F.-J. Schmitz

Activities of the Glycylcycline Tigecycline (GAR-936) against 1,924 Recent European Clinical Bacterial Isolates

ABSTRACT The in vitro activities of tigecycline against 1,924 clinical isolates were examined. The new glycylcycline exhibited excellent activity against all gram-positive cocci (MICs at which 90% of the isolates tested were inhibited [MIC90s], ≤1 μg/ml). In addition, it was also very potent against most members of the Enterobacteriaceae, with most MIC90s being ≤2 μg/ml. Among the nonfermenters, Acinetobacter spp. and Stenotrophomonas maltophilia are included in the in vitro spectrum of tigecycline activity.

Frequency of Isolation of Pathogens from Bloodstream, Nosocomial Pneumonia, Skin and Soft Tissue, and Urinary Tract Infections Occurring in European Patients

Abstract The frequency of isolation of pathogens that cause different types of infections is an important guide for empiric therapy. As part of the SENTRY Antimicrobial Surveillance Program, the frequency of isolation of different bacterial species from bloodstream, nosocomial pneumonia, skin and soft tissue, and urinary tract infections occurring in European patients was determined. A total of 15,704 isolates were collected in 1997 and 1998 from 24 university hospitals in 14 European countries: 9,194 from bloodstream, 2,052 from nosocomial pneumonia, 2,320 from skin and soft tissue, and 2,138 from urinary tract infections. More than 95% of all bacterial infections were caused by only 15 different genera. Staphylococcus spp. and Escherichia spp. accounted for more than 50% of the infectious isolates, with the exception of those obtained from cases of nosocomial pneumonia. In the latter type of infection, isolates belonging to these two genera were responsible for 30% of the infections. An analysis at the individual species level showed that Escherichia coli caused a large proportion of bloodstream and urinary tract infections (20.8% and 49.3% of isolates, respectively). Staphylococcus aureus was the main causative species for nosocomial pneumonia and skin and soft tissue infections (21.5% and 37.4% of isolates, respectively). In addition, Pseudomonas aeruginosa played an important role in all types of infection analyzed.

Frequency of Isolation and Antimicrobial Resistance of Gram-Negative and Gram-Positive Bacteria from Patients in Intensive Care Units of 25 European University Hospitals Participating in the European Arm of the SENTRY Antimicrobial Surveillance Program 1997-1998

Abstract.A total of 3,981 isolates from patients treated at intensive care units were collected in 25 European university hospitals during 1997 and 1998 as part of the SENTRY Antimicrobial Surveillance Program. Overall, the most important species isolated were Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, coagulase-negative staphylococci (CNS), Enterobacter spp., Haemophilus influenzae, Streptococcus pneumoniae, and Enterococcus faecalis. Thirty-nine percent of all Staphylococcus aureus isolates were resistant to oxacillin. All Staphylococcus aureus isolates were fully susceptible to linezolid and vancomycin. Moreover, all CNS isolates were susceptible to vancomycin and minocycline. All Enterococcus faecalis isolates were susceptible to vancomycin, and 99% of these isolates were also susceptible to ampicillin. The antimicrobial agents most effective against Pseudomonas aeruginosa isolates were amikacin, piperacillin/tazobactam, meropenem, and cefepime, with 87, 85, 84, and 83% of isolates being susceptible, respectively. Escherichia coli isolates were fully susceptible to carbapenems, and at least 99% of these isolates were susceptible to ceftriaxone, cefepime, and amikacin. The Enterobacter spp. were also highly susceptible to carbapenems, amikacin, and cefepime, with 99, 97, and 96% of isolates being susceptible, respectively. Haemophilus influenzae was susceptible to most of the antibiotics tested. Only 68% of the pneumococcal isolates were fully susceptible to penicillin, yet 100% were susceptible to a number of fluoroquinolones and vancomycin. There are still sufficient treatment options for patients infected with the most important bacterial species involved in infections in intensive care units. However, the situation for patients with Pseudomonas aeruginosa infections is critical.

Mutations in GyrA, ParC, MexR and NfxB in clinical isolates of Pseudomonas aeruginosa

The target enzymes GyrA and ParC and two efflux pump regulatory genes mexR and nfxB were analysed to determine changes associated with fluoroquinolone resistance in Pseudomonas aeruginosa. Both low- and high-level ciprofloxacin resistance was associated with a Thr-83Ile substitution in GyrA. A ParC Ser-80Leu substitution was found in highly resistant isolates in tandem with the Thr-83Ile substitution in GyrA. Mutations in the efflux regulatory genes were associated with resistance only when in tandem with a mutation in GyrA or ParC. These data show that the main mechanism of fluoroquinolone resistance in P. aeruginosa is mediated primarily through mutations in GyrA, and that mutations in ParC and the efflux regulatory genes are secondary.

Fluoroquinolones: Structure and Target Sites

The quinolones are a potent group of drugs that target the essential bacterial enzymes DNA gyrase and topoisomerase IV. DNA gyrase is the primary target of Gram negative organisms however, it is topoisomerase IV that is the primary target of Gram positive organisms. Within these enzymes is a highly conserved region centered round the active site where resistance mutations occur. These mutations are almost always identical, irrespective of organism. In spite of the homology of this region, amino acid sequence analysis shows that there are defined differences between the Gram groups, particularly in topoisomerase IV, and it is speculated that herein lies the origin of target preference. Since the first quinolone nalidixic acid was developed, the quinolones have undergone structural modifications, in particular the addition of a fluorine at position 6, to produce the fluoroquinolones. This has seen their potency and pharmakokinetic profile greatly increase. In vitro selection of resistance mutations has allowed the observation of how resistance is acquired and some of the modifications in newer fluoroquinolones have resulted in the shift of primary target from topoisomerase IV to gyrase with Gram positives. Curiously, purified topoisomerase IV is still more sensitive even if gyrase is the primary target. Gyrase remains the primary target for Gram negatives.

