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Activity of the new quinolone WCK 771 against pneumococciP. C. Appelbaum1, G. A. Pankuch1, B. Bozdogan1, G. Lin1, M. R. Jacobs2, M. V. Patel3, S. V. Gupte3,M. A. Jafri3, N. J. De Souza3 and H. F. Khorakiwala3 1Department of Pathology, Hershey Medical Center, Hershey, PA, 2Department of Pathology, CaseWestern Reserve University, Cleveland, OH, USA and 3Wockhardt Research Centre, Aurangabad,India The activity of WCK 771, a new experimental quinolone being developed to overcome quinoloneresistance in staphylococci, against quinolone-susceptible and -resistant pneumococci was determined.
Comparative activities of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, clinafloxacin, vanco-mycin, linezolid, amoxycillin, cefuroxime, azithromycin and clarithromycin were determined with MICand time-kill experiments. Animal experiments were also performed to test the in-vivo anti-pneumococcal activity of WCK 771 compared to levofloxacin. WCK 771 MIC50 ⁄ 90 values for 300quinolone-susceptible Streptococcus pneumoniae isolates (108 penicillin-susceptible, 92 penicillin-inter-mediate and 100 penicillin-resistant) were 0.5 ⁄ 0.5 mg ⁄ L; the MICs of b-lactams and macrolides rose withthose of penicillin G, and all isolates were susceptible to vancomycin and linezolid. WCK 771 MIC50 ⁄ 90values for 25 quinolone-resistant pneumococcal isolates were 4 ⁄ 8 mg ⁄ L, compared to 0.5 ⁄ 1 mg ⁄ L forclinafloxacin, 2 ⁄ 4 mg ⁄ L for gatifloxacin and moxifloxacin, 8 ⁄ 16 mg ⁄ L for levofloxacin, and16 ⁄ >32 mg ⁄ L for ciprofloxacin. Time-kill studies showed that WCK 771 was bactericidal againstpneumococci after 24 h at 4· MIC, as were the other quinolones tested. Animal model studies showedthat WCK 771 had efficacy comparable to that of levofloxacin, by both the oral and subcutaneous routes,for systemic infection caused by three quinolone-susceptible isolates of pneumococci. Overall, WCK 771was potent both in vivo and in vitro against quinolone-susceptible, but not quinolone-resistant,S. pneumoniae, regardless of penicillin susceptibility.
Activity, new antibiotics, quinolones, Streptococcus pneumoniae, WCK 771 Original Submission: 20 April 2004; Revised Submission: 16 July 2004; Accepted: 21 July 2004 Clin Microbiol Infect 2005; 11: 9–14 resistance to penicillin G and other b-lactam and non-b-lactam compounds has also increased As the prevalence of multiresistant strains of worldwide, including in the USA. Major foci of Streptococcus pneumoniae has increased world- resistance include South Africa, Spain and central wide, there has been an attendant need for new and eastern Europe [3–5]. In the USA, surveys antimicrobial agents. Introduced in the 1980s, have shown an increase in resistance to penicillin fluoroquinolones fulfilled this need initially, and (including resistance classed as penicillin-inter- these agents are still important for the treatment mediate) from < 5% before 1989 to 6.6% in 1991– of a wide range of infections. However, resistance 1992 and, more recently, to 28.7–37% [6,7]. The to many members of this class of agent is problem of drug-resistant pneumococci is com- emerging in pneumococci [1,2], although the pounded by the spread of resistant clones from prevalence of resistance remains low (< 2%) in country to country and worldwide [8–10].
