Showing papers on "Quinolone published in 2000"

New classification and update on the quinolone antibiotics.

Abstract: The newer fluoroquinolones have broad-spectrum bactericidal activity, excellent oral bioavailability, good tissue penetration and favorable safety and tolerability profiles. A new four-generation classification of the quinolone drugs takes into account the expanded antimicrobial spectrum of the more recently introduced fluoroquinolones and their clinical indications. First-generation drugs (e.g., nalidixic acid) achieve minimal serum levels. Second-generation quinolones (e.g., ciprofloxacin) have increased gram-negative and systemic activity. Third-generation drugs (e.g., levofloxacin) have expanded activity against gram-positive bacteria and atypical pathogens. Fourth-generation quinolone drugs (currently only trovafloxacin) add significant activity against anaerobes. The quinolones can be differentiated within classes based on their pharmacokinetic properties. The new classification can help family physicians prescribe these drugs appropriately.

Evidence for Active Efflux as the Primary Mechanism of Resistance to Ciprofloxacin in Salmonella enterica Serovar Typhimurium

Abstract: Fluoroquinolones are often the treatment of choice in the cases of life-threatening salmonellosis due to multidrug-resistant strains (4, 27) Salmonella sp strains that exhibit treatment-compromising resistance to fluoroquinolones are uncommon, but the increasing incidence of strains with decreased susceptibility is a matter of concern (12, 28) In other gram-negative bacteria, such as Escherichia coli, Neisseria gonorrhoeae, or Klebsiella pneumoniae, high-level fluoroquinolone resistance is always associated with the presence of multiple mutations in the quinolone resistance-determining regions (QRDRs) of the genes that code for the intracellular targets of these antibiotics, gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) (2, 7, 11) For Salmonella enterica serovar Typhimurium, however, we showed in a previous study (9) that fluoroquinolone resistance is not well correlated with the presence of such mutations: highly fluoroquinolone-resistant mutants selected in vitro had no mutations in the genes that code for topoisomerase IV, and some had only one mutation in the gyrA gene, whereas E coli isolates that exhibited the same level of resistance harbored at least two mutations in gyrA and one in parC (11) In addition to this mechanism of target modification that is strictly specific to quinolones, gram-negative bacteria can face the presence of toxic compounds, including antibiotics, by excluding them from the cell Changes in the cell envelope, including loss of outer membrane porins or alterations of the lipopolysaccharide (LPS), can be partially responsible for decreased susceptibility to a wide range of unrelated antibiotics (5, 26) Active efflux systems that act synergistically with the outer membrane could have a high level of participation in the intrinsic and the acquired antibiotic resistance of gram-negative bacteria (16, 22) Some of the multidrug efflux pumps, which belong to several families, exhibit a low specificity and thus confer decreased susceptibility or even clinically significant resistance to several classes of antibiotics when they are overexpressed It was recently shown that an S enterica serovar Typhimurium mutant that overproduces the AcrAB efflux pump (initially identified in E coli as a close homolog of the MexAB efflux system of Pseudomonas aeruginosa) was more resistant than the parent strain to a wide variety of compounds such as fusidic acid, chloramphenicol, tetracycline, norfloxacin, and penicillin G (23) The goal of the present study was to investigate if additional resistance mechanisms such as decreased cell envelope permeability or active efflux could explain the phenotype of S enterica serovar Typhimurium mutants that were selected in vitro and that reached different levels of resistance to fluoroquinolone but that harbored not more than one gyrA mutation (9)

In vitro antibacterial spectrum of a new broad-spectrum 8-methoxy fluoroquinolone, gatifloxacin

Abstract: The in vitro antibacterial spectrum of gatifloxacin was compared with those of ciprofloxacin and ofloxacin. Gatifloxacin was two- to four-fold more potent than comparator quinolones against staphylococci, streptococci, pneumococci and enterococci (gatifloxacin MIC 90 s, ≤1 mg/L, except 4 mg/L against methicillin-resistant Staphylococcus aureus and Enterococcus faecium). Gatifloxacin was two-fold less potent than ciprofloxacin, and the same as or two-fold more potent than ofloxacin against Enterobacteriaceae (MIC 90 s, 0.06-0.5 mg/L against most members of the Enterobacteriaceae and ≤ 1 mg/L against Proteus/Morganella spp.). Relative to the comparator quinolones, gatifloxacin was two- to four-fold more potent against Providencia spp., and had good potency against Acinetobacterspp. (MIC 90 s, 0.25-1 mg/L). Gatifloxacin and ofloxacin had similar anti-pseudomonal potency, with corresponding MIC 90 s of 4, 8 and 0.25 mg/L for Pseudomonas aeruginosa, Pseudomonas fluorescens and Pseudomonas stutzeri, while ciprofloxacin had two- to eight-fold more potency. The three quinolones were equipotent against Burkholderia cepacia (MIC 90 s, 8 mg/L), but gatifloxacin was two-fold more potent against Stenotrophomonas maltophilia (MIC 90 , 4 mg/L). Gatifloxacin was highly potent (MIC 90 s, 0.03-0.06 mg/L) against Haemophilus influenzae, Legionella spp., Helicobacter pylori and had at least eight-fold better anti-chlamydial and anti-mycoplasma potency (gatifloxacin MIC 90 s, 0.13 mg/L). The higher quinolone MICs for ureaplasma (MIC 90 s, 4-8 mg/L) may be due to the acidic pH of the ureaplasma test medium, which antagonizes quinolones. Like other quinolones, gatifloxacin had poor potency against Mycobacterium avium-intracellulare, though it was eight- to 16-fold more potent against Mycobacterium tuberculosis (MIC 90 , 0.25 mg/L). Of the three quinolones, only gatifloxacin had activity against Bacteroides fragilis and Clostridium difficile. In summary, gatifloxacin is a broad-spectrum 8-methoxy fluoroquinolone that is more potent than ciprofloxacin and ofloxacin against Gram-positive bacteria, chlamydia, mycoplasma, mycobacteria and anaerobes.

