Comparative In-vitro Antibacterial Activities of Meetoofloxacin, a Novel Extended-spectrum Fluoroquinolone, and Other Antimicrobial Agents against Representative Clinical Isolates
The in vitro activities of meetofloxacin against six (6) clinical isolates were examined compared to those of ciprofloxacin and amoxycillin. Meetoofloxacin was potent against Gram-negative and positive bacetria. Furthermore, meetoofloxacin demonstrated superior activity against penicillin-resistant Streptococcus pneumonia (PRSP) with a MIC90 of 0.4mg/L against higher MIC90 values for the comparator agents ciprofoloxacin and amoxicillin at 4mg/L and 3mg/L respectively, a 10- to 7.5-fold difference.
Consequently, this new fluoroquinolone could potentially form the basis of treatment for infections caused by PRSP including bacteremia, septic arthritis, brain abscess and meningitis. Further investigation of this extended-spectrum fluoroquinolone appears warranted.
Objectives: The aim of this study was to analyze the antibiotic susceptibility of aerobic and anaerobic clinical isolates from Respiratory Tract Infection (RTI) patients to a novel fluoroquinolone (Meetoofloxacin) and other pre-selected antibacterial agents.
Methods: Six aerobic and anaerobic clinical isolates from RTI patients were tested for susceptibility to meetoofloxacin and two other antibiotics (Ciprofloxacin and Amoxycillin) using the referenced agar plate dilution method. The inoculums were isolated from RTI patients at 20 diagnostic laboratories in the U.K. during the 2006-2007 winter period. As part of the Phase 1 studies, meetoofloxacin was administered as a single daily dose of 300 mg, yielding a maximum serum concentration (Cmax) of 1.2 mg/L and an area under the plasma drug concentration-time curve (AUC0-24 h) of 20.3 mg.h/L.
Results: Meetoofloxacin exhibited excellent anti-pathogenic activity than the comparative fluoroquinolone (Ciprofloxacin) and Amoxycillin against selected Gram- negative and -positive organisms. All pharamacologic agents tested were effective against the selection of bacterial pathogens. Amoxyxillin had the lowest minimum inhibitory concentration 90% (MIC90) against Streptococcus pneumonia, while meetofloxacin had the second-lowest comparative MIC90 0.15mg/L. Penicillin-resistant S.pneumoniae (PRSP) strains were inhibited by meetoofloxacin at <0.2mg/L of serum concentration, 7.5-fold lower than amoxicillin and 10-fold lower than ciprofloxacin. Overall, meetofloxacin had the lowest MIC90 for all other inoculate cultures, thereby demonstrating its comparatively favorable in-vitro activity.
Conclusions: These Phase I study findings suggest that meetoofloxacin achieved a disproportionately higher MIC90 against 100% of both aerobic and anaerobic respiratory isolates compared to Ciprofloxacin and Amoxycillin. This novel extended-spectrum fluoroquinolone may become an indispensable and effective treatment, together with the selected comparator pharmacological agents, for community-acquired pneumonia, primary atypical pneumonia, exacerbations of Chronic Obstructive Pulmonary Disease (COPD) and chronic bronchitis, laryngitis, otitis media, conjunctivitis and acute bacterial sinusitis. Additionally, due to the superior action against PRSP, the novel drug shows promise in the treatment of complicated pneumococcal infections.
Keywords: Fluoroquinolones, Meetoofloxacin, In-vitro Susceptibility, Respiratory Tract Infections/ Drug Therapy, Bacterial Drug Resistance, Pneumococcal Infections
The introduction of fluorinated quinolones in the late 1980s heralded a new era in the clinical treatment of Gram-negative infections. Fluoroquinolones (FQs) had a broader spectrum than the naphthyridine series such as nalidixic acid and could also be administered orally (1). The trademark representative of the FQ series is ciprofloxacin. Newer generation FQs have been developed to extend this efficacy against Gram-positive bacteria without critical loss of antimicrobial activity against Gram-negative pathogens.
