Comparative antimicrobial activity of ABT-773, a novel ketolide, tested against drug-resistant Gram-positive cocci and Haemophilus influenzae

The antimicrobial activity of ABT-773, a novel ketolide, was tested against 618 Gram-positive strains collected from various surveillance programmes between 1997 and 2000. ABT-773 has potent activity against Streptococcus pneumoniae (MIC₉₀, ≤0.03–0.12 mg/l), β-haemolytic streptococci (MIC₉₀, ≤0.03 mg/l) and viridans group streptococci (MIC₉₀, ≤0.03 mg/l), including erythromycin-resistant strains. In contrast, ABT-773 was less active against erythromycin-resistant Staphylococcus aureus (31% susceptible at ≤0.25 mg/l), coagulase-negative staphylococci (41% susceptible) and enterococci (30% susceptible). Haemophilus influenzae (MIC_90, 4 mg/l) was less inhibited by the two ketolides tested, and ABT-773 was generally two- to fourfold more potent than telithromycin. The ketolides appear to have potential clinical use against some Gram-positive species resistant to macrolides.     

In vitro activity of ABT-773, telithromycin and eight other antimicrobials against erythromycin-resistant Streptococcus pneumoniae respiratory isolates of children.

The activity of the ketolide ABT-773 against 180 erythromycin-resistant Streptococcus pneumoniae obtained from children was compared with telithromycin, azithromycin, clarithromyin, roxithromycin, clindamycin, penicillin, levofloxacin and gatifloxacin. Ketolide MICs were all ≤1 mg/l, with ABT-773 being the most potent of all drugs tested. MIC₉₀s for macrolides and azithromycin in mefE+ isolates were 16–32 compared with >128 mg/l for ermB+ isolates. ABT-773 and telithromycin MIC₉₀s for mefE+ isolates were 0.125 and 0.5, compared with 0.032 and 0.016 mg/l for ermB+ isolates and 0.5 and 1 mg/l, respectively, for isolates containing both genes. Clindamycin was active against mefE+ but not ermB+ isolates. 155 isolates were resistant to penicillin. All fluoroquinolone MICs were <1 mg/l. Further studies of ketolides for treatment of paediatric S. pneumoniae infections are warranted.     

Inhibitory and bactericidal activities of gemifloxacin and other antimicrobials against Mycoplasma pneumoniae

The MIC of gemifloxacin was compared with that of sparfloxacin, levofloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, doxycycline, erythromycin, azithromycin and clarithromycin using 97 clinical isolates of Mycoplasma pneumoniae. MBCs of fluoroquinolones were determined for a subgroup of 12 isolates. Macrolides were the most potent agents with MIC₉₀s for all drugs 0.001 mg/l. The doxycycline MIC₉₀ was 0.5 mg/l. Gemifloxacin MICs ranged from 0.001 to 0.25 mg/l. The gemifloxacin MIC₉₀ (0.125 mg/l) was equivalent to moxifloxacin and gatifloxacin, was 2-fold lower than sparfloxacin, 8-fold lower than levofloxacin and 32-fold lower than ciprofloxacin. MBCs for gemifloxacin were predominantly within 2–4 times the corresponding MIC values, indicating a bactericidal effect.     

