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.     

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.     

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.     

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 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.     

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 activity of evernimicin and selected antibiotics against methicillin-resistant staphylococci: a 24-country study

Objective   To collect and analyze data on susceptibility of methicillin-resistant staphylococci to evernimicin and other antimicrobial agents.
Methods   Recent clinical isolates of methicillin-resistant staphylococci from 33 laboratories in North America, Europe and South Africa were investigated.
Results   Of the antimicrobial agents tested, evernimicin had the lowest MIC₉₀s for methicillin-resistant Staphylococcus aureus and methicillin-resistant coagulase-negative staphylococci (0.75 and 1.0 mg/L, respectively). Resistance to ciprofloxacin and erythromycin was widespread, with higher levels of resistance in North America than in other regions.
Conclusions   Susceptibility surveys help to determine the antimicrobial activity of new agents. Ciprofloxacin- and erythromycin-resistant staphylococci were prevalent throughout all regions.     

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).     

Prevalence of erm methylase genes in clinical isolates of non-pigmented, rapidly growing mycobacteria

The aim of this study was to determine the frequency of erm genes coding for macrolide resistance among clinical isolates of non-pigmented rapidly growing mycobacteria (NPRGM) and to evaluate their importance in phenotypic resistance. Broth microdilution susceptibility testing was performed for all NPRGM tested. A PCR assay with consensus primers was used to evaluate the presence of erm genes among the 167 clinical isolates studied, which belonged to nine species of NPRGM; erm genes were detected in all nine species and 109 strains were erm -positive. The highest percentage of erm -positive isolates was found among Mycobacterium mageritense (100%) and the lowest among Mycobacterium mucogenicum (14%). The MICs of macrolides were found to be lower for erm -negative isolates (MIC₉₀: 2 mg/L) than for erm- positive isolates (MIC₉₀: 16 mg/L), although in some cases high MICs were found for erm -negative isolates. The finding that erm methylases are present in the majority of the species of NPRGM analysed in this study is not in agreement with conventional susceptibility studies. It therefore appears necessary to use a combination therapy to treat infections caused by NPRGM.     

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 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.     

Susceptibility of strains of Streptococcus agalactiae to macrolides and lincosamides, phenotype patterns and resistance genes

The Group B streptococcus ( Streptococcus agalactiae ) is a pathogen of increasing importance in human disease. We therefore studied the susceptibility of clinical isolates of S. agalactiae to penicillin G, erythromycin, azithromycin and clindamycin using National Committee for Clinical Laboratory Standards methodology, and we also determined the phenotypes of macrolide-lincosamide susceptibility and the resistance genes implicated in a group of selected isolates of the different phenotypes. We used 221 isolates collected between 1997 and 1999 in two Health Authority Areas in Móstoles and Granada, Spain. The minimal concentration for 90% inhibition (MIC₉₀) for penicillin G was 0.12 mg/L and all the isolates tested were susceptible. One hundred and eighty-five (83.7%) were susceptible to erythromycin and azithromycin and 191 (86.4%) were susceptible to miocamycin and clindamycin. Twenty-three isolates (10.4%) had a constitutive MLS_B phenotype, seven (3.2%) an inducible phenotype, and six (2.7%) an M phenotype. All except one of the MLS_B phenotype isolates tested ( n  = 23) carried erm genes; in two strains with the mef (A) gene, all the M phenotype ( n  = 6) isolates tested carried mef genes, while erm and mef (A) genes were absent in all the macrolide-lincosamide-susceptible ( n  = 12) isolates tested. In our environment, resistance to macrolide and lincosamide in S. agalactiae was present in 10–16% of the isolates. The majority of resistant strains had the MLS_B phenotype.     

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.     

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.     