most parts of the world [2–7]. Pneumococcal There is a need for oral compounds for outpa- tient treatment of respiratory tract infectionscaused by penicillin- and macrolide-resistant Corresponding author and reprint requests: P. C. Appelbaum, pneumococci [11,12]. Older quinolones, such as Department of Pathology, Hershey Medical Center, PO Box ciprofloxacin and ofloxacin, have only moderate 850, Hershey, PA 17033, USAE-mail: pappelbaum@psu.edu activity in vitro against pneumococci, with MICs  2004 Copyright by the European Society This material is copyrighted to Wockhardt. of Clinical Microbiology and Infectious Diseases 10 Clinical Microbiology and Infection, Volume 11 Number 1, January 2005 clustering around resistance breakpoints. Newer patients from throughout the USA and countries in western quinolones, such as levofloxacin, gatifloxacin, Europe during 1998–2002. Quinolone-susceptible isolateswere defined as those with ciprofloxacin MICs £ 2.0 mg ⁄ L, moxifloxacin and gemifloxacin, have greater anti- pneumococcal activity than the older agents ‡ 4 mg ⁄ L [23]. Among the 300 quinolone-susceptible isolates, [4,5,13–19]. However, recent reports from Hong 108 were penicillin-susceptible (MICs £ 0.06 mg ⁄ L), 92 were Kong [20], Canada [21] and Spain [22] have penicillin-intermediate (MICs 0.12–1.0 mg ⁄ L), and 100 were described an increasing prevalence of quinolone- penicillin-resistant (MICs 2.0–16.0 mg ⁄ L). All penicillin-sus-ceptible pneumococci were recent isolates from the USA, resistant pneumococci. Quinolone resistance in while penicillin-intermediate and -resistant pneumococci S. pneumoniae is mediated by stepwise changes in were recent isolates from the USA, South Africa, Spain, the quinolone resistance-determining regions of France, central and eastern Europe and Korea. The 25 type II topoisomerase; mutations in parC and gyrA quinolone-resistant pneumococcal isolates were selectedfrom our collection. Mechanisms of quinolone resistance are commonest, but parE and gyrB mutations are for these isolates included alterations in the quinolone- also encountered [2]. The prevalence of resistant resistance-determining regions of ParC, GyrA, ParE and ⁄ or strains is likely to increase with increased use of GyrB. Mutations in parC were at S79F, S79Y, D83N, D83G, broad-spectrum quinolones for empirical therapy N91D, R95C or K137N. Mutations in gyrA were at S81A, of community-acquired respiratory tract infec- S81C, S81F, S81Y, E85K or S114G. Nineteen isolates had amutation in parE at D435N or I460V. Only one isolate had a mutation in gyrB at E474K. Nineteen isolates had a total of WCK 771 (Fig. 1; Wockhardt Research Centre, three or four mutations in the quinolone-resistance-deter- Aurangabad, India), the hydrate of the arginine mining regions of parC, gyrA, parE, and ⁄ or gyrB.
salt of S-(–)-nadifloxacin, is a new experimentalquinolone Antimicrobial agents and MIC testing activity that is undergoing phase I studies in WCK 771 was synthesised at Wockhardt Research Centre, India as a parenteral antibacterial agent. The Aurangabad, India. Other antimicrobial agents were either present study sought to shed more light on the synthesised at Wockhardt Research Centre (clinafloxacin) orobtained from their respective manufacturers. Agar dilution activity of WCK 771 against Gram-positive bac- testing was performed on Mueller–Hinton agar (BBL Micro- teria by examining its activity against S. pneumo- biology Systems, Cockeysville, MD, USA) supplemented with niae isolates with differing susceptibilities to sheep blood 5% v ⁄ v, with incubation in air for 24 h [23]. MICs penicillin G and quinolones in comparison with of the pneumococci tested with time-kill kinetics were deter- ciprofloxacin, levofloxacin, gatifloxacin, moxifl- mined by broth microdilution in Mueller–Hinton broth (BBLMicrobiology Systems) supplemented with sheep blood 5% oxacin, clinafloxacin, vancomycin and linezolid.
v ⁄ v. Standard quality control strains, including S. pneumoniae Additionally, nine pneumococcal isolates were ATCC 49619, were included in each batch of agar or broth tested in time-kill experiments with all six quino- microdilution tests [23]. Data were interpreted according to lones. Finally, the in-vivo efficacy of WCK 771 standard recommendations [24].
was assessed in comparison with levofloxacin in amouse systemic infection model with three quino- Determination of the efflux mechanism of quinolone-resistant pneumococci lone-susceptible pneumococcal isolates, as well asin a lung pneumococcal load-reduction study.
Quinolone MICs for quinolone-resistant pneumococci weredetermined in the presence and absence of reserpine (Sigma,St Louis, MO, USA) 10 mg ⁄ L as described previously [25–27].