Colistin susceptibility testing by Etest and disk diffusion methods

The accuracy of disk susceptibility methods for colistin against 778 bacterial pathogens was evaluated in comparison with Etest using interpretive criteria available from the Clinical and Laboratory Standards Institute (CLSI). Colistin exhibited excellent activity against Acinetobacter baumannii and Escherichia coli isolates (minimum inhibitory concentration for 90% of the organisms (MIC₉₀) = 0.5 mg/L), whilst it was less active both against Enterobacter spp. and Klebsiella pneumoniae (MIC for 50% of the organisms (MIC₅₀) = 0.5 mg/L, MIC₉₀ = 16 mg/L). Colistin also showed good activity against Pseudomonas aeruginosa (MIC₉₀ = 2 mg/L, MIC₅₀ = 1 mg/L) but poor activity against Stenotrophomonas maltophilia (MIC₅₀ = 8 mg/L, MIC₉₀ = 128 mg/L). Only 0.8% of minor errors were observed between the studied methods for P. aeruginosa isolates when the CLSI criteria were applied. All A. baumannii isolates with a zone diameter ≤12 mm were resistant and those with a zone diameter ≥14 mm were susceptible according to MIC breakpoints established by the CLSI. Among nine isolates exhibiting a zone diameter of 13 mm, one was resistant to colistin (MIC = 8 mg/L) and eight isolates were susceptible (MIC = 0.5 mg/L). Applying a MIC breakpoint of ≤2 mg/L for susceptibility in Enterobacteriaceae, all isolates with a zone diameter ≥14 mm were susceptible, whilst all isolates with a zone diameter ≤11 mm were resistant. Among isolates with zone diameters of 12–13 mm, 59% were characterised as susceptible. Major errors were observed only in K. pneumoniae isolates at a rate of 0.8%. The poor agar diffusion characteristics of colistin limit the predictive accuracy of the disk diffusion test and consequently values of 12–13 mm should be confirmed with MIC determination by Etest or broth dilution method.     

Susceptibility of Canadian isolates of Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae to oral antimicrobial agents

We measured the susceptibility of Canadian isolates of three respiratory tract pathogens (Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae) to several currently approved antimicrobial agents by two different methods. We also measured the susceptibility of isolates to seven fluoroquinolones. Beta-lactamase was produced by 123/566 (21.7%) of H. influenzae isolates compared with 178/200 (89%) of M. catarrhalis isolates. For S. pneumoniae 83/374 (22.2%) isolates were penicillin resistant and of these 2.1% (8/374) showed high level resistance (MIC≥2 mg/l). Regardless of methodology, all fluoroquinolones were highly active against H. influenzae (MIC₉₀ ≤0.031 mg/l) and M. catarrhalis (MIC₉₀ ≤0.064 mg/l) isolates. Susceptibility of H. influenzae to cefuroxime and amoxycillin/clavulanic acid was 99–100% whereas 84–85.5% were susceptible to cefaclor and cefprozil. Azithromycin susceptibility ranged from 82.6 to 99.2% depending on the method. M. catarrhalis isolates were uniformly susceptible to all agents tested except amoxycillin. Cross-resistance in S. pneumoniae to all non-quinolone agents was concurrent with increasing penicillin resistance as shown by increasing MIC₉₀ values. For the fluoroquinolones tested, the rank order of potency based on MIC₉₀ values was as follows: gemifloxacin (0.031–0.063 mg/l), trovafloxacin (0.125 mg/l), moxifloxacin (0.125–0.25 mg/l), grepafloxacin (0.125–0.25 mg/l), gatifloxacin (0.5 mg/l), levofloxacin (1 mg/l) and ciprofloxacin (2 mg/l). Our study confirms either a high or increasing prevalence of antimicrobial resistant respiratory pathogens in Canada and also compares the new and old fluoroquinolones and their potential role as therapy for community-acquired infections. The prevalence of β-lactamase positive H. influenzae may have decreased from levels reported in previous studies.     

In vitro activity of ceftiofur tested against clinical isolates of Escherichia coli and Klebsiella pneumoniae including extended spectrum β-lactamase producing strains

In vitro activity of ceftiofur, a cephalosporin used in veterinary practice was compared using ceftriaxone-resistant (producing extended spectrum β-lactamase (ESBL)) and -susceptible clinical isolates of Esherichia coli and Klebsiella pneumoniae. The ceftriaxone-susceptible isolates exhibited a lower range of ceftiofur MICs (MIC₅₀, 0.5 mg/l, MIC₉₀ 1.0 mg/l). Those isolates known to produce an ESBL were also resistant to ceftiofur (MIC₅₀, ≥ 32 mg/l). The latter isolates were also less susceptible to other comparator drugs (cefquinome, gentamicin and trimethoprim/sulphamethoxazole) in contrast to the ceftriaxone-susceptible strains. The clinical isolates showed high correlation between ceftriaxone and ceftiofur MICs (y=2.6+0.89x, r=0.95). Using the current ceftiofur susceptible breakpoint (≤2 mg/l) used for veterinary practice (respiratory tract pathogens), the ESBL-producing strains of E. coli and K. pneumoniae could be accurately separated from susceptible strains. This ceftiofur breakpoint MIC corresponds to the National Committee for Clinical Laboratory Standards ESBL screening concentration for ceftriaxone set at ≤1 mg/l=negative for ESBL production. Ceftiofur was also observed to be very active in vitro against ampicillin-resistant, non-ESBL producing enteric isolates. This new cephem appears to be very potent against the tested Enterobacteriaceae and of potential wide clinical veterinary utility.     