Chemistry and Mechanism of Action of the Quinolone Antibacterials

Abstract: Publisher Summary Quinolone agents exhibit a bicyclic aromatic core, containing a carbon at the 8th position, yielding a true quinolone, or a nitrogen, and provide a ring system technically termed as naphthyridone. In common usage, both quinolone and naphthyridone structures are encompassed in the class descriptor “quinolone antibacterial agents.” The first generation quinolone compounds generally displayed increased Gram-negative activity over nalidixic acid, but lacked useful activity against Gram-positive cocci, Pseudomonas aeruginosa, and anaerobes. They were, however, generally well absorbed after oral administration and attained high concentrations in the urinary tract, making them useful therapeutically for treatment of urinary tract infections. In the second-generation quinolones, the piperazine ring remains relatively undisturbed, except for alkylation on the distal nitrogen or, less frequently, on the ring carbons. The second-generation compounds are characterized by good to excellent Gram-negative activity, with ciprofloxacin exhibiting the strongest Gram-negative spectrum. The third- and fourth-generation quinolones are characterized by increased structural novelty and complexity, which has resulted in new and useful characteristics. Clinafloxacin, sitafloxacin, and BAY y 3118, all of which bear a chlorine atom at C-8, are among the most potent broad-spectrum agents that have been in the development, and are the only compounds that exhibit Gram-negative activity superior to that of ciprofloxacin. These compounds, with the exception of pazufloxacin, show improved activity against S. pneumoniae compared to ciprofloxacin. The most potent of these agents are gemifloxacin and BAY y 3118, followed by clinafloxacin, sitafloxacin, moxifloxacin, and trovafloxacin.

Engineering the Specificity of Antibacterial Fluoroquinolones: Benzenesulfonamide Modifications at C-7 of Ciprofloxacin Change Its Primary Target in Streptococcus pneumoniae from Topoisomerase IV to Gyrase

Abstract: We have examined the antipneumococcal mechanisms of a series of novel fluoroquinolones that are identical to ciprofloxacin except for the addition of a benzenesulfonylamido group to the C-7 piperazinyl ring. A number of these derivatives displayed enhanced activity against Streptococcus pneumoniae strain 7785, including compound NSFQ-105, bearing a 4-(4-aminophenylsulfonyl)-1-piperazinyl group at C-7, which exhibited an MIC of 0.06 to 0.125 μg/ml compared with a ciprofloxacin MIC of 1 μg/ml. Several complementary approaches established that unlike the case for ciprofloxacin (which targets topoisomerase IV), the increased potency of NSFQ-105 was associated with a target preference for gyrase: (i) parC mutants of strain 7785 that were resistant to ciprofloxacin remained susceptible to NSFQ-105, whereas by contrast, mutants bearing a quinolone resistance mutation in gyrA were four- to eightfold more resistant to NSFQ-105 (MIC of 0.5 μg/ml) but susceptible to ciprofloxacin; (ii) NSFQ-105 selected first-step gyrA mutants (MICs of 0.5 μg/ml) encoding Ser-81-to-Phe or -Tyr mutations, whereas ciprofloxacin selects parC mutants; and (iii) NSFQ-105 was at least eightfold more effective than ciprofloxacin at inhibiting DNA supercoiling by S. pneumoniae gyrase in vitro but was fourfold less active against topoisomerase IV. These data show unequivocally that the C-7 substituent determines not only the potency but also the target preference of fluoroquinolones. The importance of the C-7 substituent in drug-enzyme contacts demonstrated here supports one key postulate of the Shen model of quinolone action.

Highly Selective Antibacterial Activity of Novel Alkyl Quinolone Alkaloids from a Chinese Herbal Medicine, Gosyuyu (Wu-Chu-Yu), against Helicobacter pylori In Vitro

Abstract: To elucidate the antibacterial activity of Gosyuyu, the crude extract from the fruit of Evodia rutaecarpa, a Chinese herbal medicine, has been fractionated chromatographically, and each fraction was assayed for antibacterial activity against Helicobacter pylori (H. pylori) in vitro. As the result, a single spot having marked antibacterial activity against H. pylori was obtained and the chemical structure was analyzed. The isolated compound was revealed to be a novel alkyl quinolone alkaloid based on the solubility, IR spectra, NMR analysis and mass spectrometric data after purification by TLC of silica. We compared the antimicrobial activity of this compound with that of other antimicrobial agents and examined susceptibility of various intestinal pathogens. As the result, the new quinolone compounds obtained from Gosyuyu extracts were found to be a mixture of two quinolone alkaloids, 1-methyl-2-[(Z)-8-tridecenyl]-4-(1H)-quinolone and 1-methyl-2-[(Z)-7-tridecenyl]-4-(1H)-quinolone (MW: 339), reported previously. The minimum inhibitory concentration (MIC) of these compounds against reference strains and clinically isolated H. pylori strains were less than 0.05 μg/ml, which was similar to the MIC of amoxicillin and clarithromycin that are used worldwide for the eradication of H. pylori, clinically. Furthermore, it was noted that the antimicrobial activity of these compounds was highly selective against H. pylori and almost non-active against other intestinal pathogens. The above results showed that these alkyl methyl quinolone (AM quinolones) alkaloids were useful for the eradication of H. pylori without affecting other intestinal flora.

