Changes in fluoroquinolone-resistant Streptococcus pneumoniae after 7-valent conjugate vaccination, Spain.The bacterium Streptococcus pneumoniae Streptococcus pneu·mo·ni·ae n. Pneumococcus. Streptococcus pneumoniae Microbiology A pathogenic streptococcus with 90 serotypes associated with pneumonia, bacteremia, meningitis Transmission Person to person Incidence is a serious cause of illness and death and a major etiologic agent of community-acquired pneumonia community-acquired pneumonia Pneumonia caused by an infection currently present in the community; CAP is the most common cause of infectious death–US, and number 6 killer overall; of the 57% of CAPs in which a pathogen is identified, S pneumoniae , meningitis, and acute otitis media Acute otitis media Inflammation of the middle ear with signs of infection lasting less than three months. Mentioned in: Myringotomy and Ear Tubes acute otitis media . Pneumococcal pneumococcal /pneu·mo·coc·cal/ (-kok´al) pertaining to or caused by pneumococci. resistance to antimicrobial antimicrobial /an·ti·mi·cro·bi·al/ (-mi-kro´be-al) 1. killing microorganisms or suppressing their multiplication or growth. 2. an agent with such effects. drugs (including [beta]-lactams, macrolides, tetracycline tetracycline (tĕ'trəsī`klēn), any of a group of antibiotics produced by bacteria of the genus Streptomyces. They are effective against a wide range of Gram positive and Gram negative bacteria, interfering with protein , and cotrimoxazole) has become a worldwide problem (1); new fluoroquinolones are being used as therapeutic alternatives for treatment of adult patients with community-acquired pneumonia (2). Resistance to fluoroquinolones in S. pneumoniae can be acquired by point mutations point mutation n. A mutation that involves a single nucleotide and may consist of loss of a nucleotide, substitution of one nucleotide for another, or the insertion of an additional nucleotide. , intraspecific in·tra·spe·cif·ic also in·tra·spe·cies adj. Arising or occurring within a species: intraspecific competition. recombination recombination, process of "shuffling" of genes by which new combinations can be generated. In recombination through sexual reproduction, the offspring's complete set of genes differs from that of either parent, being rather a combination of genes from both parents. (3) or interspecific in·ter·spe·cif·ic adj. Arising or occurring between species. interspecific also interspecies Arising or occurring between species. Adj. 1. recombination with the S. mitis group (3-7). Resistance is caused mainly by amino acid amino acid (əmē`nō), any one of a class of simple organic compounds containing carbon, hydrogen, oxygen, nitrogen, and in certain cases sulfur. These compounds are the building blocks of proteins. changes in quinolone resistance-determining regions (QRDRs) of the subunits of DNA topoisomerase DNA topoisomerase /DNA topo·isom·er·ase/ (to?po-i-som´er-as) either of two types of isomerase that catalyze the breakage, passage, and rejoining of one or both DNA strands, type I topoisomerases IV (topo IV; [parC.sub.2] and [parE.sub.2]) and DNA gyrase DNA gyrase (ji´ras) a type II DNA topoisomerase. ([gyrA.sub.2] and [gyrB.sub.2]) enzymes that control DNA topology DNA topology is the focus of an interdiscipline between molecular biology and mathematics and as a term refers to DNA supercoiling, knotting and catenation. More simply put, DNA topology studies the shape and path of the DNA helix in three dimensional space. . In addition, fluoroquinolone fluoroquinolone /flu·o·ro·quin·o·lone/ (-kwin´o-lon) any of a subgroup of fluorine-substituted quinolones, having a broader spectrum of activity than nalidixic acid. fluor·o·quin·o·lone n. efflux efflux Medtalk That which flows outward also contributes to resistance (8). Genetic and biochemical studies have shown that for most fluoroquinolones, such as ciprofloxacin ciprofloxacin /cip·ro·flox·a·cin/ (sip?ro-flok´sah-sin) a synthetic antibacterial effective against many gram-positive and gram-negative bacteria; used as the hydrochloride salt. cip·ro·flox·a·cin n. and levofloxacin, topo IV and gyrase are primary and secondary targets, respectively (9-13). However, gyrase is the primary target for moxifloxacin (14). Although current prevalence of fluoroquinolone resistance in pneumococci is <5% (15-17), surveillance is necessary. Introduction of the 7-valent conjugate conjugate /con·ju·gate/ (kon´jdbobr-gat) 1. paired, or equally coupled; working in unison. 