Activity of gatifloxacin against strains resistant to ofloxacin and ciprofloxacin and its ability to select for less susceptible bacterial variants.

Gatifloxacin is an 8-methoxy fluoroquinolone. On quinolones, this side chain imparts increased activity against Gram-positive bacteria and enhanced killing. Gatifloxacin was tested against ofloxacin non-susceptible (ofloxacin MIC>2 mg/l) strains of Streptococcus pneumoniae (gatifloxacin MIC(90), 1 mg/l) and methicillin-resistant Staphylococcus aureus (MRSA, gatifloxacin MIC(90), 4 mg/l), and to ciprofloxacin non-susceptible (ciprofloxacin MIC>1 mg/l) strains of Escherichia coli (gatifloxacin MIC(90),>16 mg/l) and ciprofloxacin non-susceptible (ciprofloxacin MIC>0.06 mg/l) Neisseria gonorrhoeae (gatifloxacin MIC(50), 0.12 mg/l and MIC(90), 0.5 mg/l). Though gatifloxacin showed some reduced susceptibility to these populations, the MIC(50) and MIC(90) values suggest that gatifloxacin may be useful against pneumococci and some gonococcal strains not susceptible to other fluoroquinolones. Gatifloxacin did not select for less susceptible variants of MRSA and pneumococci, in contrast to the 10- to 100-fold higher selection frequencies with ciprofloxacin and ofloxacin. The single-step E. coli mutants selected by gatifloxacin and the comparator quinolones had quinolone MICs within the susceptible range. These data suggest that gatifloxacin use may hinder the development of quinolone-resistance, particularly in Gram-positive bacteria.     

Canadian Pseudomonas aeruginosa susceptibility study from 48 medical centers: focus on ciprofloxacin

We tested 1503 clinical isolates of Pseudomonas aeruginosa, from 48 Canadian medical centers, against ciprofloxacin and 11 other antimicrobial agents to determine in vitro activity. The frequency of susceptibility was highest for carbenicillin and ticarcillin (91% each) followed by imipenem and ceftazadime (90% each). Overall susceptibility (≤1.0 mg/l) to ciprofloxacin was 84% while resistance (≥4.0 mg/l) was 12%. Ciprofloxacin resistant isolates were more common from urinary tract specimens than from specimens collected from the respiratory and/or skin and soft tissue. Isolates from cystic fibrosis patients were more resistant to all agents tested than isolates from non-cystic fibrosis patients.     

Antifungal susceptibility of candida isolates at the American University of Beirut Medical Center

For the first time from Lebanon, the antifungal susceptibility patterns of 70 consecutive clinical candida isolates (each from one patient) representing 48 C. albicans, 12 C. tropicalis, 6 C. parapsilosis, 2 C. kruseii, and 2 C. (Torulopsis) glabrata were studied against amphotericin B (AP), 5-fluorocytosine (FC), ketoconazole (KE), fluconazole (FL), and itraconazole (IT) using the Epsilometer test (E-test; AB Biodisk, Solna, Sweden). The MIC₉₀ (and MIC range, mg/l) determined, at 24 h incubation, for each antifungal agent against C. albicans were: AP 0.032 (≤0.002–0.064), FC 0.75 (0.023–2), KE 0.064 (0.002–>32), FL 2 (0.064–>256), and IT 0.19 (0.012–2), against C. tropicalis were: AP 0.016 (<0.002–0.047), FC 0.125 (0.023–0.19), KE 0.094 (0.012–0.19), FL 2 (0.5–2), and IT 0.5 (0.047–1) and against C. parapsilosis were: AP<0.002 (<0.002–0.002), FC 0.047 (0.003–0.5), KE 0.004 (0.002–0.004), FL 0.125 (0.032–0.19), and IT 0.004 (<0.002–0.004). Based on the NCCLS established MICs breakpoints, resistance was found among C. albicans to FL (MIC ≥6 mg/l) and IT (MIC ≥1 mg/l) in 6 and 4%, respectively, and among C. tropicalis to IT in 17% of the isolates. The susceptibility dependent upon dose (S-DD) was noted only to IT (MIC 0.25–0.5 mg/l) among C. albicans (8%) and C. tropicalis (58%). MICs determination at 48 h incubation were higher, showed more resistance rates and more endpoint trailing particularly with the azoles drugs. The small numbers of C. kruseii and C. glabrata preclude providing meaningful results. Thus, this study indicates that the antifungal susceptibility by E-test can be conveniently incorporated and performed in a hospital-based clinical laboratory. Despite the uniform susceptibility to AP and FC, resistance to azoles drugs is encountered in a range of 4–17% among candida isolates in this country.     