The interaction of drugs with DNA gyrase: a model for the molecular basis of quinolone action.

Abstract: DNA gyrase supercoils DNA in bacteria. The fact that it is essential in all bacteria and absent from eukaryotes makes it an ideal drug target. We discuss the action of coumarin and quinolone drugs on gyrase. In the case of coumarins, the drugs are known to be competitive inhibitors of the gyrase ATPase reaction. From a combination of structural and biochemical studies, the molecular details of the gyrase-coumarin complex are well established. In the case of quinolones, the drugs are thought to act by stabilising a cleavage complex between gyrase and DNA that arrests polymerases in vivo. The exact nature of the gyrase-quinolone-DNA complex is not known; we propose a model for this complex based on structural and biochemical data.

Anti-Toxoplasma Activities of 24 Quinolones and Fluoroquinolones In Vitro: Prediction of Activity by Molecular Topology and Virtual Computational Techniques

Abstract: The apicoplast, a plastid-like organelle of Toxoplasma gondii, is thought to be a unique drug target for quinolones. In this study, we assessed the in vitro activity of quinolones against T. gondii and developed new quantitative structure-activity relationship models able to predict this activity. The anti-Toxoplasma activities of 24 quinolones were examined by means of linear discriminant analysis (LDA) using topological indices as structural descriptors. In parallel, in vitro 50% inhibitory concentrations (IC50s) were determined in tissue culture. A multilinear regression (MLR) analysis was then performed to establish a model capable of classifying quinolones by in vitro activity. LDA and MLR analysis were applied to virtual structures to identify the influence of each atom or substituent of the quinolone ring on anti-Toxoplasma activity. LDA predicted that 20 of the 24 quinolones would be active against T. gondii. This was confirmed in vitro for most of the quinolones. Trovafloxacin, grepafloxacin, gatifloxacin, and moxifloxacin were the quinolones most potent against T. gondii, with IC50s of 0.4, 2.4, 4.1, and 5.1 mg/liter, respectively. Using MLR analysis, a good correlation was found between measured and predicted IC50s (r2 = 0.87, cross-validation r2 = 0.74). MLR analysis showed that the carboxylic group at position C-3 of the quinolone ring was not essential for anti-Toxoplasma activity. In contrast, activity was totally dependent on the presence of a fluorine at position C-6 and was enhanced by the presence of a methyl group at C-5 or an azabicyclohexane at C-7. A nucleophilic substituent at C-8 was essential for the activity of gatifloxacin and moxifloxacin.

Efflux and target mutations as quinolone resistance mechanisms in clinical isolates of Streptococcus pneumoniae

Abstract: The aim of this study was to characterize quinolone resistance mechanisms in strains of Streptococcus pneumoniae with increased MICs of ofloxacin. These strains were also tested for their susceptibility to a battery of quinolone antimicrobial agents, including gemifloxacin. Of the S. pneumoniae isolates used, 27 were susceptible to ofloxacin, 18 intermediate and 48 resistant (ofloxacin MIC 4 mg/L, respectively). In general, the ofloxacin-susceptible strains had no amino acid substitutions in GyrA, GyrB, ParC or ParE. Moderate increases in MIC were associated with substitutions in the quinolone resistance-determining region (QRDR) of ParC, while the highest MICs were found for strains that also had substitutions in the QRDR of GyrA. The most common substitutions were Ser79� Phe in ParC and Ser81� Phe in GyrA. Other substitutions were identified within the QRDR of ParC and outside the QRDR of ParC and ParE; these did not appear to affect susceptibility. The effects of antimicrobial efflux pumps were studied by determining MICs of a range of quinolones in the presence and absence of reserpine, an inhibitor of Gram-positive efflux pumps. Our results indicated that high-level resistance, caused entirely by efflux, was seen in a minority of ofloxacin-resistant S. pneumoniae strains. Testing the susceptibility of quinolone-resistant strains to gemifloxacin, ciprofloxacin, norfloxacin, ofloxacin and trovafloxacin revealed that gemifloxacin was least affected by this large variety of resistance mechanisms and was the only quinolone with MICs of 0.5 mg/L for all strains in this study. These results suggest that gemifloxacin is highly potent against S. pneumoniae and may also be effective against strains resistant to other quinolones.

The Quinolones: Prospects

Abstract: Publisher Summary This chapter discusses the importance of the fluoroquinolones in clinical medicine, the advances already accomplished during the past decade, and their future prospects. These advances have led to the introduction of new compounds that are innovative and have improved clinical applications. Many infectious diseases can be treated successfully with oral quinolone therapy. Specifically, respiratory infections such as acute bacterial exacerbations of chronic bronchitis, community-acquired pneumonia and sinusitis, uncomplicated and some complicated urinary tract infections, as well as bacterial prostatitis, skin and soft tissue infections and bone and joint infections respond well to oral quinolone therapy. Gastrointestinal infections, particularly infectious diarrhea caused by toxigenic Escherichia coli , Salmonella , Shigella , Campylobacter , Aeromonas , and Vibrio species as well as Plesiomonas shigelloides are highly responsive to the oral quinolone therapy. In addition, some sexually transmitted diseases and pelvic infections can be cured with the oral quinolone therapy. Future developments of quinolone might provide compounds with greater activity against staphylococci, streptococci, corynebacteria, Listeria , Chlamydia , Mycoplasma, Legionella , and the anaerobes. Another key potential for the quinolones would be to develop new compounds with higher specific affinity for the DNA of human malignant cells. Success in this area may require the development of effective agents that can be used either alone or in combination with other chemotherapeutic agents.

