CQ-397 and CQ-414: antimicrobial activity and spectrum of two fluoroquinolone–cephalosporin, dual-action compounds with carboxamido bonds

Objective: To evaluate the potential spectrum of activity of two novel dual-action compounds with carboxamido bonds (CQ-397 and CQ-414; Laboratories Aranda, San Rafael, Mexico) against human pathogens.
Method: Approximately 800 Gram-positive and Gram-negative aerobic clinical bacteria were tested in vitro using the Mueller-Hinton broth microdilution method of the National Committee of Clinical Laboratory Standards.
Results: CQ-397 (cefamandole+enrofloxacin) and CQ-414 (cefamandole+norfloxacin) were equally potent against Enterobacteriaceae (MIC₉₀ range, 0.06–0.5 μg/mL and 0.06-1 μg/mL, respectively). Citrobacter freundii (MIC₉₀, 4 μg/mL) and Providencia spp. (MIC₉₀,>32 μg/mL) exhibited elevated study drug MICs. Enterobacteriaceae resistant to fluoroquinolones generally remained resistant. CQ-397 and CQ-414 were active against Stenotrophomonas maltophilia (MIC₉₀, 4 μg/mL) and oxacillin-susceptible staphylococci (MIC₉₀, 0.25 μg/mL), but not oxacillin-resistant Staphylococcus aureus (MIC₉₀,>32 μg/mL), Staphylococcus epidermidis (MIC₉₀, 8 μg/mL), and enterococci (MIC₉₀s, 8 to>32 μg/mL). There was no difference in the dual-action drug activity (MIC₉₀, 2 μg/mL) between penicillin-susceptible and -resistant pneumococci. Haemophilus influenzae and Moraxella catarrhalis were very susceptible (MIC range, <0.015-0.06 μg/mL) to both compounds.
Conclusions: The activity of these novel dual-action compounds, formed from the bonding of older antimicrobials, warrants further investigation for potential human and/or animal health use, including toxicology and pharmacokinetics.     

Comparative activity of linezolid against staphylococci and enterococci isolated in Italy

The activity of linezolid, a new oxazolidinone, was tested against 862 Gram-positive cocci isolated in Italy and compared with the activities of 12 antibiotics. Overall, MIC₉₀s for linezolid (2–4 mg/L) indicated an in vitro activity comparable to that of vancomycin in methicillin-resistant Staphylococcus aureus (4 mg/L), S. epidermidis (2 mg/L) and methicillin-susceptible strains. Enterococcus faecalis strains were susceptible to linezolid (MIC₉₀ 2–4 mg/L), glycopeptides and β -lactams. In E. faecium , only glycopeptides (MIC₉₀ 2 mg/L) and linezolid (MIC₉₀ 2 mg/L) were active. Linezolid was the only drug active against two strains of Enterococcus showing a VanA phenotype. Owing to its antibacterial profile, linezolid represents a promising drug for the treatment of Gram-positive infections.     

Susceptibility testing by E-test and agar dilution of 30 strains of Legionella spp. isolated in Portugal

Objective: To evaluate the activity of erythromycin, roxithromycin, ciprofloxacin, doxycycline, sulfamethoxazole trimethoprim and rifampin against 32 strains of Legionella spp. under different testing conditions.
Method: Minimum inhibitory concentrations (MICs) were determined by the E-test (Ab Biodisk, Solna, Sweden) and agar dilution reference technique (National Committee for Clinical Laboratory Standards (NCCLS), 1990) on two different media, buffered charcoal yeast extract agar (BCYE-α) and buffered yeast extract agar (BYE-α), under 48- and 72-h incubation, without CO₂.
Results: All the antimicrobial agents were inhibited by BCYE-α agar. The MIC₉₀ values on BYE-α were lower than those on BCYE-α but the variation factor was not the same: ciprofloxacin and rifampin, followed by erythromycin, suffered the greatest inhibition by the charcoal in the culture medium. Except for ciprofloxacin and rifampin, the 72-h MIC₉₀ readings were always higher than the 48-h results whenever the agar dilution method was used. The E-test results showed slight variations with some, but not all, antibiotics. The most active agents against the 32 Legionella strains tested were rifampin and ciprofloxacin.
Conclusions: BCYE-α is not suitable for susceptibility testing of Legionella spp. The E-test method on BYE-α agar with 48-h incubation is recommended.     