Activity of nine fluoroquinolones against strains of Bordetella bronchiseptica

Thirty-two strains of Bordetella bronchiseptica were tested for their antimicrobial susceptibilities to nine fluoroquinolones. The most active agents were fleroxacin, temafloxacin, ciprofloxacin (MIC₉₀ 1 μg/ml), ofloxacin, lomefloxacin and enoxacin (MIC₉₀ 2 μg/ml). Pefloxacin and norfloxacin were active only against 59.3 and 83.1%, respectively, of the strains tested, whereas rufloxacin lacked activity against all the strains of B. bronchiseptica tested.     

In vitro activity of gatifloxacin compared with gemifloxacin, moxifloxacin, trovafloxacin, ciprofloxacin and ofloxacin against uropathogens cultured from patients with complicated urinary tract infections

Minimum inhibitory concentrations (MICs) of gatifloxacin were compared with those of gemifloxacin, moxifloxacin, trovafloxacin, ciprofloxacin and ofloxacin using an agar dilution method for 400 uropathogens cultured from the urine of urological patients with complicated and/or hospital-acquired urinary tract infections (UTI). The collection of strains was made up of Enterobacteriaceae (34.5%), enterococci (31.5%), staphylococci (21.2%) and non-fermenting bacteria (12.8%). The antibacterial activity of the three newer fluoroquinolones, gatifloxacin, gemifloxacin, and moxifloxacin, were similar, but showed some drug specific differences. Gemifloxacin was most active against Escherichia coli, but less so against Proteus mirabilis. In this series all isolates of E. coli were inhibited at a MIC of 0.25 mg/l gatifloxacin and moxifloxacin and by 0.125 mg/l gemifloxacin. The MIC distribution of all fluoroquinolones showed a bimodal distribution for staphylococci, enterococci and Pseudomonas aeruginosa. The two modes for P. aeruginosa were 1 and 64 mg/l for gemifloxacin and moxifloxacin and 0.5 and 64 mg/l for gatifloxacin. For staphylococci the two modes were 0.125 and 2 mg/l for gatifloxacin, 0.03 and 4 mg/l for gemifloxacin, and 0.03 and 2 mg/l for moxifloxacin; for enterococci, 0.25 and 16 mg/l for gatifloxacin, 0.06 and 2 mg/l for gemifloxacin, and 0.25 and 8 mg/l for moxifloxacin. Compared with trovafloxacin the MICs were similar, but the newer fluoroquinolones were more active than ciprofloxacin and ofloxacin against Gram-positive bacteria. Of the newer fluoroquinolones gatifloxacin had the highest rate of renal excretion and could be considered a promising alternative fluoroquinolone agent for the treatment of UTI.     

Antimicrobial activity of tigecycline (GAR-936) tested against 3498 recent isolates of Staphylococcus aureus recovered from nosocomial and community-acquired infections

Tigecycline is a novel 9-t-butylglycylamido derivative of minocycline that has demonstrated activity against a variety of Gram-positive and -negative bacterial pathogens. In vitro activity of tigecycline and comparator agents was determined for 3498 recent (2000–2003) strains of Staphylococcus aureus recovered from patients with either nosocomial or community-acquired infections. Oxacillin-susceptible and -resistant S. aureus from both patient populations displayed identical results for tigecycline (MIC₅₀ and MIC₉₀ results at 0.25 and 0.5 mg/L, respectively) and all strains were inhibited by 1 mg/L or less. While co-resistances to other antimicrobial classes were present in oxacillin-resistant strains, susceptibility to tigecycline remained unaffected, making the compound an attractive candidate for treatment of serious hospital as well as community-acquired staphylococcal infections.     