Pharmacodynamics to combat resistance

Abstract: The ability to identify agents with the optimal combination of potency, pharmacokinetics and pharmacodynamics should help to maximize bacteriological cure and thus minimize the potential for selection and spread of resistance. Gemifloxacin demonstrated excellent correlation between efficacy and the AUC0-24h/MIC ratio whereas there was little correlation with time above MIC. Thus, gemifloxacin is similar to other quinolones in that it is the amount of drug present, not the frequency of administration, that determines antibacterial effect. In a neutropenic murine thigh model of infection, caused by Gram-negative bacilli, a AUC0-24h/MIC ratio of approximately 100 was necessary to protect >90% of the animals, which is similar to data reported previously for other quinolones. However, in order to achieve the same protection in an immunocompetent murine infection caused by Streptococcus pneumoniae, the AUC-24h/MIC ratio was approximately 25. The magnitude of this AUC0-24h/MIC ratio did not alter for strains exhibiting penicillin or macrolide resistance. Importantly, when gemifloxacin was examined against strains of S. pneumoniae with well-characterized ciprofloxacin resistance (including mutations in gyrase, parC and parE as well as efflux strains) there was little impact on the in vivo efficacy. Overall, the data showed a trend towards a decrease in the AUC0-24h/MIC ratio for these more resistant strains. The lower AUC0-24h/MIC ratio was especially noticeable for the efflux mutants suggesting that the quinolone efflux mechanism may be down-regulated in vivo and may be of minimal relevance to the clinical activity of gemifloxacin against S. pneumoniae. The efficacy of gemifloxacin, in comparison with other oral agents used to treat respiratory infections, has also been evaluated in a rat model using doses, and therefore AUC0-24h/MIC ratios, that approximate those in man. These data confirm the excellent activity of gemifloxacin against strains of Haemophilus influenzae and S. pneumoniae, including those demonstrating penicillin, macrolide and quinolone resistance.

Synthesis and In‐vitro Antibacterial Activity of N‐Piperazinyl Quinolone Derivatives with a 2‐Thienyl Group

Abstract: Background and the purpose of the study: Fluoroquinolones are an important group of antimicrobial agents that are used widely in the treatment of various infectious diseases. The purpose of the present study was to synthesize new N-piperazinyl quinolone derivatives with 5-chloro-2-theinyl group having possible antimicrobial activity. Methods: Reaction of ciprofloxacin (1), norfloxacin (2) and enoxacin (3) with α-bromoketone 10 or α-bromooxime derivatives 11a-c in DMF, in the presence of NaHCO3 at room temperature, afforded corresponding ketones 4a-c or oxime derivatives 5-7(a-c), respectively. Results and major conclusion: The synthesized compounds were tested against a series of Grampositive and Gram-negative bacteria. The results of MIC tests against both Gram-positive and Gram-negative bacteria revealed that ciprofloxacin derivatives (compounds 4a, 5a, 6a and 7a) were more active than norfloxacin and enoxacin analogues. Compound 5a, containing N-[2-(5-chlorothiophen-2-yl)-2-hydroxyiminoethyl] residue provided a high in vitro antibacterial activity against Gram-positive bacteria, with MIC of 0.06, 0.125, 0.5 and 0.125 µg/mL against S. aureus, S. epidermidis, E. feacalis and B. subtilis, respectively. Its activity was found to be 4 to 8 times better than reference drug (ciprofloxacin) against all

In vitro antibacterial activity of gemifloxacin and comparator compounds against common respiratory pathogens.

Abstract: This study investigated the in vitro potency of the novel quinolone agent gemifloxacin (SB-265805), in comparison with other quionolones, beta-lactams, macrolides and trimethoprim- sulphamethoxazole, against a panel of common respiratory pathogens. This panel comprised recent clinical isolates of Streptococcus pneumoniae (n = 347), Haemophilus influenzae (n = 256) and Moraxella catarrhalis (n = 184). Overall, the quinolones were highly active against H. influenzae and were the most potent agents against M. catarrhalis. Gemifloxacin was the most potent quinolone tested against all three species and was four- to 512-fold more potent against pneumococci than trovafloxacin, grepafloxacin, levofloxacin, ciprofloxacin, ofloxacin, gentamicin, cefuroxime, penicillin, ampicillin, clarithromycin, azithromycin or trimethoprim- sulphamethoxazole. Against 19 ofloxacin-intermediate and 52 ofloxacin-resistant strains of S. pneumoniae, gemifloxacin retained activity, and was the only agent tested with MICs of < or =0.5 mg/L. The results of this study demonstrate the excellent in vitro antibacterial activity of gemifloxacin against pathogens commonly associated with respiratory tract infections and suggest that gemifloxacin has significant potential in the treatment of such infections, including those caused by pneumococci considered resistant to other quinolones.