The agents tested were WCK 771, ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin and clinafloxacin. The existence ofan efflux system was recognised by a quinolone MIC that was Bacterial isolates at least four-fold lower in the presence of reserpine compared The isolates tested comprised 300 quinolone-susceptible and to the MIC without reserpine. Testing was repeated three times.
25 quinolone-resistant S. pneumoniae. All isolates were fromclinical specimens (sputum, bronchial and tracheal aspirates, Time-kill testing eye cultures, blood, cerebrospinal fluid) obtained from The time-kill activity of quinolones was tested against nine selected pneumococcal isolates, in Mueller–Hinton broth with COOH . 4H O
lysed horse blood 5% v ⁄ v, as described previously [28]. The isolates tested included three penicillin-susceptible, three peni- cillin-intermediate and three penicillin-resistant isolates. One of the penicillin-resistant isolates was also quinolone-resistant, with a ciprofloxacin MIC of 32 mg ⁄ L. This latter isolate had Fig. 1. Chemical structure of WCK 771.
mutations in gyrA (S81Y), parC (S79F, K137N) and parE (I460V).
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Appelbaum et al.
Anti-pneumococcal activity of WCK 771 11 Antibiotic concentrations were chosen to provide three doub- ling dilutions above and one dilution below the previously determined MIC. Growth controls with inoculum but no antibiotic were included in each experiment [28]. The original viable count was determined with use of the untreated growth control. Only inocula within the range 5 · 105 - 5 · 106 CFU ⁄ mL were acceptable [28], and testing of out-of-range samples was repeated. Viability counts of antibiotic-containing suspensions were performed at 0, 3, 6 and 24 h. Colony counts were performed on plates yielding 30–300 colonies. The lower sensitivity limit of colony counts was 300 CFU ⁄ mL [28].
WCK 771 (100) WCK 771 (75)
Levo (100)
Levo (75)
The results of time-kill assays were analysed by determining Drug and Drug Dose (mg/kg)
the number of strains which yielded Dlog10 CFU ⁄ mL reduc-tions of ) 1, ) 2 and ) 3 at 3, 6, 12 and 24 h respectively, Fig. 2. Percentage of mice with sterile lungs following compared to baseline counts (0 h). Antimicrobial agents were exposure to Streptococcus pneumoniae strain 6303. MIC considered bactericidal at the lowest concentration that reduced (mg ⁄ L): WCK 771, 0.25; levofloxacin (Levo), 1.0. Route of the original inoculum by ‡ 3 log infection: intraperitoneal. Route of treatment: oral.
10 CFU ⁄ mL (99.9%) at each of the time periods, and bacteriostatic if the inoculum was reducedby < 3 log10 CFU ⁄ mL. The problem of drug carryover wasaddressed by dilution, as described previously [28].
Table 1. Agar dilution MICs (mg ⁄ L) for 300 quinolone-susceptible Streptococcus pneumoniae isolatesa Systemic infection model Antimicrobial agent The comparative in-vivo efficacies of WCK 771 and levofloxa- cin were studied in an intraperitoneal mouse septicaemia model with the use of three quinolone-susceptible S. pneumo- niae strains, SPN 727, SPN 731 and SPN 733. Treatment was given 1 h and 4 h post-infection by the subcutaneous and oral routes for each respective group. Survival was monitored until day 7, and 50% effective dose (ED 50) and 90% effective dose (ED90) values with 95% confidence intervals were calculated by probit analysis [29] and the method of Litchfield and Wilcoxin [30], respectively.
Lung load-reduction study (3 · 104 CFU ⁄ animal) with S. pneumoniae strain 6303 (type 3) by the intraperitoneal route. Treatment was given 1 h and 4 h £ 0.008 to > 64 post-infection with an oral dose of either 75 or 100 mg ⁄ kg, twice-daily for 2 days, for both WCK 771 and levofloxacin. The animals were killed humanely 24 h after the last dose, and £ 0.008to > 64 lungs were excised and homogenised in 5 mL of chilled saline.
Viable counts in lung homogenates were determined in terms of lung load ⁄ animal. The percentage of animals showing sterile lungs (a count of £ 10 CFU ⁄ mL) was calculated for aCiprofloxacin MICs £ 2.0 mg ⁄ L.