2. a conjugate diameter of the pelvic inlet; used alone usually to denote the true conjugate diameter; see pneumococcal vaccine pneu·mo·coc·cal vaccine n. A vaccine containing purified capsular polysaccharide antigen from the most common infectious types of Streptococcus pneumoniae, used to immunize against pneumonococcal disease. (PCV PCV packed-cell volume. PCV packed-cell volume, the volume of packed red cells in milliliters per 100 ml of blood. 7), which includes serotypes such as 6B, 9V, 14, and 23F that are often associated with resistance to fluoroquinolones and other antimicrobial drugs, has resulted in changes in the epidemiology of invasive pneumococcal disease (18-20). Since the introduction of PCV7 in Spain in late 2001, [approximately equal to]47% of children have been vaccinated (21). In this study, we investigated the prevalence of fluoroquinolone-resistant pneumococci in Spain during 2006. Mutations in the QRDRs of parC, parE, and gyrA were identified, and the presence of reserpine-sensitive fluoroquinolone efflux was determined. In addition, resistance associations with other antimicrobial drugs and characteristics of drug-resistant clones were determined. To better evaluate changes in the epidemiology of resistance after the introduction of PCV7 in children, we compared our results with those of a similar study that tested isolates from 2002. Methods Bacterial Isolates, Serotyping, Susceptibility Testing susceptibility test Antimicrobial susceptibility test, see there , and Genetic Transformation We studied 4,215 S. pneumoniae isolates from 2 hospitals (in Barcelona and San Sebastian), and a sample from 110 hospitals throughout Spain (Spanish Reference Laboratory, Madrid). Of the isolates, 2,682 were from adults, 1,400 from children, and 133 from persons whose ages were unknown. A total of 2,101 (49.9%) isolates were obtained from blood or other sterile sites; 1,055 (25%) from the lower respiratory tract Noun 1. lower respiratory tract - the bronchi and lungs lung - either of two saclike respiratory organs in the chest of vertebrates; serves to remove carbon dioxide and provide oxygen to the blood ; 960 (22.8%) from the upper respiratory tract respiratory tract n. The air passages from the nose to the pulmonary alveoli, including the pharynx, larynx, trachea, and bronchi. Respiratory tract , otic and conjunctival con·junc·ti·val adj. Relating to the conjunctiva. conjunctival pertaining to or emanating from conjunctiva. congenital conjunctival membrane sites; and 99 (2.3%) from other sites. Isolates were confirmed as S. pneumoniae by standard methods, and serotypes were determined by the Quellung reaction quel·lung reaction n. See Neufeld capsular swelling. . Ciprofloxacin susceptibility was determined by broth broth liquid media for culturing microorganisms. cooked meat broth a medium useful for culturing anaerobic bacteria. enrichment broth one modified to permit growth by selected bacteria. microdilution tests (Sensititer; Trek Diagnostics Inc., East Grinstead Coordinates: East Grinstead (archaically spelt Grimstead[1]) is a town and civil parish in the northeastern corner of Mid Sussex, West Sussex in England near the East Sussex, Surrey, and Kent borders. , UK) and by agar dilution according to according to prep. 1. As stated or indicated by; on the authority of: according to historians. 2. In keeping with: according to instructions. 