Cloning and Nucleotide Sequence of the DNA Gyrase (gyrA) Gene from Mycoplasma hominis and Characterization of Quinolone-Resistant Mutants Selected In Vitro with Trovafloxacin

Abstract: We report the cloning and characterization of the gyrA gene of the Mycoplasma hominis DNA gyrase, which was previously shown to be associated with quinolone resistance in this organism. The 2,733-bp gyrA gene encodes a protein of 911 amino acids with a calculated molecular mass of 102.5 kDa. As expected, M. hominis GyrA exhibits higher homology with the GyrA subunits of the gram-positive bacteria Clostridium acetobutylicum, Bacillus subtilis, Streptococcus pneumoniae, and Staphylococcus aureus than with its Escherichia coli counterpart. Knowing the entire sequence of the gyrA gene of M. hominis could be very useful for confirming the role of the GyrA subunit in fluoroquinolone resistance. Twenty-nine mutants of M. hominis were selected stepwise for resistance to trovafloxacin, a new potent fluoroquinolone, and their gyrA, gyrB, parC, and parE quinolone resistance-determining regions were characterized. Three rounds of selection yielded 3 first-step, 12 second-step, and 14 third-step mutants. The first-step mutants harbored a single substitution, Glu460-->Lys (E. coli coordinates), in ParE. GyrA changes, Ser83-->Leu, Glu87-->Lys, and Ala119-->Glu or Val, were found only in the second round of selection. At the third step, additional substitutions, at ParC Ser80, Ser81, and Glu84 and ParE Leu440, associated with high-level resistance to fluoroquinolones, appeared. Thus, high-level resistance to trovafloxacin required three steps and was associated with alterations in both fluoroquinolone targets. According to these genetic data, in M. hominis, as in Staphylococcus aureus and Streptococcus pneumoniae, topoisomerase IV seems to be the primary target of trovafloxacin.

Action of quinolones against Staphylococcus aureus topoisomerase IV: basis for DNA cleavage enhancement.

Abstract: Topoisomerase IV is the primary cellular target for most quinolones in Gram-positive bacteria; however, its interaction with these agents is poorly understood. Therefore, the effects of four clinically relevant antibacterial quinolones (ciprofloxacin, and three new generation quinolones: trovafloxacin, levofloxacin, and sparfloxacin) on the DNA cleavage/religation reaction of Staphylococcus aureus topoisomerase IV were characterized. These quinolones stimulated enzyme-mediated DNA scission to a similar extent, but their potencies varied significantly. Drug order in the absence of ATP was trovafloxacin > ciprofloxacin > levofloxacin > sparfloxacin. Potency was enhanced by ATP, but to a different extent for each drug. Under all conditions examined, trovafloxacin was the most potent quinolone and sparfloxacin was the least. The enhanced potency of trovafloxacin correlated with several properties. Trovafloxacin induced topoisomerase IV-mediated DNA scission more rapidly than other quinolones and generated more cleavage at some sites. The most striking correlation, however, was between quinolone potency and inhibition of enzyme-mediated DNA religation: the greater the potency, the stronger the inhibition. Dose-response experiments with two topoisomerase IV mutants that confer clinical resistance to quinolones (GrlA(Ser80Phe) and GrlA(Glu84Lys)) indicate that resistance is caused by a decrease in both drug affinity and efficacy. Trovafloxacin is more active against these enzymes than ciprofloxacin because it partially overcomes the effect on affinity. Finally, comparative studies on DNA cleavage and decatenation suggest that the antibacterial properties of trovafloxacin result from increased S. aureus topoisomerase IV-mediated DNA cleavage rather than inhibition of enzyme catalysis.

Biological Activity of Some Magnesium(II) Complexes of Quinolones.

Abstract: A new magnesium complex of quinolone antibacterial agent was prepared. This new complex as well as a previously isolated complex of magnesium with ciprofloxacin were tested against various Gram positive and Gram negative microorganisms. Antimicrobial activities were evaluated using the agar diffusion test. The results have shown that all magnesium complexes are significantly less active than the parent quinolone drugs. It was also found that the activity of quinolones is reduced when the solutions of quinolones are titrated with magnesium ions.

Bacterial Resistance to Quinolones: Mechanisms and Clinical Implications

Abstract: Publisher Summary This chapter describes the two main mechanisms of bacterial resistance to the quinolones and their prevalence among medically relevant bacteria. Bacteria can become resistant to the quinolones by mutations in the target molecules—that is, the topoisomerases II and IV, or by active efflux. Active efflux is not fully documented in every bacterial species, but seems to be widespread, if not universal, in clinically relevant bacteria. Active efflux is responsible for a low-level resistance that might act as a first step in resistance selection. Outer membrane permeability contributes to the intrinsic level of resistance to quinolones in some species, but its role in acquired resistance remains unclear because porin mutations do not significantly alter quinolone minimum bactericidal concentrations (MICs). Resistance is much more commonly encountered in hospital practice, particularly among the nonfermenters, the enterococci, and, above all, methicillin-resistant S. aureus (MRSA) strains, than in the community-acquired infections. However, increasing resistance in N. gonorrhoeae and S. pneumoniae is a growing concern. Before their launch, most of the nosocomial pathogens were susceptible to fluoroquinolones, but their use in the therapy of hospital infections has been followed by a marked increase of resistant isolates both in the United States and in Europe. Quinolone resistance in staphylococci depends on the susceptibility to methicillin and it is notably more prevalent in the methicillin-resistant strains. Resistance is also frequently encountered in P. aeruginosa and other Pseudomonas spp. ( P. paucimobilis is generally susceptible), S. maltophilia , Acinetobacter spp. (with the exception of A. lwoffii ), and Alcaligenes spp. Fluoroquinolone drugs are a well-established therapy for gonorrhea, but resistance has emerged in N. gonorrhoeae very sharply in some areas. Fluoroquinolone underdosing in patients with gonorrhea should be avoided in order to limit the risk of resistance selection.