WCK 771 and levofloxacin (Fig. 2).
b108 penicillin-susceptible, 92 penicillin-intermediate and 100 penicillin-resistantisolates.
For the 25 quinolone-resistant pneumococcal MICs for the 300 quinolone-susceptible S. pneumo- isolates (ciprofloxacin MICs ‡ 4 mg ⁄ L), clinafloxa- niae isolates are presented in Table 1. Clinafloxacin cin had the lowest MICs (range 0.25–1.0 mg ⁄ L, had the lowest MICs of all quinolones tested MIC50 ⁄ 90 0.5 ⁄ 1 mg ⁄ L). MICs of the other quinolo- (MIC50 and MIC90 both 0.12 mg ⁄ L), followed by nes ranged between 0.25 and > 32 mg ⁄ L, with (0.12 ⁄ 0.25 mg ⁄ L), MIC50 ⁄ 90 values of 2 ⁄ 4 mg ⁄ L for moxifloxacin, (0.25 ⁄ 0.25 mg ⁄ L), WCK 771 (0.5 ⁄ 0.5 mg ⁄ L), levo- 2 ⁄ 4 mg ⁄ L for gatifloxacin, 4 ⁄ 8 mg ⁄ L for WCK floxacin (1 ⁄ 1 mg ⁄ L) and ciprofloxacin (1 ⁄ 2 mg ⁄ L).
8 ⁄ 16 mg ⁄ L MICs of b-lactams and macrolides rose with those 16 ⁄ > 32 mg ⁄ L for ciprofloxacin (Table 2). In 12 of of penicillin G, and all isolates were susceptible to the 25 quinolone-resistant isolates, evidence was vancomycin and linezolid.
found for the presence of an efflux mechanism for  2004 Copyright by the European Society This material is copyrighted to Wockhardt. of Clinical Microbiology and Infectious Diseases, CMI, 11, 9–14 12 Clinical Microbiology and Infection, Volume 11 Number 1, January 2005 Table 2. Agar dilution MICs (mg ⁄ L) for 25 ciprofloxacin- Table 4. Streptococcus pneumoniae time-kill results for nine resistant Streptococcus pneumoniae isolatesa isolates, showing the numbers of isolates with 1, 2 and3 log10 decreases in viable counts in relation to MICs at the time-points indicated aCiprofloxacin MICs ‡ 4.0 mg ⁄ L.
Table 3. MICs for Streptococcus pneumoniae isolates tested in time-kill experiments (n = 9), including one quinolone- resistant isolate MICs (mg ⁄ L) for each isolate a90%, 99%, 99.9% killing.
some of the quinolones tested, but MICs of WCK771 were unaffected by the presence of reserpine.
In the presence of reserpine, 11 of the 25 isolates with defined mutations in type II topoisomerase had lower ciprofloxacin MICs (four- to 16-fold), (Table 4). Other quinolones gave similar time-kill three had lower clinafloxacin MICs (four- to eight- kinetics relative to their differing MICs.
fold), two had lower gatifloxacin and levofloxacin The comparative in-vivo efficacies of WCK 771 MICs (four-fold), and one had a lower moxifloxa- and levofloxacin against three pneumococcal iso- cin MIC (four-fold).
lates are shown in Table 5. The efficacy of WCK Microdilution MICs for the nine S. pneumoniae 771 administered by the subcutaneous and oral isolates tested in time-kill experiments are pre- routes was comparable to that of levofloxacin, sented in Table 3. Time-kill analysis showed that with both having ED50 values in the range WCK 771 was bactericidal (99.9% killing) at 2· 3–50 mg ⁄ kg. In a lung load-reduction study with MIC after 24 h with all nine pneumococcal isolates S. pneumoniae strain 6303 and an oral dose of tested, including the quinolone-resistant isolate 75 mg ⁄ kg (Fig. 2), levofloxacin resulted in sterile Table 5. In-vivo efficacy of WCK Effective subcutaneous dose Effective oral dose (mg ⁄ kg) (mg ⁄ kg) (95% CI) 771 for the treatment of Streptococcus pneumoniae infectionsa aRoute of infection: intraperitoneal. Infecting dose: 2–3 · 108 CFU ⁄ animal. Treatment: 1 h and 4 h post-infection.