Regardless, due to the worldwide development of antimicrobial resistance and rapid emergence of multi-drug resistant strains, especially penicillin-resistant Streptococcus pneumonia, new anti-infectives are required in the treatment of attendant infections such as bacterial meningitis, bacterial bronchitis and otitis media (2). Mainstays of multi-drug resistant infection therapy, namely vancomycin and linezolid, are already under threat due to the emergence of vancomycin-resistant and linezolid-resistant methicillin-resistant S.aureus (MRSA) and enterococci (3, 4, 5, 6). In this worrying context, a novel extended-spectrum, meetoofloxacin, is proposed
In this study, the author compares the in-vitro antimicrobial of meetoofloxacin with those of ciprofloxacin and amoxicillin against isolated bacteria. Bacterial strains were collected from clinical subjects with RTI at 20 diagnostic laboratories across the United Kingdom. The bacterial strains isolated for inoculation included: Streptococcus pneumonia, penicillin-resistant Streptococcus pneumonia (PRSP), C. pneumonia, M. pneumonia, H. influenza and M. catarhalis.
For this study, the minimum inhibitory concentration (MIC) was defined as the lowest serum drug concentration required to or capable of preventing viable bacterial growth. In this scenario, only an MIC of 90% is considered, that is, an MIC in which 90% of respiratory isolates are inhibited. MICs were determined by performing antibacterial susceptibility testing using the standard agar dilution method as recommended by the National Committee for Clinical Laboratory Standards (7, 8).
Table 1 below shows the antimicrobial activity of meetoofloxacin against a variety of bacteria and that of the comparator agents. The MIC90 of meetoofloxacin against S. pneumonia, H. influenza, C. pneumonia. B. catarhalis, PRSP, M. pneumonia were 0.15, 0.0008, 0.12, 0.007, 0.15 and 0.4 mg/L respectively. Meetoofloxacin performed impressively against amoxicillin, with a MIC90 1,875-fold lower and 285-fold lower in antibacterial activity against H. influenza and B. catarhalis respectively. Generally, meetoofloxacin out-performed both ciprofloxacin and amoxicillin.
Table 1. Antibacterial Activities of Meetoofloxacin and Comparator Pharmacologic Compounds against Respiratory Isolates.Pathogen MIC90
MeetoofloxacinCiprofloxacin AmoxycillinS. pneumonia 0.15 3 0.015
H. influenza 0.0008 0.017 1.5
C. pneumonia 0.12 1 N.D.*
B. catarhalis0.007 0.05 2
PRSP 0.15 4 3
M. pneumonia 0.4 2.5 N.D.*
*N.D= not done
Barry, A. L. 1990. In vitro activity of the quinolones and related compounds, p. 79105. In C. Siporin, C. L. Heifetz, and J. M. Domagala, (ed.), The new generation of quinolones. Marcel Dekker, Inc., New York, N.Y.
Goldstein, F.W. & Garau, J. 1997. 30 Years of Penicillin-Resistant S. Pneumoniae: Myth Or Reality? Lancet 350, 233-4
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Chang, S., D. M. Sievert, J. C. Hageman, M. L. Boulton, F. C. Tenover, F. P. Downes, S. Shah, J. T. Rudrik, G. R. Pupp, W. J. Brown, D. Cardo, S. K. Fridkin, and the Vancomycin-Resistant Staphylococcus aureus Investigative Team. 2003. Infection with vancomycin-resistant Staphylococcus aureus containing the vanA resistance gene. N. Engl. J. Med. 348:13421347.5. Kacica, M. 2004. Vancomycin-resistant Staphylococcus aureusNew York, 2004. Morb. Mortal. Wkly. Rep. 53:322323.
Rahim, S., S. K. Pillai, H. S. Gold, L. Venkataraman, K. Inglima, and R. A. Press. 2003. Linezolid-resistant, vancomycin-resistant Enterococcus faecium infection in patients without prior exposure to linezolid. Clin. Infect. Dis. 36:E146E148.
National Committee for Clinical Laboratory Standards. 2001. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 5th ed. M7-A5. National Committee for Clinical Laboratory Standards, Wayne, Pa.
National Committee for Clinical Laboratory Standards. 1997. Methods for antimicrobial susceptibility tests of anaerobic bacteria, 4th ed. Approved standard M11A4. National Committee for Clinical Laboratory Standards, Wayne, Pa.
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