Bactericidal activity of gemifloxacin and other quinolones against Streptococcus pneumoniae

Abstract: This study compared the bactericidal activity of gemifloxacin (SB-265805) and a panel of test quinolones against two ciprofloxacin-resistant pneumococcal strains (Streptococcus pneumoniae 502226 and 503244) and one ciprofloxacin-sensitive strain (S. pneumoniae C3LN4). Activities were compared by calculating the bactericidal index of these agents. Gemifloxacin was found to be the most bactericidal quinolone tested against these strains. This finding confirms previous data indicating the superior in vitro activity of gemifloxacin against pneumococci, including ciprofloxacin-resistant strains. Although both ciprofloxacin-resistant strains tested had similar quinolone MICs, they differed considerably in their susceptibility to the bactericidal action of these agents. S. pneumoniae 502226 was more readily killed by quinolones than S. pneumoniae 503244 but, as would be expected, both were less susceptible than the ciprofloxacin-sensitive strain. Of the quinolones tested, trovafloxacin showed disproportionally poor activity against the ciprofloxacin-resistant strains even though potent activity was present against the ciprofloxacin-sensitive strain. These data highlight the importance of assessing quinolone bactericidal activity in addition to the MIC when evaluating new members of this antimicrobial class.

Fluoroquinolones: is there a different mechanism of action and resistance against Streptococcus pneumoniae?

Abstract: Starting in the 1950s, study and elucidation of the biochemical mechanisms of resistance to antibiotics led to the understanding of both the biology of bacteria and the mode of action of antibiotics. This holds true for the relationship between Streptococcus pneumoniae and the fluoroquinolones. A new feature in this approach is the availability of the nearly complete chromosome sequence of this major human pathogen. In S. pneumoniae, resistance appears to be mainly due to mutational alterations in the intracellular targets of the fluoroquinolones, the type II DNA topoisomerase gyrase and topoisomerase IV. Both enzymes appear to be the primary targets of the drugs in this species. Mutations in the quinolone resistance-determining region (QRDR) of the gyrA gene or the parC gene, which encode the A subunits of DNA gyrase and topoisomerase IV respectively, confer resistance to single-step mutants. Mutations in gyrB and parE, which encode the B subunits of DNA gyrase and topo IV, respectively, have also been implicated in the fluoroquinolone resistance of certain mutants obtained in vitro. The antibiotics most affected by a single mutation are those for which the mutation occurs in their preferred target e.g. gyrase for sparfloxacin and gatifloxacin and topo IV for ciprofloxacin and levofloxacin. The activity of all fluoroquinolones is decreased further when two or more mutations are present. Because they possess similar targets of action, there is cross resistance, albeit at various degrees depending on the intrinsic activity of the molecule, among fluoroquinolones. This stresses, once more, the misleading concept of breakpoints for clinical categorization. A second mechanism of resistance, enhanced active efflux of hydrophilic quinolones such as norfioxacin and ciprofloxacin, is mediated by the membrane-associated protein, PmrA (pneumococcal multidrug resistance). This protein is a 12-transmembrane segment proton-dependent multidrug efflux pump of the major facilitator family. The combinatorial approach of bacteria to fluoroquinolone resistance implies that the molecule actually used, as well as a less active member of the class that is more apt to detect resistance mechanisms (e.g. ciprofloxacin), should be tested in vitro.

Mechanisms of Fluoroquinolone Action and Resistance

Abstract: Intracellular fluoroquinolone action involves two steps. First, drug-topoisomerase-DNA complexes form in which the DNA is broken. These complexes reversibly block DNA replication and bacterial growth. Second, lethal DNA breaks are released from the complexes. Inhibitors of protein synthesis, such as chloramphenicol, block cell death and the release of DNA breaks from complexes trapped by oxolinic acid, a first generation quinolone. However, they only partially protect cells from the lethal action of fluoroquinolones, suggesting that these compounds act by the chloramphenicol-sensitive pathway and by a second pathway. Resistance to fluoroquinolones arises step-wise from mutations in the two intracellular targets, DNA gyrase and DNA topoisomerase IV. Addition of a methoxy group to N1-cyclopropyl fluoroquinolones improves bacteriostatic and bactericidal action, especially against first-step, resistant mutants. Consequently, C-8-methoxy derivatives restrict the selection of resistance by bacterial populations, a feature that has been shown for several bacterial species including clinical MDR isolates ofMycobacterium tuberculosis. Since minimum inhibitory concentration (MIC) against wild-type cells fails to accurately predict attack of resistant mutants or selection of resistance, a new parameter called mutant prevention concentration (MPC) is proposed as an additional measure of quinolone potency.