In vitro activities of new quinolones against Brucella melitensis isolated in a tertiary-care hospital in Turkey

We have evaluated the in vitro activities of seven fluoroquinolones against 69 strains of Brucella melitensis . According to their minimum inhibitory concentration for 90% growth (MIC₉₀) values, the most active agent was found to be sparfloxacin (MIC₉₀ 0.12 mg/L) followed by levofloxacin, ciprofloxacin, ofloxacin (MIC₉₀ 0.50 mg/L) and grepafloxacin (MIC₉₀ 1 mg/L), gemifloxacin (MIC₉₀ 2 mg/L) and gatifloxacin (MIC₉₀ 4 mg/L).     

The DUEL study: a multi-center in vitro evaluation of linezolid compared with other antibiotics in the Netherlands

Objective   To evaluate bacterial susceptibility to linezolid in the Netherlands in comparison with other antibiotics.
Methods   Bacterial strains were isolated between September 1999 and January 2000 from patients presumed to require antibiotic treatment. The in vitro activity of 1226 strains from 34 participating laboratories was tested against linezolid, vancomycin, teicoplanin, oxacillin, penicillin, erythromycin, ampicillin and other antibiotics against enterococci, coagulase-negative staphylococci, Staphylococcus aureus and Streptococcus pneumoniae . Minimal inhibitory concentrations (MIC) were obtained with the E test on Mueller-Hinton agar: every laboratory included control strains. For vancomycin and teicoplanin only, brain–heart infusion agar and an inoculum of 2.0 McFarland was used for Staphylococcus aureus , coagulase-negative staphylococci and enterococci to support a better growth and clear recognition of hetero-resistant colonies.
Results   The values of MIC₉₀ for linezolid were 1.5, 0.75, 0.75 and 1 mg/L for Staphylococcus aureus , coagulase-negative staphylococci, Streptococcus pneumoniae and enterococci, respectively. Six enterococcal strains with decreased susceptibility against vancomycin or teicoplanin were identified as Enterococcus faecium , E. gallinarum and E. casseliflavus (two strains each) and they were found to harbor vanA , vanC1 and vanC2/3 genes, respectively. Nine per cent of Streptococcus pneumoniae (an increase from 1% 4 years ago) showed decreased susceptibility to erythromycin, of both the ermB and mefE type; there was no cross-resistance with linezolid. Twelve coagulase-negative staphylococcal strains were resistant to teicoplanin.
Conclusion   Linezolid is a promising drug in the treatment of infections caused by Gram-positive cocci. Cross-resistance with other antibiotics tested was not found.     

European survey of glycopeptide susceptibility in Staphylococcus spp.

Objectives: To reassess the relative potencies of teicoplanin and vancomycin following several years of clinical usage.
Methods: The glycopeptide susceptibilities of clinical isolates of staphylococci collected from 70 hospitals in 1995 were determined using NCCLS (National Committee for Clinical Laboratory Standards) methods.
Results: In total, 2885 isolates of Staphylococcus aureus and 1480 isolates of coagulase-negative staphylococci were collected. S. aureus was significantly less susceptible to vancomycin (MIC₅₀ 1 mg/L) than teicoplanin (MIC₅₀ 0.5 mg/L), but the reverse was the case for S. haemolyticus and S. epidermidis . No S. aureus isolate was resistant (≥32 mg/L) to either glycopeptide, but nine isolates of coagulase-negative staphylococci had an MIC of teicoplanin of 32 mg/L. Respiratory isolates of S. aureus were less susceptible to glycopeptides than those from other sites. Staphylococci from Belgium and Italy were less susceptible to teicoplanin than isolates from other countries.
Conclusions: This European survey shows that in 10 years of clinical use there have been no major changes in the susceptibility of staphylococci to the glycopeptides.     