Observation period: 7 days. Endpoint: percentage survival on day 7.
bMIC determination by agar dilution.
 2004 Copyright by the This material is copyrighted to Wockhardt. European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 9–14 Appelbaum et al.
Anti-pneumococcal activity of WCK 771 13 lungs in 60% of animals, compared with 40% for values of 0.5 ⁄ 0.5 mg ⁄ L). Thus, the activity of WCK 771; however, at a dose of 100 mg ⁄ kg, both WCK 771 against quinolone-resistant pneumo- WCK 771 and levofloxacin resulted in 100% of cocci is four- to eight-fold lower than that against animals having sterile lungs.
values of 0.5 ⁄ 1 mg ⁄ L).
The results of time-kill studies showed that WCK 771 was bactericidal if pneumococci, inclu- WCK 771 is an experimental quinolone that is ding the one quinolone-resistant isolate tested, being developed for clinical use. Preliminary data were exposed to this agent for 24 h. The bacteri- presented in 2001 indicated that WCK 771 has cidal activities of other quinolones were similar to improved potency against staphylococci, inclu- those found in previous studies [19,28,34,35].
ding methicillin-resistant strains, compared to The results of the animal model studies sug- other quinolones (41st Interscience Conference gested that the activity of WCK 771 against on Antimicrobial Agents and Chemotherapy, pneumococci was comparable to that of levofl- abstracts F-539, F-541 and F-542). MIC50 and oxacin, with ED50 values of 3–50 mg ⁄ kg for both MIC90 values (mg ⁄ L) of WCK 771 for quinolone- agents by both the oral and subcutaneous routes susceptible staphylococci were 0.008–0.015 and in a systemic mouse infection model, and with 0.015–0.03, compared to levofloxacin values of 0.125 and 0.25, respectively. Against quinolone- 100 mg ⁄ kg for both agents in pneumococcal lung resistant staphylococci, WCK 771 MIC50 and MIC90 values (mg ⁄ L) were 0.5 and 1, compared In summary, WCK 771 showed superior to 8 and 32 for levofloxacin, respectively (abstract potency to older agents (ciprofloxacin, levofloxa- F-542), while anti-pneumococcal MICs were cin) and similar potency to newer agents reported to be about one dilution lower than (gatifloxacin, moxifloxacin) against quinolone- those of levofloxacin (abstract F-541). The results susceptible pneumococci. However, as with other of the current study supported these preliminary quinolones, activity against quinolone-resistant findings, in that anti-pneumococcal MICs were isolates was considerably lower. During the one or two dilutions lower than those of levofl- dose-escalation stage of phase I studies, a favour- oxacin. MICs of other quinolones for S. pneumo- able safety and human pharmacokinetic profile resulted in sustained drug levels above the MIC90 previously [4,5,15–19,31,32]. MICs of non-quino- for quinolone-susceptible pneumococci, as well as lone agents against pneumococci were similar to methicillin-resistant staphylococci. On the basis of those described previously, with higher cefurox- these observations, WCK 771 has the potential to ime and macrolide MICs for isolates with raised provide coverage against methicillin-resistant sta- penicillin MICs [4,5,16–19].
phylococci as well as quinolone-susceptible pneu- In the present study, clinafloxacin, which is no longer being developed, had the lowest MICs ofthe agents tested for all pneumococcal isolates, followed by moxifloxacin, gatifloxacin, WCK 771,levofloxacin and ciprofloxacin. Quinolone efflux 1. Thomson CJ. The global epidemiology of resistance to was present in 12 of the 25 quinolone-resistant ciprofloxacin and the changing nature of antibiotic resist-ance: a 10 year perspective. J Antimicrob Chemother 1999; pneumococcal isolates studied, mainly affecting 43(suppl A): 31–40.
ciprofloxacin, which is consistent with published 2. Hooper DC. Fluoroquinolone resistance among Gram- data regarding this mechanism in c. 50% of positive cocci. Lancet Infect Dis 2002; 2: 530–538.
quinolone-resistant pneumococcal isolates [33].
3. Appelbaum PC. Antimicrobial resistance in Streptococcus The activity of WCK 771 was not affected by the pneumoniae: an overview. Clin Infect Dis 1992; 15: 77–83.