Frequency of occurrence and Antimicrobial susceptibility of bacterial pathogens associated with skin and soft tissue infections during 1997 from an international Surveillance Programme

Abstract The SENTRY Antimicrobial Surveillance Programme was established to provide a coordinated, standardised, international surveillance on antimicrobial resistance. In one part of the programme, isolates from skin and soft tissue infections sent from 20 hospitals in 12 different European countries were investigated in the European coordinating centre. Of 1013 isolates, Staphylococcus aureus and Pseudomonas aeruginosa were the most significant species, constituting almost 50% of the referred isolates. Methicillin resistance in Staphylococcus aureus averaged 22% across Europe, only slightly less than that in isolates derived from blood. Less than 5% of the enterococcal isolates were resistant to vancomycin. Piperacillin/tazobactam was the most active penicillin-derived β-lactam compound against Pseudomonas aeruginosa, inhibiting 91.3% of the isolates, while ceftazidime and cefepime were the most active cephalosporins, inhibiting 85.8% and 80.3% of the isolates, respectively. Putative extended-spectrum β-lactamase production was not detected in Escherichia coli and was found in only 5.1% of the Klebsiella pneumoniae isolates. In general, strains of the family Enterobacteriaceae remained mostly susceptible to carbapenems, cefepime, and amikacin.

Prevalence of aminoglycoside resistance in 20 European university hospitals participating in the European SENTRY Antimicrobial Surveillance Programme.

Abstract The aim of this study was to analyse the current prevalence of aminoglycoside resistance in Europe and compare the in vitro activity of amikacin, gentamicin, and tobramycin against 7057 bacterial isolates from 20 university hospitals participating in the European SENTRY Antimicrobial Surveillance Programme. Amikacin exhibited better in vitro activity than tobramycin and gentamicin against most gram-negative bacilli in Europe. The resistance levels were 0.4–3% for amikacin, 2–13.1% for gentamicin, and 2.5–15.3% for tobramycin among different members of the family Enterobacteriaceae. Of the Staphylococcus aureus isolates tested, 75% were susceptible to gentamicin. Only 21% of all enterococcal strains tested were fully susceptible to gentamicin. Although intra-country variations in the prevalence of resistance phenotypes in Escherichia coli, Klebsiella spp., and Pseudomonas aeruginosa as well as in staphylococci and enterococci did occur, aminoglycoside resistance rates were generally higher in Italy, Portugal, Spain, Greece, France, the UK, and Poland than in Austria, Belgium, Germany, the Netherlands, and Switzerland. Compared with the 1987–88 data of the European Study Group on Antibiotic Resistance, gentamicin resistance has increased up to 5% in some gram-negative bacterial species. Furthermore, a greater than 10% increase in resistance to gentamicin has been seen in Staphylococcus aureus during the last decade. The reason for this observation is unclear, although changes in antibiotic prescribing patterns that result in increased selective pressure from gentamicin may have contributed to these increased rates of aminoglycoside resistance.

In Vitro Development of Resistance to Six Quinolones in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus

ABSTRACT Streptococcus pneumoniae, Streptococcus pyogenes, andStaphylococcus aureus isolates were exposed to subinhibitory MICs of ciprofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, clinafloxacin, and gemifloxacin during a 10-day period. Subculturing led to resistance development, regardless of the initial potencies of the quinolones. None of the quinolones was associated with a significantly slower rate of resistance development.

Antimicrobial resistance in European isolates of Pseudomonas aeruginosa

Abstract Pseudomonas aeruginosa is responsible for a substantial fraction of hospital infections. Twenty-five European university hospitals submitted a total of 1411 Pseudomonas aeruginosa isolates for susceptibility testing during 1997 and 1998. The isolates showed highest susceptibility to amikacin (87.5%), meropenem (87.3%) and piperacillin/tazobactam (86.8%). Susceptibility to ciprofloxacin was 73.2%. There was no clear geographical distribution of resistance, although isolates from northwestern Europe tended to be more susceptible than those from southeastern Europe. Isolates that were resistant to one class of antibiotics were also often resistant to at least one other class of antibiotics. Imipenem-resistant isolates were generally not clonally related.

Distribution of macrolide-resistance genes in Staphylococcus aureus blood-culture isolates from fifteen German university hospitals.

Abstract The purpose of the study was to analyze the distribution of the macrolide-resistance genes in 134 erythromycin-resistant Staphylococcus aureus blood-culture isolates collected at 15 German university hospitals. The most prevalent resistance gene was ermC (68/134; 50.7%), followed by ermA (52/134; 38.8%), ereB (10/134; 7.5%), and mrsA/msrB (4/134; 6%). The least common genes were ermB (3/134; 2.2%) and ereA (1/134; 0.7%). Overall, resistance to erythromycin was predominantly due to the presence of two erm genes, although with different distributions, depending on the methicillin-resistance pattern.