3. the Clinical and Laboratory Standards Institute guidelines (22). Reserpine-sensitive fluoroquinolone efflux phenotype phenotype (fē`nətīp'): see genetics. phenotype All the observable characteristics of an organism, such as shape, size, colour, and behaviour, that result from the interaction of its genotype (total genetic makeup) with was determined as described (23). We performed genetic transformation as described (24) by using S. pneumoniae strains R6 and T1 (25) as receptors. For selection of transformants, we used media plates containing 1 [micro]g/mL (R6 derivatives) or 8 [micro]g/mL (T1 derivatives) of ciprofloxacin. Pulsed-Field Gel Electrophoresis gel electrophoresis n. Electrophoresis performed in a gel composed of agarose, polyacrylamide, or starch. and Multilocus Sequence Typing Multilocus sequence typing (MLST) is a technique in molecular biology for the typing of multiple loci. The procedure characterizes isolates of bacterial species using the DNA sequences of internal fragments of multiple (usually seven) housekeeping genes. Pulsed-field gel electrophoresis (PFGE PFGE Pulsed-Field Gel Electrophoresis ) patterns were determined by using SmaI and ApaI as described (24) and compared with 26 representative clones of the Pneumococcal Molecular Epidemiology molecular epidemiology Molecular medicine An evolving field that combines the tools of standard epidemiology–case studies, questionnaires and monitoring of exposure to external factors with the tools of molecular biology–eg, restriction endonucleases, Network (26). Isolates with patterns varying by [less than or equal to]3 bands were considered to represent the same PFGE type (27). Multilocus sequence typing was performed as described (28) with representative isolates of PFGE types shared by [greater than or equal to]3 isolates (www.mlst.net). We analyzed selected strains representative of dominant clones from the 2002 study by multilocus sequence typing. PCR PCR polymerase chain reaction. PCR abbr. polymerase chain reaction Polymerase chain reaction (PCR) Amplification and DNA Sequence DNA sequence Genetics The precise order of bases–A,T,G,C–in a segment of DNA, gene, chromosome, or an entire genome. See Base pair, Base sequence analysis, Chromosome, Gene, Genome. Determination Oligonucleotides parE398 (29) and parC152 (10) were used to amplify parE and parC QRDRs. All isolates yielded fragments of 1.6 kb, with the exception of ciprofloxacin-resistant (CipR) isolates CipR17, CipR39, CipR74, and CipR76, which yielded fragments of [approximately equal to]5, 5, 5, and 7 kb, respectively. These PCR fragments were sequenced as described (24). Oligonucleotides gyrA44 and gyrA170 (29) were used to amplify and sequence gyrA QRDRs. Oligonucleotides antUP and antDOWN (4) were used to detect the ant gene. Results Among the 4,215 isolates studied, 98 were CipR. Of these isolates, 30 (30.6%) showed low-level resistance (LL-CipR, MICs 4-8 [micro]g/mL) and 68 (69.4%) high-level resistance (HL-CipR, MICs 16-128 [micro]g/mL) (Table 1). By age group, the prevalence of CipR was 0.14% (2/1,400) among isolates from pediatric patients pediatric patient Child, see there (<15 years of age) and 3.6% (96/2,682) among isolates from adult patients. Resistance was higher among noninvasive pneumococci (3.3%, 70/2,114) than among invasive isolates (1.3%, 28/2,101, p<0.001). The highest rate of Cip resistance was found for isolates from adults >64 years of age (Table 1). All HL-CipR isolates were from adult patients; most (53/68, 77.9%) were isolated from sputum sputum /spu·tum/ (spu´tum) [L.] expectoration; matter ejected from the trachea, bronchi, and lungs through the mouth. sputum cruen´tum bloody sputum. . CipR isolates showed high rates of resistance to antimicrobial drugs. However, these rates were lower than those found in the 2002 study (Table 1). The parC, parE, and gyrA QRDRs of the 98 CipR isolates were characterized. Most CipR isolates (93/98) showed low nucleotide sequence variations ([less than or equal to]1%) in their QRDRs, but 5 isolates showed high variations (>4%). Four of them were in parC, parE, and gyrA, and only 1 was in gyrA. These results suggest an interspecific recombinant origin for these genes. In accordance, all isolates with recombinant parE and parC genes carried the ant gene, typical of the S. mitis group (4), as shown by PCR amplification. Twenty-one of the 98 isolates had efflux for Cip; 3 of them also had efflux for levofloxacin (Tables 2, 3), and none had efflux for moxifloxacin. Efflux was equally distributed among LL-CipR and HL-CipR isolates. The contribution of the efflux mechanism