Quinolone-Resistant E coli in the Community

Abstract: al. Methicillin-resistant Staphylococcus aureus (MRSA): a briefing for acute care hospitals and nursing facilities. Infect Control Hosp Epidemiol 1994;15:105-115. 6. Weber DJ, Rutala WA. Role of environmental contamination in the transmission of vancomycin-resistant enterococci. Infect Control Hosp Epidemiol 1997;18:306-309. 7. Bonten ML Hayden MK, Nathan C, van Voorhis J, Matushek M, Slaughter S, et al. Epidemiology of colonisation of patients and environment with vancomycin-resistant enterococci. Lancet 1996;348:1615-1619. 8. Samore MH, Venkataraman L, DeGirolami PC, Arbeit RD, Karchmer AW. Clinical and molecular epidemiology of sporadic and clustered cases of nosocomial Clostridium difficile diarrhea. Am J Med 1996;100:32-40. 9. Fekety R, Kim KH, Brown D, Batts DH, Cudmore M, Silva J. Epidemiology of antibiotic-associated colitis: isolation of Clostridium difficile from the hospital environment. Am J Med 1981;70:906-908. 10. Malamou-Ladas H, O'Farrell S, Nash JQ, Tabaqchali S. Isolation of Clostridium difficile from patients and the environment of hospital wards./ Clin Pathol 1983;36:88-92. 11. Kaatz GW, Gitlin SD, Schaberg DR, Wilson KH, Kauffman CA, Seo SM, et al. Acquisition of Clostridium difficile from the hospital environment. Am J Epidemiol 1988;127:1289-1294. 12. Laborde DJ, Weigle KA, Weber DJ, Kotch JB. Effect of fecal contamination on diarrheal illness rates in day-care centers. Am J Epidemiol 1993;138:243-255. 13. Ekanem EE, DuPont HL, Pickering LK, Selwyn BJ, Hawkins CM. Transmission dynamics of enteric bacteria in day-care centers. Am J Epidemiol 1983;118:562-572. 14. Finch JE, Prince J, Hawksworth M. A bacteriologic survey of the domestic environment. J Applied Bacteriol 1978;45:357-364. 15. Scott E, Bloomfield SF, Barlow CG. An investigation of microbial contamination in the home. J Hyg Camb 1982;89:279-293. 16. Gwaltney JM Jr, Hendley JO. Transmission of experimental rhinovirus infection by contaminated surfaces. Am J Epidemiol 1982;116:828-833. 17. Ward RL, Bernstein Dl, Knowlton DR, Sherwood JR, Young EC, Cusack TM, et al. Prevention of surface-to-human transmission of rotaviruses by treatment with disinfectant spray. / Clin Microbiol 1991;29:1991-1996. 18. Sattar SA, Springthorpe VS. Transmission of viral infections through animate and inanimate surfaces and infection control through chemical disinfection. In: Hurst DJ, ed. Modeling Disease Transmission and Its Prevention by Disinfection. Cambridge, England: Cambridge University Press; 1996:224-257. 19. Scott E, Bloomfield SE The survival and transfer of microbial contamination via cloths, hands and utensils. JAppl Bacteriol 1990;68:271-278. 20. Sattar SA, Jacobsen H, Springthorpe VS, Cusack TM, Rubino JR Chemical disinfection to interrupt transfer of rhinovirus type 14 from environmental surfaces to hands. Appl Environ Microbiol 1993;59:1579-1585. 21. Centers for Disease Control and Prevention. CDC Surveillance Summaries. MMWR 1996;45(SS-5):l-66. 22. Rutala WA, Weber DJ. Environmental issues and nosocomial infections. In: Farber BF, ed. Infection Control in Intensive Care. New York, NY: Churchill Livingstone; 1987:131-171. 23. Griffin PM, Boyce TG. Escherichia coli 0157:H7. In: Scheld WM, Armstrong D, Hughes JM, eds. Emerging Infections. Washington, DC: ASM Press; 1998:137-145. 24. Whittam TS, McGraw EA, Reid SD. In: Krause RM, ed. Emerging Infections. San Diego, CA: Academic Press; 1998:163-183. 25. Slutsker L Villarino ME, Jarvis WR, Goulding J. Foodborne disease prevention in healthcare facilities. In: Bennett JV, Brachman PS, eds. Hospital Infections. 4th ed. Philadelphia, PA: Iippincott-Raven; 1998:333-337. 26. Chatburn RL, Kallstrom TJ, Bajaksouzian S. A comparison of acetic acid with a quaternary ammonium compound for disinfection of hand-held nebulizers. Respir Care 1988;33:179-187. 27. Olson W, Vesley D, Bode M, Dubbel P, Bauer T. Hard surface cleaning performance of six alternative household cleaners under laboratory conditions. J Environ Health 1994;56:27-31. 28. Bauer JM, Beronio CA, Rubino JR. Antibacterial activity of environmentally \"green\" alternative products tested in standard antimicrobial tests and a simulated in-use assay. J Environ Health 1995;57:13-18. 29. Parnes CA Efficacy of sodium hypochlorite bleach and \"alternative\" products in preventing transfer of bacteria to and from inanimate surfaces. / Environ Health 1997;59:14-20. 30. Daschner F. The hospital and pollution: Role of the hospital epidemiologist in protecting the environment. In: Wenzel RP, ed. Prevention and Control of Nosocomial Infections. 3rd ed. Baltimore, MD: Williams & Wilkins; 1997:595-605. 31. Rutala WA, Stiegel MM, Sarubbi FA, Weber DJ. Susceptibility of antibiotic-susceptible and antibiotic-resistant hospital bacteria to disinfectants. Infect Control Hosp Epidemiol 1997;18:417-421. 32. Anderson RL, Carr JH, Bond WW, Favero MS. Susceptibility of vancomycin-resistant enterococci to environmental disinfectants. Infect Control Hosp Epidemiol 1997;18:195-199. 33. Preventing the spread of vancomycin resistance—a report from the Hospital Infection Control Practices Advisory Committee prepared by the Subcommittee on Prevention and Control of Antimicrobial Resistant Microorganisms in Hospitals; comment period and public meeting— CDC. Notice. FedRegist 1994;59:25758-25763. 34. Garner JS. Guideline for isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996;17:53-80. 35. Occupational Exposure to Bloodborne pathogens—OSHA. Final rule. FedRegist 1991;56:64175-64182. 36. Rutala WA. APIC guideline for selection and use of disinfectants. Am J Infect Control 1996;24:313-342. 37. Kotch JB, Weigle KA, Weber DJ, Clifford RM, Harms TO, Loda FA, et al. Evaluation of an hygienic intervention in day-care centers. Pediatrics 1994;94:991-994. 38. Sattar SA, Jacobsen H, Rahman H, Cusack TM, Rubino JR Interruption of rotavirus spread through chemical disinfection. Infect Control Hosp Epidemiol 1994;15:751-756.

