The fluoroquinolones, a new class of potent orally absorbed antimicrobial agents, are reviewed, considering structure, mechanisms of action and resistance, spectrum, variables affecting activity in vitro, pharmacokinetic properties, clinical efficacy, emergence of resistance, and tolerability. The primary bacterial target is the enzyme deoxyribonucleic acid gyrase. Bacterial resistance occurs by chromosomal mutations altering deoxyribonucleic acid gyrase and decreasing drug permeation. The drugs are bactericidal and potent in vitro against members of the family Enterobacteriaceae, Haemophilus spp., and Neisseria spp., have good activity against Pseudomonas aeruginosa and staphylococci, and (with several exceptions) are less potent against streptococci and have fair to poor activity against anaerobic species. Potency in vitro decreases in the presence of low pH, magnesium ions, or urine but is little affected by different media, increased inoculum, or serum. The effects of the drugs in combination with a beta-lactam or aminoglycoside are often additive, occasionally synergistic, and rarely antagonistic. The agents are orally absorbed, require at most twice-daily dosing, and achieve high concentrations in urine, feces, and kidney and good concentrations in lung, bone, prostate, and other tissues. The drugs are efficacious in treatment of a variety of bacterial infections, including uncomplicated and complicated urinary tract infections, bacterial gastroenteritis, and gonorrhea, and show promise for therapy of prostatitis, respiratory tract infections, osteomyelitis, and cutaneous infections, particularly when caused by aerobic gram-negative bacilli. Fluoroquinolones have also proved to be efficacious for prophylaxis against travelers9 diarrhea and infection with gram-negative bacilli in neutropenic patients. The drugs are effective in eliminating carriage of Neisseria meningitidis. Patient tolerability appears acceptable, with gastrointestinal or central nervous system toxicities occurring most commonly, but only rarely necessitating discontinuance of therapy. In 17 of 18 prospective, randomized, double-blind comparisons with another agent or placebo, fluoroquinolones were tolerated as well as or better than the comparison regimen. Bacterial resistance has been uncommonly documented but occurs, most notably with P. aeruginosa and Staphylococcus aureus and occasionally other species for which the therapeutic ratio is less favorable. Fluoroquinolones offer an efficacious, well-tolerated, and cost-effective alternative to parenteral therapies of selected infections.

Fluoroquinolone antimicrobial agents.

In Europe, antimicrobial resistance has been monitored since 1998 by the European Antimicrobial Resistance Surveillance System (EARSS). We examined the relationship between penicillin nonsusceptibility of invasive isolates of Streptococcus pneumoniae (an indicator organism) and antibiotic sales. Information was collected on 1998-99 resistance data for invasive isolates of S. pneumoniae to penicillin, based on surveillance data from EARSS and on outpatient sales during 1997 for betalactam antibiotics and macrolides. Our results show that in Europe antimicrobial resistance is correlated with use of beta-lactam antibiotics and macrolides. ntimicrobial resistance is a growing problem worldwide, requiring international approaches. The World Health Organization (WHO) and the European Commission have recognized the importance of studying the emergence and determinants of resistance and the need for strategies for its control (1-3). In European countries, antimicrobial resistance has been monitored in selected bacteria from humans since 1998 through the European Antimicrobial Resistance Surveillance System (EARSS). Funded by the European Commission, EARSS is an international network of national surveillance systems intended to collect comparable and reliable resistance data. The purpose of EARSS is to document variations in antimicrobial resistance over time and place and to provide the basis for and assess the effectiveness of prevention programs and policy decisions. One of the indicator organisms in EARSS is Streptococcus pneumoniae. It was included for three reasons: it is of major clinical importance for pneumonia, bacterial meningitis, and otitis media; many countries have reported that its resistance to penicillin is increasing; and S. pneumoniae is representative of organisms that are transmitted in the community. A major risk factor for the development of resistance is

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A European study on the relationship between antimicrobial use and antimicrobial resistance.

Combination antibiotic therapy for invasive infections with Gram-negative bacteria is employed in many health care facilities, especially for certain subgroups of patients, including those with neutropenia, those with infections caused by Pseudomonas aeruginosa, those with ventilator-associated pneumonia, and the severely ill. An argument can be made for empiric combination therapy, as we are witnessing a rise in infections caused by multidrug-resistant Gram-negative organisms. The wisdom of continued combination therapy after an organism is isolated and antimicrobial susceptibility data are known, however, is more controversial. The available evidence suggests that the greatest benefit of combination antibiotic therapy stems from the increased likelihood of choosing an effective agent during empiric therapy, rather than exploitation of in vitro synergy or the prevention of resistance during definitive treatment. In this review, we summarize the available data comparing monotherapy versus combination antimicrobial therapy for the treatment of infections with Gram-negative bacteria.