Comparative in vitro activities of five quinolone antibiotics, including gemifloxacin, against clinical isolates

The in vitro activities of ciprofloxacin, ofloxacin, norfloxacin, levofloxacin and gemifloxacin against 343 clinical isolates were compared. Gemifloxacin showed the greatest activity, with MIC₉₀ values as low as 0.03–0.25 mg/L against Streptococcus pneumoniae , Haemophilus influenzae , Moraxella catarrhalis , methicillin-susceptible Staphylococcus aureus and Klebsiella pneumoniae , while methicillin-resistant Staphylococcus aureus , Enterococcus spp., Pseudomonas spp., Acinetobacter spp., Escherichia coli and Enterobacter spp. strains exhibited low rates of susceptibility to all five fluoroquinolones.     

Lack of antimicrobial activity of sodium heparin for treating experimental catheter-related infection due to Staphylococcus aureus using the antibiotic-lock technique

Objective   To elucidate the potential antimicrobial activity of sodium heparin in the treatment of catheter-infection using the antibiotic-lock technique.
Methods   We performed in vitro studies of the antibiotic susceptibility, stability and synergy of sodium heparin, vancomycin and ciprofloxacin. Efficacy studies were performed in a new animal model of Staphylococcus aureus catheter-related infection in which infection was produced via the endoluminal route. White New Zealand rabbits were surgically implanted with a sylastic catheter into the inferior cava vein. Immediately afterwards, infection was induced by filling and locking the catheters with 0.7 mL of broth culture containing 10⁸ colony-forming units of S. aureus . Eighteen hours later the antibiotic-lock technique was started. Treatment groups were: control without treatment, sodium heparin at 2500 IU/mL, vancomycin at 2500 mg/L, ciprofloxacin at 1000 mg/L, vancomycin plus heparin and ciprofloxacin plus heparin.
Results   Sodium heparin showed an MIC₉₀ higher than 6000 UI/mL against S. aureus causing catheter infection. Studies of antimicrobial synergy by the time-kill method between vancomycin and ciprofloxacin at MIC with sodium heparin at 2500 IU/mL showed no interactions. Vancomycin (2000 µg/mL) and ciprofloxacin (1000 µg/mL) in a solution containing sodium heparin (2500 IU/mL) were stable at 37 °C for a 72-h period. Two sets of in vivo experiments were carried out using differents strains of S. aureus . In both cases, sodium heparin showed no therapeutic efficacy when compared to control group and did not increase the antibiotic efficacy when used in combination with vancomycin or ciprofloxacin.
Conclusion   Sodium heparin lacked antibacterial activity against S. aureus causing catheter-related infections.     

Comparative Activity of Eighteen Antimicrobial Agents against Anaerobic Bacteria Isolated in South Africa

 The in vitro activity of 18 antimicrobial agents was determined against 378 anaerobic bacteria isolated in Bloemfontein, South Africa, during 1996/97. Against the gram-positive isolates, MICs of penicillin and cefoxitin were >0.5 μg/ml and >16 μg/ml, respectively, for five and three strains of non-perfringens Clostridium spp. Seventeen Peptostreptococcus anaerobius strains were resistant to penicillin (MIC≥2 μg/ml). All gram-positive anaerobes tested except one Peptostreptococcus sp. and one Clostridium sp. were susceptible to dalfopristin-quinupristin (MICs≤1 μg/ml). The carbapenems exhibited excellent activity against the gram-positive isolates and were effective against most gram-negative anaerobes, with the exception of the fusobacteria. Only seven strains exhibited decreased susceptibility to trovafloxacin (MICs>2 μg/ml). In mixed anaerobic/aerobic infections, carbapenems and the fourth-generation quinolone trovafloxacin were the agents most suitable for us as broad-spectrum monotherapy.     

Antimicrobial activity of LB10827, a new orally administered cephalosporin, tested against Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae

A new orally administered cephalosporin, LB10827, was compared to 16 other antimicrobial agents tested against Streptococcus pneumoniae (520 strains), Haemophilus influenzae (302 strains) and Moraxella catarrhalis (188 strains) by reference broth microdilution methods. LB10827 (MIC₉₀, 0.12 mg/L; highest MIC, 0.5 mg/L) was 8–16-fold more potent than cefdinir, cefpodoxime or cefuroxime when tested against S. pneumoniae . All Gram-negative strains were inhibited at ≤ 0.5 mg/L LB10827, which is an activity equal or superior to that of currently available and tested oral β-lactams. LB10827 appears to be a promising agent worthy of continued investigations both in vitro and in vivo.     