Minimal inhibitory concentrations and time-kill determination of moxifloxacin against aerobic and anaerobic isolates

Moxifloxacin is a new oral 8-methoxy-quinolone with a wide spectrum of activity against Gram-negative and anaerobic bacteria, atypical micro-organisms and multi-resistant Gram-positive bacteria. This study was designed to assess the in vitro activity of moxifloxacin against Gram-positive bacteria with different resistance patterns, anaerobes and atypical micro-organisms such as Chlamydia and Mycoplasma. Moxifloxacin had good activity against Streptococcus pneumoniae with all strains inhibited by < or =0.12 mg/l. The minimal inhibitory concentrations (MICs) of moxifloxacin for Streptococcus pyogenes and Streptococcus agalactiae ranged from 0.03 to 0.5 mg/l while those of ciprofloxacin were about two- to four-fold higher (MICs=0.12-1 mg/l). Moxifloxacin was poorly active against enterococci but its activity against Clostridium and Bacteroides spp. was in the same range as that of metronidazole and superior to that of clindamycin. Moxifloxacin was substantially more active than both ciprofloxacin and sparfloxacin against Chlamydia.     

The in vitro effects of faropenem on lower respiratory tract pathogens isolated in the United Kingdom

Faropenem is a new oral penem with a structure different from current β-lactams including carbapenems. The susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis to faropenem, a macrolide, a β-lactam, a β-lactam/β-lactamase inhibitor combination and two fluoroquinolones was investigated. S. pneumoniae was the most susceptible of the three species to faropenem. The MIC₉₀s of faropenem against M. catarrhalis and H. influenzae were 0.5 and 1 mg/l, respectively. They were similar to amoxiclav (MIC ₉₀s of 0.25 and 0.5 mg/l). The quinolones showed strong activity against H. influenzae. A cluster analysis of the activities of amoxycillin and faropenem demonstrated a direct relationship between the two antimicrobial agent's activities and resistance profiles against both S. pneumoniae and H. influenzae.     

In vitro susceptibility of 4903 bacterial isolates to gemifloxacin--an advanced fluoroquinolone

The in vitro activity of gemifloxacin against over 4900 bacterial isolates was determined by microbroth dilution with interpretation in accordance with NCCLS guidelines. Susceptibility results were compared with those for ciprofloxacin, gatifloxacin, levofloxacin and moxifloxacin. Gemifloxacin and the other fluoroquinolones were not affected by either beta-lactamase production or penicillin-resistance in Streptococcus pneumoniae. The MIC90 values for gemifloxacin were: S. pneumoniae 0.063 mg/l; Haemophilus influenzae 0.016 mg/l; Moraxella catarrhalis 0.008 mg/l, methicillin-susceptible Staphylococcus aureus 0.063 mg/l; methicillin-susceptible Streptococcus pyogenes 0.031 mg/l; Enterobacteriaceae 0.031-0.16 mg/l; Pseudomonas aeruginosa 4 mg/l; Neisseria meningitidis 0.008 mg/l. The MIC90 for gemifloxacin was lower than those for the other quinolones tested against S. pneumoniae (ciprofloxacin 2-4 mg/l, gatifloxacin 0.5 mg/l, levofloxacin 1-2 mg/l, moxifloxacin 0.25 mg/l). This study confirms the enhanced potent activity of gemifloxacin against Gram-positive pathogens, its broad-spectrum, Gram-negative activity and indicates that gemifloxacin is likely to have an important role in treating patients with Gram-positive and/or Gram-negative infections.     