to resistance in those isolates is unclear. Mutations not previously described that produced changes in parC (D78N, S80P, D83E), parE (I476F), and gyrA (G79A, S81V, E85G, V101I) were found in 8 isolates. To test the contribution of these changes to resistance, transformation experiments using strains R6 or T1 (as R6, parC S79F) as receptors of parC or gyrA QRDRs, respectively, were performed. The QRDRs of several independent transformants were sequenced to confirm the presence of the same mutation in the donor DNA DNA: see nucleic acid. DNA or deoxyribonucleic acid One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. and MICs of these transformants were determined. Although no transformation was achieved with PCR products carrying parC D78N or parE I476F, transformation to increased resistance was observed with products carrying parC S80P, gyrA S81V, and gyrA E85G changes (Table 2). Three of these changes were accompanied by other changes known to be involved in resistance: gyrA G79A with S81F; parC D83E with S79F, and gyrA V101I with S81F. Among 5 T1 transformants obtained with a gyrA QRDR QRDR Quinolone Resistance-Determining Regions carrying G79A and S81F, 4 carried G79A and S81F and only 1 carried S81F. Because all transformants had identical Cip MICs, results suggest that G79A is not involved in drug resistance. We could not discern the role of parC D83E and gyrA S81F in resistance, given that all R6-transformants had parC D83E and S79F and all T1 transformants had gyrA V101I and S81F. However, given the contribution to resistance of the accompanied mutations, their role in resistance is unlikely. The contribution of classical and new mutations to Cip resistance described here enabled us to classify resistant isolates (Tables 2, 3). Five LL-CipR isolates did not show changes involved in resistance in their parC, parE, or gyrA QRDRs, including 1 with recombinant genes (Table 2). Four of them showed a reserpine-sensitive efflux phenotype for Cip (Table 2) as a single mechanism of resistance. Among the remaining 25 LL-CipR isolates, 24 had mutations producing changes at parC, and 1 isolate had a single change at parE. Among 68 HL-CipR isolates, 55 (80.9%) had double changes (51 in parC and gyrA and 4 in parE and gyrA), and 13 (19.1%) had triple mutations (7 had 2 changes in parC and 1 change in gyrA; 4 had 1 change in parC, 1 change in parE, and 1 change in gyrA; 2 had 1 change in parC and 2 changes in gyrA). According to Clinical and Laboratory Standards Institute guidelines (22), only 3 of the 30 LL-CipR isolates showed intermediate resistance to levofloxacin (MIC 4 [micro]g/mL), and the remaining 27 isolates were susceptible to levofloxacin; all were susceptible to moxifloxacin. HL-CipR isolates showed resistance (n = 66) or intermediate resistance (n = 2) to levofloxacin. Five HL-CipR isolates were susceptible to moxifloxacin, 11 showed intermediate resistance, and 52 were resistant. Serotype serotype /se·ro·type/ (ser´o-tip) the type of a microorganism determined by its constituent antigens; a taxonomic subdivision based thereon. se·ro·type n. See serovar. v. and genotype genotype (jēn`ətīp'): see genetics. genotype Genetic makeup of an organism. The genotype determines the hereditary potentials and limitations of an individual. distributions of CipR isolates of 2002 (24) and 2006 were compared (Figure). Although isolates from 2006 belonged to 29 different serotypes, 5 serotypes (14, 9V, 8, 19A, and 6B) accounted for 44.9% of the total. The rate of PCV7 serotypes among CipR isolates decreased (p<0.001) in 2006 (Table 1) because of a decrease in serotypes 23F, 19F, and 6B (Figure, panel A). Forty-nine genotypes were observed among the 98 CipR isolates (Figure, panel B). Clones [Spain.sup.9V]-ST156 (21 isolates) and [Sweden.sup.15A]-ST63 (13 isolates) accounted for 34.7% of the CipR isolates. Capsular cap·su·lar adj. Of, relating to, or resembling a capsule. Adj. 1. capsular - resembling a capsule; "the capsular ligament is a sac surrounding the articular cavity of a freely movable joint and attached to the bones" switch events were frequent in these clones (Figure): [Spain.sup.9V]-ST156 (12 switches) and [Sweden.sup.15A]-ST63 (11 switches). Four new genotypes related to non-PCV7 serotypes, ([ST97.sup.10A], [ST570.sup.16], [ST433.sup.22], [ST717.sup.33], each represented by 3 isolates) emerged in 2006 (Figure, panel B). [FIGURE OMITTED] As we observed, isolates that shared the same PFGE pattern also shared identical polymorphisms on their DNA topoisomerase QRDRs. All but 1 of the isolates belonging to the [Spain.sup.9V]-ST156 clone had identical polymorphisms, the same found in the ATCC ATCC American Type Culture Collection, see there 700671 strain representative of this clone (15); the only exception was an isolate with parC, parE, and gyrA recombinant genes. Discussion We observed a stabilization during 2002-2006 in the rates of fluoroquinolone resistance in Spain. Although the rate of Cip resistance in 2002 was 2.6% (2.2% for levofloxacin), it was 2.3% (1.7% for levofloxacin) in 2006. The rates of Cip resistance were also similar for the different age groups (3.5% for adults and 0.14% for children in 2006). However, a decrease in the rate of resistance in persons >64 years of age was found in 2006. Higher levels of resistance were found in S. pneumoniae isolated from sputa and in isolates from people >64 years of age, who more frequently have chronic obstructive pulmonary disease chronic obstructive pulmonary disease n. Abbr. COPD A chronic lung disease, such as asthma or emphysema, in which breathing becomes slowed or forced. and who have been treated with multiple regimens of antimicrobial drugs. In accordance, development of fluoroquinolone resistance has been reported for these patients (31-33). The frequency of HL-CipR resistance in adults was 2.5% (68/2,769), slightly higher than that reported for persons in other countries in Europe (34). Four factors may have contributed to the observed stabilization of resistance rates. These factors are fluoroquinolone use, change in circulating clones, no recommendation of fluoroquinolones for children, and fitness cost of resistance mutations The term resistance mutation is most commonly used to describe point mutations in virus genes that allow the virus to become resistant to treatment with a particular antiviral drug. The term is now being seen with more frequency in bacteriology and parasitology. . A direct correlation Noun 1. direct correlation - a correlation in which large values of one variable are associated with large values of the other and small with small; the correlation coefficient is between 0 and +1 positive correlation between use of fluoroquinolone and prevalence of resistance in S. pneumoniae has been described (30,35). Cip use in Spain has remained stable since 1997 at 1.1 defined daily doses Defined daily doses (DDDs) are a WHO statistical measure of drug consumption. DDDs are used to standardise the comparative usage of various drugs between themselves or between different healthcare environments. (DDDs)/1,000 inhabitants-days, whereas that of levofloxacin and moxifloxacin increased during 2002-2006 (from 0.2 to 0.4 DDDs/1,000 inhabitants-days for levofloxacin and from 0.3 to 0.4 DDDs/1,000 inhabitants-days for moxifloxacin, Agencia Espanola de Medicamentos, Madrid, Spain; http//agemed.es). Because the borderline borderline /bor·der·line/ (-lin) of a phenomenon, straddling the dividing line between two categories. borderline activity of Cip against S. pneumoniae favors acquisition of first-step parC mutations (15,36), we expected that the greater activity of levofloxacin and moxifloxacin would not favor the appearance of resistance, even if one considered their increased use. Regarding circulating pneumococcal clones, the rate of PCV7 serotypes among CipR isolates decreased from 65.3% in 2002 to 35.7% in 2006 (p<0.001). The same finding was found among CipR isolates from adults >64 years of age (7.2% in 2002 to 4.7% in 2006; p<0.02) and was probably caused by decreased transmission of pneumococci from vaccinated children to adults (37). Consequently, we have observed a decrease in 4 multidrug-resistant clones ([Spain.sup.23F]-ST81, [Spain.sup.6B]-ST90, [Spain.sup.14]-ST17, and [ST88.sup.19F]) related to PCV7-serotypes. In addition, new clones ([ST62.sup.11], [ST97.sup.10A], [ST570.sup.16], [ST433.sup.22], and [ST717.sup.33]) related to non-PCV7 serotypes emerged in 2006. These changes are consistent with those observed among invasive pneumococci after the introduction of PCV7 in Spain in June 2001 (38). At present, 2 clones, [Spain.sup.9V]-3-ST156 and [Sweden.sup.15A]-ST63, could be considered as the major contributors to Cip resistance in Spain, accounting for 34.7% of CipR strains. Fluoroquinolones are not recommended for children, who are the major reservoir of pneumococci. If fluoroquinolones are given to children, according to recent reports of their safety for such use (39), increased prevalence of resistance might occur. Regarding fitness cost of CipR mutations in S. pneumoniae, CipR isolates were divided into 3 groups. The first group is composed of 5 isolates without QRDR resistance mutations. Four isolates had a reserpine reserpine (rĕsûr`pēn), alkaloid isolated from the root of the snakeroot plant (Rauwolfia serpentina), a small evergreen climbing shrub of the dogbane family native to the Indian subcontinent. efflux phenotype. The fifth isolate may have had a different efflux inhibitor or an unknown resistance mechanism. The second group is composed of 25 LL-CipR isolates with single changes at topo IV, whose distribution, 24 at parC and 1 at parE (D435N), is consistent with the low-fitness cost of parC changes (25) and the high-fitness cost of the parE D435N change (40). The third group is composed of 68 HL-CipR isolates with gyrA changes associated with topo IV changes. GyrA changes mainly occurred at S81 (62/68), whereas changes at E85 were rare (8/68) because of the high-fitness cost of E85 changes (25). The frequency of CipR recombinants in 2006 remained low (5.1%, 5/98 CipR isolates), similar to that in 2002 (6.7%) and that reported previously (3,4). Four isolates with mosaic parE-parC genes and long intergenic regions An Intergenic region is a stretch of DNA sequences located between clusters of genes that comprise a large percentage of the human genome but contain few or no genes. Occasionally some intergenic DNA acts to control genes close by, but most of it has no currently known function. (4-6 kb) containing the ant gene probably originated by recombination with the S. mitis group (4). One of them belongs to the [Spain.sup.9V]-ST156 clone and was not typeable. The predominance pre·dom·i·nance also pre·dom·i·nan·cy n. The state or quality of being predominant; preponderance. Noun 1. predominance - the state of being predominant over others predomination, prepotency of this clone and the fact that the recombinant parE-ant-parC structure did not impose a fitness cost (25) suggest recombinants could become more prevalent in the future. Acknowledgment Ciber Enfermedades Respiratorias is an initiative of the Instituto de Salud Carlos III Carlos III may refer to:
This study was supported by grant BIO2008-02154 from Plan Nacional de I+D I+D Investigación y Desarrollo (Spanish: Research and Development) +I of Ministerio de Ciencia e Innovacion and COMBACT-S-BIO-0260/2006 from Comunidad de Madrid. Dr de la Campa La Campa is an aldea, or small town, in the Honduran Department of Lempira, located about 18 kilometers by dirt road from Gracias, the largest town in the immediate region. is a research scientist at the Instituto de Salud Carlos III in Madrid, Spain. Her research interest focuses primarily on the molecular basis of antimicrobial drug resistance in bacteria. References (1.) Jacobs MR, Felmingham D, Appelbaum PC, Gruneberg RN; the Alexander Project Group. The Alexander Project 1998-2000: susceptibility of pathogens isolated from community-acquired respiratory tract infection Noun 1. respiratory tract infection - any infection of the respiratory tract respiratory infection infection - the pathological state resulting from the invasion of the body by pathogenic microorganisms to commonly used antimicrobial agents Antimicrobial agents Chemical compounds biosynthetically or synthetically produced which either destroy or usefully suppress the growth or metabolism of a variety of microscopic or submicroscopic forms of life. . J Antimicrob Chemother. 