In vitro activity of gatifloxacin, a new fluoroquinolone, against 204 anaerobes compared to seven other compounds

The activity of gatifloxacin, a new fluoroquinolone derivative, was compared with the activities of ciprofloxacin, levofloxacin, amoxicillin, amoxicillin–clavulanate, imipenem, clindamycin and metronidazole against 204 anaerobes isolated from clinical specimens, by MIC determination, using the reference agar dilution method. When determining the overall activity against anaerobes, the MIC_50/90 (mg/L) values were amoxicillin 16/>64, amoxicillin–clavulanate 0.125/1, imipenem 0.25/0.5, clindamycin 0.5/>256, metronidazole 1/8, ciprofloxacin 2/32, levofloxacin 1/8 and gatifloxacin 0.5/4. The broad in vitro spectrum of gatifloxacin is promising for the treatment of mixed anaerobic infections, especially those of the respiratory tract, ear, sinus, skin and soft tissues, and bite wounds. These data suggest that gatifloxacin may have a clinical role in the treatment of infections in which anaerobic pathogens are involved.     

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.     

Pharyngeal colonization prevalence rates for Streptococcus pyogenes and Streptococcus pneumoniae in a respiratory chemoprophylaxis intervention study using azithromycin

Objectives   A prospective assessment of the pharyngeal colonization prevalence rates for Streptococcus pyogenes and Streptococcus pneumoniae before and after an azithromycin chemoprophylaxis intervention clinical trial in a cohort of US Marine Corps trainees. In addition, the minimum inhibitory concentrations (MICs) for all streptococcal isolates, for azithromycin, penicillin, erythromycin and cefotaxime are reported.
Methods   Between November 1994 and March 1995, 1108 asymptomatic male US Marine Corps trainees, located in Southern California, were randomly assigned to one of three intervention groups: (1) weekly oral azithromycin, 500 mg ( n  = 362); (2) 1.2 MU benzathine penicillin G, intramuscularly once ( n  = 374); or (3) no chemoprophylaxis ( n  = 372). Subjects provided both a pre- and post-training pharyngeal culture and microbial analysis was conducted to determine the colonization status of each study subject.
Results   The pretraining colonization prevalence was 1.2% for S. pneumoniae and 2.4% for S. pyogenes . There was no statistical difference in pretraining prevalence between the three treatment groups for either organism. Post-training pharyngeal cultures revealed an overall prevalence of 1.1% with no difference between treatment arms. However, the overall post-training prevalence of S. pyogenes colonization increased to 4.8%, with the azithromycin group having significant evidence of protection (0.7%) in comparison with the no-treatment group (8.2%). The Etest method demonstrated no significant difference in the MIC₅₀, MIC₉₀, and MIC ranges between pre- and post-training isolates for any of the tested drugs.
Conclusion The use of azithromycin as a chemoprophylactic agent to reduce the colonization and subsequent infection of streptococcal respiratory disease among healthy adult male military recruits may be beneficial.     

Highly antibiotic-resistant Acinetobacter baumannii clinical isolates are killed by the green tea polyphenol (–)-epigallocatechin-3-gallate (EGCG)

Acinetobacter baumannii is an increasingly common cause of infection in intensive-care units throughout the world, and the occurrence of multiresistant A. baumannii is increasing. The aim of this study was to determine whether a highly purified polyphenol, (–)-epigallocatechin-3-gallate (EGCG), from green tea ( Camellia sinesis ), had antimicrobial effects against multiresistant clinical isolates of A. baumannii. Standard microplate assays were performed to determine the MIC of EGCG for 21 clinical isolates of A. baumannii. MICs ranged from 0.078 to 0.625 mg/mL, with MIC₅₀ and MIC₉₀ of 0.312 mg/mL and 0.625 mg/mL, respectively. All of the isolates of A. baumannii tested were killed by EGCG. In time-kill assays, EGCG resulted in a 3-log reduction in CFU/mL of A. baumannii after 5 h of incubation with the polyphenol. Synergy between the commonly used topical agent 5% mafenide acetate (Sulfamylon) and EGCG was noted for one clinical isolate, and partial synergy was noted for three other isolates. These findings demonstrate that EGCG is an effective bactericidal agent against antibiotic-resistant A. baumannii clinical strains in laboratory settings. EGCG has previously been shown to be safe, and therefore may be an attractive addition for the treatment of cutaneous A. baumannii infections where high concentrations of the drug can be applied to the wound surface.     