New real-time PCR-based method for in vitro susceptibility testing of Anaplasma phagocytophilum against antimicrobial agents

Up to now, only a few isolates of Anaplasma phagocytophilum have been tested for their susceptibility against a small number of antimicrobial agents. In addition, as with other fastidious or intracellular bacteria, the test methods are laborious and neither minimal inhibitory concentration (MIC) definitions, nor the test conditions and the inocula are standardised to date. A new 16S-rDNA-based real-time PCR assay has been developed and used under standardised conditions to analyse the activity of seven antimicrobial agents against two A. phagocytophilum isolates. After 72 h incubation, MICs were determined by software-assisted calculation of bacterial growth in samples and controls from semi-quantitative PCR results. In our study, the rank order of potency on a mg/l basis for the antimicrobial agents with enhanced in vitro activity against A. phagocytophilum was moxifloxacin (MIC: ≤0.03 mg/l) > doxycycline (MIC: ≤0.125 mg/l) > ciprofloxacin (MIC: 0.125 mg/l). Gentamicin, ampicillin, azithromycin and cethromycin showed no activity against the isolates tested in this investigation. Our new 16S-rDNA-PCR-based microdilution test system was shown to be sensitive, reproducible and reliable. The assay is capable of testing larger numbers of isolates and antimicrobial agents under standardised and very precise test conditions and may therefore offer a competent technical solution of the difficulties known to be associated with in vitro testing of other bacterial pathogens that grow intracellularly, such as chlamydia or rickettsia.     

Activity of RBx 7644 and RBx 8700, new investigational oxazolidinones, against Mycobacterium tuberculosis infected murine macrophages

The decision to develop a new chemical entity should not only be based on its ability to inhibit multidrug-resistant tuberculosis (MDR-TB) strains but also on its ability to enter macrophages and be active against intracellular bacteria. RBx 7644 and RBx 8700, two novel extended spectrum oxazolidinones, were investigated for their activity against sensitive and MDR isolates of Mycobacterium tuberculosis and for activity against bacteria within a macrophage cell line. RBx 8700 showed excellent in vitro activity against sensitive as well as MDR M. tuberculosis strains with MIC₅₀ and MIC₉₀ values of 0.032 and 0.25 mg/L (sensitive) and 0.25 and 1.0 mg/L (MDR) strains. The corresponding MIC₅₀ and MIC₉₀ values of RBx 7644, linezolid, rifampicin and isoniazid were 8 and 16; 32 and 64; 64 and 64; 64 and 64 mg/L, respectively. RBx 8700 and rifampicin were bactericidal at 0.5 and 0.25 mg/L when tested intracellularly whereas linezolid reduced the count by 100-fold at a concentration of 8 mg/L. In combination studies with standard antimycobacterial drugs, RBx 8700 did not show any antagonistic effect.     

In vitro activity of moxifloxacin,levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis

The in vitro activity of moxifloxacin, gatifloxacin, levofloxacin and linezolid was evaluated against 234 strains of Mycobacterium tuberculosis isolated in the Southeast of Spain. All drugs tested showed good activity, with an MIC₉₀ of less than 1 mg/l, and were active against isociacide and rifampicin resistant strains. Three strains were resistant to isoniazid and to the fluoroquinolones, which suggested the existence of mechanisms of resistance not yet described. These new compounds may prove to be therapeutic alternatives for treatment of multi-resistant tuberculosis and further studies should be done to demonstrate their true usefulness.     

Steady-state serum and intrapulmonary pharmacokinetics and pharmacodynamics of tigecycline

The steady-state serum and intrapulmonary pharmacokinetic and pharmacodynamic parameters of tigecycline were determined after intravenous administration in 30 subjects. Tigecycline was administered as a 100 mg loading dose followed by six 50 mg doses given every 12 h and was measured using HPLC/mass spectrometry. Ratios of tigecycline maximum serum concentration and area under the serum concentration–time curve to 90%—minimum inhibitory concentrations (C_max/MIC₉₀; AUC/MIC₉₀), and percentage time above MIC₉₀ were calculated for common respiratory pathogens (Streptococcus pneumoniae, Chlamydia pneumoniae, Mycoplasma pneumoniae, Moraxella catarrhalis and Haemophilus influenzae). The C_max (mean ± S.D.), AUC and half-life for serum were 0.72 ± 0.24 μg/mL, 1.73 ± 0.64 μg*h/mL and 15.0 ± 1.10 h; for lung epithelial lining fluid (ELF) the values were 0.37 μg/mL, 2.28 μg*h/mL and 39.1 h; and for alveolar cells (AC) were 15.2 μg/mL, 134 μg*h/mL and 23.7 h. Tigecycline was concentrated in AC: C_max/MIC₉₀ ratios ranged from 30.4 (H. influenzae) to 507 (S. pneumoniae); AUC/MIC₉₀ ratios ranged from 268 (H. influenzae) to 4467 (S. pneumoniae); and percentage dose interval above MIC₉₀ was 100% for the five respiratory pathogens. The C_max/MIC₉₀, AUC/MIC₉₀ ratios, T > MIC₉₀ and extended serum and intrapulmonary half-lives following the regimen used in this study are favourable for the treatment of tigecycline-susceptible pulmonary infections.     