Antibacterial Agents, Quinolones

Abstract: Quinolone carboxylic acids are a class of totally synthetic antibacterial agents which encompass 4-oxo-3-quinolinecarboxylic acids as well as the corresponding 1,8-naphthyridines, cinnolines, and pyrido [2,3-d]-pyrimidines. These classes are illustrated by ciprofloxacin, nalidixic acid, cinoxacin, and piromidic acid, respectively. Established quinolone antibacterial agents are ciprofloxacin, ofloxacin, enoxacin, norfloxacin, and pefloxacin. Quinolones exert their antibacterial activity by interfering with the replication of bacterial DNA by inhibition of the enzyme DNA gyrase. The critical reaction is the negative supercoiling of bacterial DNA, a process involving the breaking and resealing of double-stranded circular DNA. The general method by which most newer fluoro quinolones are prepared involves a ring closure reaction to form the quinolone nucleus. For the most part quinolones are well tolerated with few reports of adverse reactions, but because of a concern that they cause arthropathy in juvenile animals, quinolones are contraindicated for children and during pregnancy. A second problem is adverse side effects of the central nervous system (CNS) and adverse reactions with other drugs. Earlier quinolones have had little impact on the domestic antiinfective market as their utility was limited primarily to urinary tract infections. Newer quinolones, because of safety, seemingly low propensity toward bacterial resistance, and vastly improved therapeutic utility, enjoy a much greater market share.

Accumulation and efflux of quinolones by clinical isolates of Stenotrophomonas maltophilia

Abstract: The presence of quinolone efflux pumps was analyzed in clinical isolates of Stenotrophomonas maltophilia. The presence of the protein Omp54, which is associated with the expression of multidrug resistant systems, was also tested. Western blot analysis of outer membrane proteins demonstrated that Omp54 was expressed in strains with high-level resistance to quinolones, whereas those strains with low MIC values did not express this protein. This result shows that Omp54 has an important role in the phenotype of quinolone resistance in clinical S. maltophilia isolates. Biochemical analyses have shown that clinical S. maltophilia strains are capable of quinolone efflux (namely norfloxacin, ofloxacin and ciprofloxacin). Quinolone efflux is dependent on the integrity of membrane potential. These data indicate the presence of active quinolone efflux pump systems in clinical S. maltophilia isolates.

[Results of antimicrobial susceptibilities of strains clinically isolated at 8 institutions in Hiroshima City to major oral antimicrobial drugs, mainly new quinolone drugs. Hiroshima Levofloxacin Susceptibility Surveillance Group].

Abstract: To evaluate the resistance for major oral antimicrobial agents, mainly new quinolones, we carried out a drug susceptibility surveillance of 3,050 strains of 11 microbial species clinically isolated at 8 institutions such as general hospitals and examination centers in Hiroshima city. 10 antimicrobial agents were used: 3 new quinolone drugs, 5 beta-lactam drugs, minocycline and clarithromycin. Among Gram-positive bacteria, methicillin resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis showed low susceptibility to the new quinolone drugs, while methicillin susceptible Staphylococcus aureus (MSSA) and Streptococcus pneumoniae were highly sensitive to these drugs. Among Gram-negative bacteria, Pseudomonas aeruginosa showed high resistance for the new quinolone drugs, but enteric bacteria and Haemophilus influenzae did not show marked resistance, maintaining almost good sensitivity to these drugs. To reduce the appearance of resistant bacteria, appropriate antimicrobial agents should be selected. Drug susceptibility surveillance in the community will be also important in the future.

Recent Progress in Novel Macrolides, Quinolones, and 2-Pyridones to Overcome Bacterial Resistance

Abstract: Macrolides, such as clarithromycin and azithromycin, having good activity against pathogens such as Legionella, Chlamydia, Campylobacter spp, Branhamella spp, Pasteurella multocida and streptococci, have gained wide acceptance for the treatment of both upper and lower respiratory tracts, as well as cutaneous infections. Emergence of bacterial resistance, particularly in gram-positive bacteria, has been observed. Macrolide-resistant Streptococcus pneumoniae and S. pyogenes are found in France and many other countries, resulting in failure of therapy for pneumonia, pharyngitis, and skin infection. RU 004, HMR 3647, and TE 802 were reported to be active against these resistant strains. Research at Abbott produced several macrolide derivatives in the anhydrolide, tricyclic and tetracyclic ketolides as well as 6-O-alkyl ketolides series having potent activity against macrolide resistant S. pyogenes and S. pneumoniae . Research on streptogramins to overcome bacterial resistance in gram-positive bacteria has produced interesting compounds. Another class of antibacterial agent called quinolones is useful for the treatment of bacterial infections of respiratory tract, urinary tract, skin and soft tissues, as well as sexually transmitted diseases. Ciprofloxacin, the market leader, however, has low potency against anaerobes. Bacterial resistance ( such as Pseudomonas aeruginosa and methicillin- resistant Staphylococcus aureus ) to ciprofloxacin is increasing rapidly. Many quinolone compounds are being synthesized to address these drawbacks. The new quinolones currently under development are characterized by enhanced activities against streptococci, staphylococci, enterococci, and anaerobes. This presentation reviews the current research in the identification of agents to overcome the macrolide and quinolone resistance. © 1999 John Wiley & Sons, Inc. Med Res Rev, 19, No. 6, 497–520, 1999