In vitro activity of tigecycline and occurrence of tetracycline resistance determinants in isolates from patients enrolled in phase 3 clinical trials for community-acquired pneumonia

The in vitro activity of tigecycline was evaluated against baseline pathogens isolated from patients enrolled in phase 3 clinical trials for community-acquired pneumonia conducted in 29 countries worldwide. Tigecycline was active against the most prevalent pathogens, including Streptococcus pneumoniae (MIC₉₀ 0.06 mg/L), Staphylococcus aureus (MIC₉₀ 0.25 mg/L), Haemophilus influenzae (MIC₉₀ 0.5 mg/L) and Klebsiella pneumoniae (MIC₉₀ 1 mg/L). Twelve isolates of S. pneumoniae expressing tet (M) and two isolates of K. pneumoniae producing extended-spectrum β-lactamases isolated during the study were susceptible to tigecycline. The excellent in vitro activity of tigecycline against these clinical isolates confirmed its potential utility against pathogens associated with community-acquired pneumonia.     

Activity of telithromycin against 26 quinolone-resistant pneumococci with known quinolone-resistance mechanisms

NCCLS agar dilution was used to test activity of telithromycin compared to clarithromycin, penicillin G, ciprofloxacin, levofloxacin, sparfloxacin and moxifloxacin against 26 pneumococci with defined quinolone resistance (type II topoisomerase and efflux) mechanisms. Thirteen strains were penicillin susceptible, six intermediate and seven resistant. Clarithromycin resistance ( mef and/or erm ) was seen in eight strains. Ciprofloxacin MICs (mg/L) were 8–64 compared to 1–32 (levofloxacin), 0.5 ≥ 32 (sparfloxacin) and 0.125–4 (moxifloxacin). Telithromycin MIC₅₀ and MIC₉₀ values (mg/L) were 0.016 and 0.25, with only one strain having an MIC of 2 mg/L.     

In vitro anti-anaerobic activity of the cephalosporin derivative RWJ 54428, compared to seven other compounds

Agar dilution MIC was used to test the activity of RWJ 54428, a new cephalosporin derivative, compared to imipenem, meropenem, ceftriaxone, piperacillin, piperacillin–tazobactam, clindamycin and metronidazole against 363 anaerobes isolated from clinical specimens. RWJ 54428 had low MICs against most β -lactamase-negative Gram-negative rods, and all Gram-positive strains except Clostridium difficile . Imipenem and meropenem had the lowest MICs (MIC₅₀s of 0.125 mg/L and MIC₉₀s of 1.0 mg/L). Piperacillin–tazobactam, clindamycin and metronidazole were active against most strains, and ceftriaxone was active mainly against β -lactamase-negative organisms.     

In vitro activity of the new glycopeptide decaplanin

The activity of decaplanin, a new glycopeptide, was compared to that of vancomycin, teicoplanin and daptomycin. Decaplanin was two- to four-fold less active than vancomycin, teicoplanin and daptomycin againstStaphylococcus aureus andStaphylococcus epidermidis, with an MIC90 of 2 µg/ml for methicillin-susceptible and 4 µg/ml for methicillin-resistant isolates. Decaplanin had activity similar to that of vancomycin againstStreptococcus pyogenes, Streptococcus agalactiae, group C and G streptococci, with an MIC90 of 0.12 µg/ml. It was less active than the other agents against the viridans group streptococci (MIC90 4 µg/ml). The activity of decaplanin against enterococci (MIC90 4 µg/ml) was similar to that of vancomycin.Clostridium spp. were inhibited by 0.5 µg/ml, peptostreptococci and peptococci by 0.25 µg/ml. Decaplanin was active from pH 5.5 to 7.5. Inoculum size had a minimal effect on MICs, and increased concentrations of Ca²⁺ and Mg²⁺ and 50 % serum did not alter MICs or MBCs.     