Urinary bactericidal activity, urinary excretion and plasma concentrations of gatifloxacin (400 mg) versus ciprofloxacin (500 mg) in healthy volunteers after a single oral dose

In an open randomised double-crossover study 12 volunteers (six men, six women) received a single oral dose of gatifloxacin (400 mg) or ciprofloxacin (500 mg) to assess urinary bactericidal activity (in eight intervals up to 120 h) and pharmacokinetic (PK) parameters (up to 36 h). Plasma concentrations and urinary excretion were determined by HPLC with fluorescence detection, and urinary bactericidal titers (UBT) by microdilution-method, using antibiotic-free urine of each volunteer. The mean maximum plasma concentration of gatifloxacin was 3.35 mg/l and that of ciprofloxacin 2.12 mg/l. The mean (median) cumulative renal excretion of the parent drug was for gatifloxacin 81 (83)% of the administered dose within 120 h and for ciprofloxacin 43 (45)%. The UBTs, i.e. the highest two-fold dilution (antibiotic-free urine as diluent) of urine still being bactericidal, were determined for an Escherichia coli ATCC reference strain and nine clinical uropathogens with the following MICs (mg/l) for gatifloxacin/ciprofloxacin (microdilution, MHB): E. coli ATCC 25922 (0.008/0.008); E. coli 523 (0.06/0.06); Klebsiella pneumoniae 1058 (0.03/0.016); Proteus mirabilis 524 (0.125/0.016); Pseudomonas aeruginosa 561 (1/0.125); Enterococcus faecalis strains 60 an 55 (0.5/1 and 8/32); Staphylococcus aureus strains 248 and 596 (both 0.03/0.125) and S. saprophyticus Ho94 (0.125/0.25). The median UBTs measured within the first 6h for gatifloxacin were between 1:16 and 1:>or=1024 for the Gram-negative strains including P. aeruginosa and between 1:8 and 1:>or=1024 for the five Gram-positive strains. The median UBTs for ciprofloxacin were between 1:64 and 1:>or=1024 for the Gram-negative strains (incl P. aeruginosa) and between 1:1.5 and 1:768 for the five Gram-positive strains. The UBTs up to 12 < 0.05 h showed no difference (P<0.05 ) for both E. coli strains, but ciprofloxacin was superior to gatifloxacin against Klebsiella, Proteus and Pseudomonas strains and gatifloxacin was superior to ciprofloxacin against all Gram-positive strains. For the UBTs at 12-24 h, gatifloxacin was generally superior to ciprofloxacin, but showed no difference in the Proteus and Pseudomonas strains. The areas under the UBT-time-curve (AUBT) up to 120 h showed statistically significant (P ) differences between both quinolones in favour of gatifloxacin against 8 of 10 strains tested, no difference for P. mirabilis and significantly higher activity of ciprofloxacin against P. aeruginosa. In conclusion, gatifloxacin and ciprofloxacin had overall comparable initial urinary bactericidal activity with some differences for specific pathogens, some times in favour of gatifloxacin (Gram-positives) and some times of ciprofloxacin (usually Gram-negatives), suggesting that for empiric therapy a single oral dose of gatifloxacin (400mg) would be clinically equivalent to ciprofloxacin (500 mg) twice daily-in agreement with the results of a clinical study in complicated UTI performed previously [Int. J. Antimicrob. Agents (2004)].