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

From 1995 to 2000, a total of 673 Enterococcus faecium and 1,088 Enterococcus faecalis isolates from pigs together with 856 E. faecium isolates from broilers were isolated and tested for susceptibility to four classes of antimicrobial agents used for growth promotion as part of the Danish program of monitoring for antimicrobial resistance. The four antimicrobials were avilamycin, erythromycin, vancomycin, and virginiamycin. Major changes in the use of antimicrobial agents for growth promotion have occurred during the last 6 years in Denmark. The government banned the use of avoparcin in 1995 and of virginiamycin in 1998. Furthermore, the producers have voluntarily stopped all use beginning in 1999. The avoparcin ban in 1995 was followed by a decrease in the occurrence of glycopeptide-resistant E. faecium (GRE) in broilers, from 72.7% in 1995 to 5.8% in 2000. The occurrence of glycopeptide resistance among isolates from pigs remained constant at around 20% from 1995 to 1997. It was shown that, in GRE from pigs, the genes encoding macrolide and glycopeptide resistance were genetically linked and that, following the decrease in the use of tylosin during 1998 and 1999, the occurrence of GRE in pigs decreased to 6.0% in 2000. From 1995 to 1997 the occurrence of erythromycin resistance among E. faecium and E. faecalis isolates from pigs was almost 90%. Use of tylosin decreased considerably during 1998 and 1999, and this decrease was followed by decreases in the occurrence of resistance to 46.7 and 28.1% among E. faecium and E. faecalis isolates from pigs, respectively. Erythromycin resistance among E. faecium isolates from broilers reached a maximum of 76.3% in 1997 but decreased to 12.7% in 2000 concomitantly with more limited use of virginiamycin. Use of virginiamycin increased from 1995 to 1997 and was followed by an increased occurrence of virginiamycin resistance among E. faecium isolates in broilers, from 27.3% in 1995 to 66.2% in 1997. In January 1998 the use of virginiamycin was banned in Denmark, and the occurrence of virginiamycin resistance decreased to 33.9% in 2000. Use of avilamycin increased from 1995 to 1996 and was followed by an increase in avilamycin resistance among E. faecium isolates from broilers, from 63.6% in 1995 to 77.4% in 1996. Since 1996 avilamycin usage has decreased, followed by a decrease in resistance to 4.8% in 2000. Our observations show that it is possible to reduce the occurrence of antimicrobial resistance in a national population of food animals when the selective pressure is removed. Cases in which resistance to vancomycin was linked to resistance to erythromycin were exceptions. In such cases resistance did not decrease until the use of both avoparcin and tylosin was limited.

http://www.ouvertures.net/wp-content/uploads/AAC_01_45_2054.pdf

Effect of Abolishment of the Use of Antimicrobial Agents for Growth Promotion on Occurrence of Antimicrobial Resistance in Fecal Enterococci from Food Animals in Denmark

Sociological interest in pharmaceuticals has intensified, heightening awareness of `pharmaceuticalization. It is argued that pharmaceuticalization should be understood by reference to five main biosociological explanatory factors: biomedicalism, medicalization, pharmaceutical industry promotion and marketing, consumerism, and regulatory-state ideology or policy. The biomedicalism thesis, which claims that expansion of drug treatment reflects advances in biomedical science to meet health needs, is found to be a weak explanatory factor because a significant amount of growth in pharmaceuticalization is inconsistent with scientific evidence, and because drug innovations offering significant therapeutic advance have been declining across the sector, including areas of major health need. Some elements of consumerism have undermined pharmaceuticalization, even causing de-pharmaceuticalization in some therapeutic sub-fields. However, other aspects of consumerism, together with industry promotion, medicalization, and deregulatory state policies are found to be drivers of increased pharmaceuticalization in ways that are largely outside, or sub-optimal for, significant therapeutic advances in the interests of public health.

Pharmaceuticalization of Society in Context: Theoretical, Empirical and Health Dimensions

The correlation between antibiotic consumption, expressed in defined daily doses (DDD), and antibiotic resistance rates was studied, using 976 isolates of coagulase negative staphylococci (CNS) from human pathological material. Data from four hospitals, including 14 participating departments, were analysed for this purpose. Susceptibility tests were performed according to Dutch national standards, except for methicillin, which for the majority of isolates was tested according to adapted NCCLS standards. Resistance to methicillin was most frequent in Staphylococcus epidermidis (29%) and S. haemolyticus (16%). Among the departments, thoracic surgery (29-47%), surgical intensive care (68%) and neonatology (32%) scored highest. Significant correlations were found between percentages of methicillin resistance in CNS and consumption (DDD/month/bed) of (flu)cloxacillin (P0.008), of cephalosporins (P0.01) and of gentamicin (P0.005). (Flu)cloxacillin was used mainly prophylactically, cephalosporins and gentamicin therapeutically. Results were similar for S. epidermidis (n = 639) alone. There was no significant correlation between consumption and resistance to trimethoprim, erythromycin (P0.08) or gentamicin (P0.09). Analysis of data from individual patients showed significant differences in proportions of methicillin resistance rates in CNS, between use and non-use of penicillinase resistant beta-lactams or gentamicin. It is concluded that clinical use of both (flu)cloxacillin and cephalosporins selects for methicillin resistant CNS.

