinolone antimicrobial agent, in comparison with those of other agents. Antimicrob Agents Chemother 1988;32:617-622. 6 Wise R, Lister D, McNulty CAM. Griggs D. An­ drews JM: The comparative phamacokinetics and tissue penetration of four quinolones. In­

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13 Gudmundsson S. Turnidge J, Craig WA: Effect of different dosage regimens on in vivo efficacy of antibiotics against Klebsiella pneumoniae. Clin Res 1982:30:777-783. 14 Rooscndaal R, Bakker-Woundenberg IA, Van Den Berg JC. Micheli MF: Therapeutic efficacy of continuous versus intermittent administration of ceftazidime in experimental Klebsiella pneu­ moniae pneumonia in rats. J Infect Dis 1985; 152:373-378. 15 Nordstrom L, Ringber H. Cronbcrg S, Tjcrnström O, Wälder M: Does administration of an aminoglycoside in a single daily dose affect its efficacy toxicity? J Antimicrob Chemothcr 1990; 25:159-173.

J. Prieto Prieto Departamento de Microbiología Facultad de Medicina Universidad Complutense Ciudad Universitaria s/u E-28040 Madrid (Spain)

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eluding intravenously administered enoxacin. In­ fection 1986;14:196-202. Dominguez Gil-Hurle A. Sánchez Navarro A: Farmacocinética de las nuevas quinolonas. Enf Infec y Microbiol Clin (Spain) 1988;6:208-212. Vogelman B, Craig WA: Kinetics of antimicro­ bial. J Pcdiatr 1986;108:835-840. McDonald PJ, Craig WA. Kunin CM: Persistent effect of antibiotics on Staphylococcus aureus af­ ter exposure for limited periods of time. J Infect Dis 1977;135:217-223. Craig WA, Gudmundsson S: The postantibiotic effect; in Lorian V (ed): Antibiotics in Laborato­ ry Medicine. Baltimore, Williams and Wilkins, 1986, pp 515-536. Jones RW, Barry AL, Gavan TL, Washington JA II: Susceptibility tests: Microdilution and macro­ dilution broth procedures; in Lennette EH, Blows A, Hanstcr WJ, Shadomy HJ (eds): Manual of Clinical Microbiology, ed 4. Washing­ ton, American Society for Microbiology, 1985, pp 972-977. Fernandes PB: Mode of action, and in vitro and in vivo activities of the fluoroquinolones. J Clin Pharmacol 1988;28:156-168.

Postantibiotic effect of ciprofloxacin compared with that of five other quinolones.

The antimicrobial activity (minimal inhibitory concentration, MIC, and killing kinetics) and postantibiotic effect (PAE) of different concentrations (...
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