In vitro activity of levofloxacin against contemporary clinical isolates of Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae from North America and Europe

Objective   To assess the activities of levofloxacin and the comparator agents erythromycin, clarithromycin, azithromycin and doxycycline against atypical respiratory pathogens.
Methods   One hundred and forty-six Legionella pneumophila , 41 Mycoplasma pneumoniae and nine Chlamydia pneumoniae isolates were procured from various culture collections in North America and Europe and tested for susceptibility to the above agents by broth microdilution. The isolates came primarily from clinical sources and were collected from patients between 1995 and 1999.
Results   Against L. pneumophila , levofloxacin was the most active agent, with an MIC₉₀ of 0.03 mg/L, twofold more active than clarithromycin (0.06 mg/L), 16-fold more active than erythromycin and azithromycin (0.5 mg/L) and 64-fold more active than doxycycline. Against M. pneumoniae , azithromycin (MIC₉₀ ≤ 0.0005 mg/L) was the most active agent. However, two isolates of M. pneumoniae , one from the USA and one from Finland, were macrolide resistant (MIC ≥ 4 mg/L), but levofloxacin susceptible (MIC 0.25 mg/L). The geographic origin of L. pneumophila and M. pneumoniae did not affect the MIC range for any antimicrobial agent tested. Against C. pneumoniae , clarithromycin was the most active agent, with an MIC range of ≤0.008–0.03 mg/L.
Conclusions   Levofloxacin had comparable activity to the other agents tested against the atypical respiratory pathogens, confirming its potential as an alternative for empirical therapy of community-acquired pneumonia.     

In vitro activity of quinupristin/dalfopristin in comparison with five antibiotics against worldwide clinical isolates of staphylococci

Objective   To evaluate the in vitro activity of quinupristin/dalfopristin (Q/D), a streptogramin combination, in comparison with five antibiotics against worldwide clinical isolates of staphylococci.
Methods   A multicenter in vitro study was performed using the E test during a period of 3 months (April to June) in 1997 on fresh, clinically significant, non repetitive strains of staphylococci from patients hospitalized in 23 different hospitals in 18 countries tested.
Results   A total of 2132 staphylococcal isolates including methicillin resistant (MR), methicillin susceptible (MS) S. aureus (1003 MS, 462 MR), S. epidermidis (169 MS, 251 MR), S. haemolyticus (28 MS, 46 MR), S. hominis (28 MS, 16 MR), and coagulase negative staphylococci (86 MS, 43 MR) were analyzed.
Q/D was highly active against all species tested. MIC₉₀ (mg/L) ranged from 0.5 to 2 depending on the species. Strains had MIC≤1 mg/L in 97.6%. For S. aureus , S. epidermidis , S. hominis and other coagulase-negative staphylococci no differences in MIC₉₀ were observed for MS or MR. One dilution difference was observed for S. haemolyticus , which overall was the less susceptible species. Erythromycin resistance was observed among 57– 87% of MR-strains and was lower among MS-strains (18–56%). Erythromycin resistance had no or little influence on MIC of Q/D. In comparison to vancomycin, Q/D was two to four times more active.
Conclusions   The streptogramin combination Q/D showed an excellent in vitro activity against all staphylococcal species tested regardless of the resistance pattern to other drug classes, particularly resistance to methicillin. Q/D was two to four times more active than vancomycin and MIC values varied from 0.5–2 according to the species. The synergy of Q/D was well conserved in macrolide-resistant strains.     

Pharmacokinetics of 18F-labeled trovafloxacin in normal and Escherichia coli-infected rats and rabbits studied with positron emission tomography