Correlations between consumption of antibiotics and methicillin resistance in coagulase negative staphylococci

Penicillinase-producing Neisseria gonorrhoeae strains were isolated in the Netherlands with increasing frequency during the period of 1976 to 1979. About 3% of the gonococci isolated in the first half of 1979 produced penicillinase. In contrast to the period of 1976 to 1977, most penicillinase-producing N. gonorrhoeae infections during the period of 1978 to 1979 were contracted in the Netherlands. The results of genetic and molecular studies on 80 penicillinase-producing N. gonorrhoeae strains were similar to earlier observations of others: resistance plasmids of only two sizes, 4.5 and 3.3 megadaltons (Md), occurred in penicillinase-producing N. gonorrhoeae strains, and these encoded for the TEM-1 enzyme. The 4.5-Md plasmid could be transferred to Escherichia coli when it coexisted with a plasmid of 24 Md. The latter plasmid was present in the vast majority of the strains carrying the 4.5-Md plasmid. One strain carried a cryptic 7.5-Md plasmid in addition to the commonly found 2.5-Md plasmid. Two penicillinase-producing strains of Haemophilus parainfluenzae isolated were found to carry a 3.3-Md plasmid species which was indistinguishable from the 3.3-Md gonococcal resistance plasmids. No plasmid deoxyribonucleic acid was found in two strains of penicillinase-producing Branhamella catarrhalis, and these strains produced a penicillinase different from the TEM-1 enzyme.

Penicillinase-producing Neisseria gonorrhoeae in the Netherlands: epidemiology and genetic and molecular characterization of their plasmids.

OBJECTIVE: To evaluate the prevalence and epidemiology of penicillinase producing Neisseria gonorrhoeae (PPNG) and tetracycline resistant N gonorrhoeae (TRNG) in the period 1977-95 in the Netherlands. To compare auxotypes, serovars, and antibiograms of PPNG, non-PPNG, and TRNG. To identify determinants in patient characteristics for the epidemic spread of TRNG/PPNG. METHODS: With respect to the national gonococcal surveillance all PPNG isolates from 30 laboratories over the country in 1977-90 and all gonococcal isolates from five sentinel laboratories (during 1 month per quarter) in 1991-5 were collected. Isolates were auxotyped and serotyped, the susceptibility for various antibiotics was tested and plasmid contents were evaluated. Additional data on PPNG infected individuals were collected retrospectively during a microepidemic of TRNG/PPNG. Univariate and multivariate analyses were performed to identify risk factors for TRNG/PPNG infections. RESULTS: In 1995 an overall high prevalence of PPNG infection (27%) and TRNG among PPNG infection (24%) was found in the Netherlands. Importantly, PPNG were found to have higher MICs for ceftriaxone and ciprofloxacin than non-PPNG; clinically relevant resistance to these antibiotics (or related agents) may emerge first among these strains. The observed diversity of strains (123 auxo/serovar classes since 1988) indicates a continuous introduction of new strains into the community. The epidemic increase of TRNG/PPNG was mainly caused by A/S classes NR/1B-6, PRO/1A-3, and PRO/1A-6, suggesting a clonal spread of a few strains; the rapid spread was associated with transmission in high risk individuals (that is, prostitutes and their clients). CONCLUSION: The prevalence of PPNG in the Netherlands remains high and reduced sensitivity to other antimicrobials was detected among the PPNG strains. This underlines the necessity for a continuous national surveillance of resistance in gonococci including limited epidemiological information.

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B. Van Klingeren

Papers

Correlations between consumption of antibiotics and methicillin resistance in coagulase negative staphylococci

Penicillinase-producing Neisseria gonorrhoeae in the Netherlands: epidemiology and genetic and molecular characterization of their plasmids.

Surveillance of antibiotic resistance in Neisseria gonorrhoeae in The Netherlands, 1977-95.

Emergence in the Netherlands of penicillinase-producing gonococci carrying "Africa" plasmid in combination with transfer plasmid.

Outbreak of multiresistant non-encapsulated Haemophilus influenzae infections in a pulmonary rehabilitation centre.