Antimicrobial Activity of SCH 27899, Oligosaccharide Member of the Everninomycin Class with a Wide Gram-Positive Spectrum

The in vitro antimicrobial activity of SCH 27899 (everninomycin), a novel oligosaccharide compound of the everninomycin class, was compared with vancomycin, chloramphenicol, clinafloxacin, teicoplanin and doxycycline against 428 clinical strains of bacteria. Everninomycin base exhibited the greatest antimicrobial activity compared to other formulations against all strains tested (MIC₉₀: 0.25 μ/ml) followed by clinafloxacin and teicoplanin (MIC₉₀: 0.5 μg/ml), vancomycin (MIC₉₀: 2 μg/ml), and doxycycline (MIC₉₀: 16 μg/ml). Everninomycin demonstrated the best activity against Streptococcus spp. (serogroups A, B, C, F, G) and Streptococcus pneumoniae , and lower activity against coagulase-negative staphylococci (MIC₉₀: 0.5 μg/ml). All enterococci had an everninomycin MIC of 0.5 μg/ml or less. Everninomycin had no measurable antimicrobial activity against gram-negative aerobic organisms except Flavo-bacterium meningosepticum (MIC₅₀: 2 μg/ml). Some everninomycin activity was observed against Clostridium spp., Peptostreptococcus spp., and the Prevotella bivius-disiens group. Everninomycin showed excellent activity (MIC₉₀: 0.25 μg/ml) against the fluoroquinolone-resistant strains and all gram-positive strains resistant to vancomycin (MICs 4 μg/ml). The MBC/MIC ratios and killing curve data suggest that everninomycin is not uniformly or rapidly bactericidal. These in vitro data indicate that everninomycin could be useful against emerging gram-positive strains resistant to other contemporary antimicrobials.     

Antimicrobial resistance in viridans group streptococci among patients with and without the diagnosis of cancer in the USA, Canada and Latin America

Objective   To investigate antimicrobial resistance in viridans group streptococci (VGS) among patients with and without the diagnosis of cancer in the USA, Canada and Latin America.
Methods   All bloodstream isolates of VGS collected from SENTRY centers in the Western Hemisphere between January 1997 and December 1999 were tested by reference broth microdilution methods (NCCLS). Results for isolates from patients with cancer were compared to those from other patient populations.
Results   Overall, 438 unique patient bloodstream isolates of VGS were collected during the study. Percentage susceptible/MIC₉₀ (mg/L) values for antimicrobials tested were as follows: penicillin, 66/1; erythromycin, 60/4; clindamycin, 92/0.12; cefepime, 86/1; trimethoprim–sulfamethoxazole, 80/2; ciprofloxacin, 44/> 2; gatifloxacin, 98/0.5; and vancomycin, 100/1. Of these isolates, 70 (16%) were confirmed to be from cancer patients. VGS isolates from cancer patients were less susceptible to most antimicrobials tested than were isolates from non-cancer patients. The greatest differences in susceptibility rates for cancer- versus non-cancer-associated VGS isolates were seen for ciprofloxacin (34% versus 46%, P  = 0.07) and trimethoprim–sulfamethoxazole (64% versus 83%, P  < 0.001), two agents which are often used for prophylaxis or as presumptive therapy in cancer patients.
Conclusions   Susceptibility rates for VGS isolates from cancer patients are lower than those for isolates from patients without a cancer diagnosis. These differences are greatest for agents that have seen widespread prophylactic and empirical use. Ongoing surveillance of VGS infections in this patient population is important and should help to guide therapy decisions.