4. Jacobs MR. Treatment and diagnosis of infections caused presence of a quinolone efflux mechanism in by drug-resistant Streptococcus pneumoniae. Clin Infect Dis quinolone-resistant S. pneumoniae isolates. How- 1992; 15: 119–127.
ever, the activity of WCK 771 against quinolone- 5. Jacobs MR, Appelbaum PC. Antibiotic-resistant pneumo- cocci. Rev Med Microbiol 1995; 6: 77–93.
6. Van Beneden CA, Lexau C, Baughman W et al. Aggre- 4 ⁄ 8 mg ⁄ L) was not as good as its activity against gated antibiograms and monitoring of drug-resistant  2004 Copyright by the European Society This material is copyrighted to Wockhardt. of Clinical Microbiology and Infectious Diseases, CMI, 11, 9–14 14 Clinical Microbiology and Infection, Volume 11 Number 1, January 2005 Streptococcus pneumoniae. Emerg Infect Dis 2003; 9: 1089– resistant strains of Streptococcus pneumoniae in Hong Kong.
Antimicrob Agents Chemother 1999; 43: 1310–1313.
7. Jacobs MR, Felmingham D, Appelbaum PC, Gruneberg 21. Chen DK, McGeer A, de Azavedo JC, Low DE. Decreased RN. The Alexander Project 1998–2000: susceptibility of susceptibility of Streptococcus pneumoniae to fluoroquino- pathogens isolated from community-acquired respiratory lones in Canada. Canadian Bacterial Surveillance Net- tract infection to commonly used antimicrobial agents.
work. N Engl J Med 1999; 341: 233–239.
J Antimicrob Chemother 2003; 52: 229–246.
22. Lin˜ares J, de la Campa AG, Pallares R. Fluoroquinolone 8. McDougal LK, Facklam R, Reeves M et al. Analysis of resistance in Streptococcus pneumoniae. N Engl J Med 1999; multiply antimicrobial-resistant isolates of Streptococcus 341: 1546–1547.
pneumoniae from the United States. Antimicrob Agents 23. National Committee for Clinical Laboratory Standards.
Chemother 1992; 36: 2176–2184.
Methods for dilution antimicrobial susceptibility tests for 9. Munoz R, Musser JM, Crain M et al. Geographic distri- bacteria that grow aerobically, 6th edn. Approved Standard bution of penicillin-resistant clones of Streptococcus pneu- M7-A6. Wayne, PA: NCCLS, 2003.
moniae: characterization by penicillin-binding protein 24. National Committee for Clinical Laboratory Standards.
profile, surface protein A typing, and multilocus enzyme Performance standards for antimicrobial susceptibility testing, analysis. Clin Infect Dis 1992; 15: 112–118.
fourteenth informational supplement. M100-S14. Wayne, PA: 10. Okeke IN, Edelman R. Dissemination of antibiotic-resist- NCCLS, 2004.
ant bacteria across geographic borders. Clin Infect Dis 2001; 25. Brenwald NP, Gill MJ, Wise R. Prevalence of a putative 33: 364–369.
efflux mechanism among fluoroquinolone-resistant clin- 11. Friedland IR, Istre GR. Management of penicillin-resistant ical isolates of Streptococcus pneumoniae. Antimicrob Agents pneumococcal infections. Pediatr Infect Dis J 1992; 11: 433– Chemother 1998; 42: 2032–2035.
26. Davies TA, Pankuch GA, Dewasse BE, Jacobs MR, 12. Friedland IR, McCracken GH. Management of infections Appelbaum PC. In vitro development of resistance to five caused by antibiotic-resistant Streptococcus pneumoniae.
quinolones and amoxicillin–clavulanate in Streptococcus N Engl J Med 1994; 331: 3773–3782.
pneumoniae. Antimicrob Agents Chemother 1999; 43: 1177– 13. Hoellman DB, Lin G, Jacobs MR, Appelbaum PC. Anti- pneumococcal activity of gatifloxacin compared with other 27. Nagai K, Davies TA, Pankuch GA, Dewasse BE, Jacobs quinolone and non-quinolone agents. J Antimicrob Chemo- MR, Appelbaum PC. In vitro selection of resistance to ther 1999; 43: 645–649.
clinafloxacin, ciprofloxacin, and trovafloxacin in Strepto- 14. Davies TA, Kelly LM, Pankuch GA, Credito KL, Jacobs coccus pneumoniae. Antimicrob Agents Chemother 2000; 44: MR, Appelbaum PC. Antipneumococcal activities of gemifloxacin compared to those of nine other agents.