Objective: To measure tissue pharmacokinetics of trovafloxacin (CP 99,219) in normal and infected animals by both direct tissue radioactivity measurements and positron emission tomography (PET).
Method: Concentrations of [ ¹⁸ ]Ftrovafloxacin were measured in normal and infected rats ( n =6/group), at 10, 30, 60, and 120 min after injection, by radioactivity measurements. In normal rabbits ( n =4) and rabbits with Escherichia coli thigh infection ( n =4), tissue concentrations of drug were measured over 2 h with PET. After acquiring the final images, the rabbits were killed and tissue concentrations measured with PET were compared to the results of direct tissue radioactivity measurements.
Results: In both species, there was rapid distribution of [ ¹⁸ ]F trovafloxacin in most peripheral organs. Peak concentrations of more than five times the MIC₉₀ of most Enterobacteriaceae and anaerobes (>100-fold for most organisms) were achieved in all tissues and remained above this level for >2 h. Particularly high peak concentrations were achieved in the kidney (>75 μg/g), liver (>100 μg/g), blood (>40 μg/g), and lung (>10 μg/g). Even though the concentration of trovafloxacin in infected muscle was reduced ( p <0.01), the peak concentration was still >4 μg/g and tissue levels remained above 2 μg/g for more than 2 h. Due to the lower concentrations that were achieved in the brain (peak ˜5 μg/g), it is expected that trovafloxacin will have limited central nervous system toxicity.
Conclusions: PET with [¹⁸F] trovafloxacin is a useful technique for non-invasive measurements of tissue pharmacokinetics.     

Antimicrobial susceptibility of 840 clinical isolates of Haemophilus influenzae collected in four European countries in 2000–2001

In 2000–2001, 840 clinical isolates of Haemophilus influenzae were collected from laboratories in France, Germany, Italy and Spain (210 isolates/country). β -Lactamase production among the isolates varied considerably by country, ranging from 8.1% in Germany to 34.8% in France. H. influenzae from patients ≤4 years old showed the highest prevalence of β -lactamase production (23.2%), compared with isolates from patients aged 5–17 years (17.8%) and ≥18 years (16.5%). All isolates were susceptible to amoxicillin–clavulanate, ciprofloxacin and levofloxacin; 99.6% and 98.9% of isolates were susceptible to azithromycin and cefuroxime, respectively. Among the macrolides tested, azithromycin (MIC₉₀, 2 mg/L) was eight-fold more potent than clarithromycin (MIC₉₀, 16 mg/L) and roxithromycin (MIC₉₀, 16 mg/L). Despite variations in β -lactamase production between different countries, > 99% of all isolates were susceptible to amoxicillin–clavulanate, ciprofloxacin, levofloxacin, and azithromycin.     

Antimicrobial activity against strains of Escherichia coli and Klebsiella spp. with resistance phenotypes consistent with an extended-spectrum β-lactamase in Europe

Extended-spectrum β-lactamases (ESBLs) have continued to evolve after their initial detection in Europe nearly two decades ago. The summary results from the MYSTIC Program (31 medical centers) were utilized to assess the extent of ESBL occurrence in Europe from 1997 to 2000. ESBL phenotype rates in Klebsiella spp. (32.8%) and Escherichia coli (14.4%) were generally stable, but extensive hospital-to-hospital and unit-to-unit variations were noted. The highest ESBL rates were found in eastern Europe (including Turkey) and in intensive care unit patient populations. Carbapenems remained active against the ESBL-producing strains (meropenem MIC₉₀, 0.25–1 mg/L), while some other agents, such as aminoglycosides, fluoroquinolones, and piperacillin–tazobactam, were significantly less effective. International surveillance initiatives should be maintained to monitor future progression of this important resistance.     

In vitro activity of telithromycin (HMR 3647) against Greek Streptococcus pyogenes and Streptococcus pneumoniae clinical isolates with different macrolide susceptibilities

The susceptibilities to macrolides and telithromycin of 161 Streptococcus pyogenes and 145 Streptococcus pyogenes strains, consecutively isolated from five Greek hospitals, were determined by Etest. Moreover, mechanisms of resistance to macrolides were phenotypically and genetically determined by double disk induction test and PCR, respectively. Of the S. pneumoniae and S. pyogenes isolates, 42.8% and 30.8%, respectively, were found to be resistant to erythromycin. Of the erythromycin-resistant S. pneumoniae and S. pyogenes isolates, 57.5% and 59.5%, respectively, displayed the M phenotype and harbored the mefA/E gene. Telithromycin was found to be more active than both erythromycin and clarithromycin against both species, with considerably lower MIC₅₀ and MIC₉₀ values.