28. Pankuch GA, Jacobs MR, Appelbaum PC. Study of com- Antimicrob Agents Chemother 2000; 44: 304–310.
parative antipneumococcal activities of penicillin G, RP 15. Pankuch GA, Jacobs MR, Appelbaum PC. Activity of CP 59500, erythromycin, sparfloxacin, ciprofloxacin, and 99,219 compared with DU-6859a, ciprofloxacin, ofloxacin, vancomycin by using time-kill methodology. Antimicrob levofloxacin, lomefloxacin, tosufloxacin, sparfloxacin and Agents Chemother 1994; 38: 2065–2072.
grepafloxacin against penicillin-susceptible and -resistant 29. Miller LC, Tainter ML. Estimation of the ED50 and its error pneumococci. J Antimicrob Chemother 1995; 35: 230–232.
by means of logarithmic-probit graph paper. Proc Soc Exp 16. Spangler SK, Jacobs MR, Appelbaum PC. Susceptibilities Biol Med 1994; 57: 261–264.
of penicillin-susceptible and -resistant strains of Strepto- 30. Litchfield JT, Wilcoxin F. A simplified method of evalu- coccus pneumoniae to RP 59500, vancomycin, erythromycin, ating dose–effect experiments. J Pharm Exp Ther 1949; 96: PD 131628, sparfloxacin, temafloxacin, WIN 57273, ofloxacin, and ciprofloxacin. Antimicrob Agents Chemother 31. Jorgensen JH, Weigel LM, Ferraro MJ, Swenson JM, Ten- 1992; 36: 856–859.
over FC. Activities of newer fluoroquinolones against 17. Spangler SK, Jacobs MR, Pankuch GA, Appelbaum PC.
Streptococcus pneumoniae clinical isolates including those Susceptibility of 170 penicillin-susceptible and penicillin- with mutations in the gyrA, parC, and parE loci. Antimicrob resistant pneumococci to six oral cephalosporins, four Agents Chemother 1999; 43: 329–334.
quinolones, desacetylcefotaxime, Ro 23-9424 and RP 32. Pong A, Thomson KS, Moland ES, Chartrand SA, Sanders 67829. J Antimicrob Chemother 1993; 31: 273–280.
CC. Activity of moxifloxacin against pathogens with 18. Visalli MA, Jacobs MR, Appelbaum PC. MIC and time-kill decreased susceptibility to ciprofloxacin. J Antimicrob study of activities of DU-6859a, ciprofloxacin, levofloxacin, Chemother 1999; 44: 621–627.
sparfloxacin, cefotaxime, imipenem, and vancomycin 33. Piddock LJ. Mechanisms of fluoroquinolone resistance: an against nine penicillin-susceptible and -resistant pneu- update 1994–1998. Drugs 1999; 58: 11–18.
mococci. Antimicrob Agents Chemother 1996; 40: 362–366.
34. McCloskey L, Moore T, Niconovich N et al. In vitro 19. Visalli MA, Jacobs MR, Appelbaum PC. Antipneumococ- activity of gemifloxacin against a broad range of recent cal activity of BAY 12-8039, a new quinolone, compared clinical isolates from the USA. J Antimicrob Chemother 2000; with activities of three other quinolones and four oral 45(suppl 1): 13–21.
b-lactams. Antimicrob Agents Chemother 1997; 41: 2786– 35. Gradelski E, Valera L, Kolek B, Bonner D, Fung-Tomc J.
Comparative killing kinetics of the novel des-fluoro (6) 20. Ho PL, Que TL, Tsang DN, Ng TK, Chow KH, Seto WH.
quinolone BMS-284756, fluoroquinolones, vancomycin Emergence of fluoroquinolone resistance among multiply and beta-lactams. Int J Antimicrob Agents 2001; 18: 43–48.
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