2003;52:229-46. DOI (Digital Object Identifier) A method of applying a persistent name to documents, publications and other resources on the Internet rather than using a URL, which can change over time. : 10.1093/jac/dkg321 (2.) Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases infectious diseases: see communicable diseases. Society of America/ American Thoracic Society American Thoracic Society (ATS ), established in 1905, is an independently incorporated, international, educational and scientific society, serving its 18,000 members world-wide who are dedicated in respiratory and critical care medicine. consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27-72. DOI: 10.1086/511159 (3.) Stanhope stan·hope n. A light, open, horse-drawn carriage with one seat and two or four wheels. [After the Reverend Fitzroy Stanhope (1787-1864), British clergyman.] Noun 1. MJ, Walsh SL, Becker JA, Italia MJ, Ingraham KA, Gwynn MN, et al. Molecular evolution perspectives on intraspecific lateral DNA transfer of topoisomerase topoisomerase an enzyme involved in DNA replication that introduces a single-strand nick in the DNA enabling it to swivel and thereby relieve the accumulated winding strain generated during unwinding of the double helix. and gyrase loci loci [L.] plural of locus. loci Plural of locus, see there in Streptococcus pneumoniae, with implications for fluoroquinolone resistance development and spread. Antimicrob Agents Chemother. 2005;49:4315-26. DOI: 10.1128/AAC.49.10.4315-4326.2005 (4.) Balsalobre L, Ferrandiz MJ, Linares J, Tubau F, de la Campa AG. Viridans group streptococci Streptococcus (plural, streptococci) A genus of spherical-shaped anaerobic bacteria occurring in pairs or chains. Sydenham's chorea is considered a complication of a streptococcal throat infection. are donors in horizontal transfer of topoisomerase IV Topoisomerase IV is one of two type-II topoisomerases in bacteria, the other being DNA gyrase. Like gyrase, topoisomerase IV is able to pass one double-strand of DNA through another double-strand of DNA, thereby changing the linking number of DNA by two in each enzymatic step. genes to Streptococcus pneumoniae. Antimicrob Agents Chemother. 2003;47:2072-81. DOI: 10.1128/ AAC (Advanced Audio Coding) An audio compression technology that is part of the MPEG-2 and MPEG-4 standards. AAC, especially MPEG-4 AAC, provides greater compression and better sound quality than MP3, which also came out of the MPEG standard. .47.7.2072-2081.2003 (5.) Bast Bast, in Egyptian religion Bast (băst), ancient Egyptian cat goddess. At first a goddess of the home, she later became known as a goddess of war. The center of her cult was at Bubastis. Her name also appears as Ubast. DJ, de Azevedo JCS JCS abbr. Joint Chiefs of Staff JCS (US) n abbr (= Joint Chiefs of Staff) → Stabschefs pl , Tam TY, Kilburn L, Duncan C, Mandell LA, et al. Interspecies recombination contributes minimally to fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother. 2001;45:2631-4. DOI: 10.1128/AAC.45.9.2631-2634.2001 (6.) Yokota S Yokota can refer to:
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Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob Agents Chemother. 1996;40:2321-6. (13.) Fernandez-Moreira E, Balas D, Gonzalez I, de la Campa AG. Fluoroquinolones inhibit preferentially Streptococcus pneumoniae DNA topoisomerase IV than DNA gyrase native proteins. Microb Drug Resist. 2000;6:259-67. DOI: 10.1089/mdr.2000.6.259 (14.) Houssaye S, Gutmann L, Varon E. Topoisomerase mutations associated with in vitro selection of resistance to moxifloxacin in Streptococcus pneumoniae. Antimicrob Agents Chemother. 2002;46:2712-5. DOI: 10.1128/AAC.46.8.2712-2715.2002 (15.) de la Campa AG, Ferrandiz MJ, Tubau F, Pallares R, Manresa F, Linares J. Genetic characterization of fluoroquinolone-resistant Streptococcus pneumoniae strains isolated during ciprofloxacin therapy from a patient with bronchiectasis bronchiectasis Abnormal expansion of bronchi in the lungs. It usually results when preexisting lung disease causes bronchial inflammation and obstruction. Bronchial wall fibres degenerate, and bronchi become dilated or paralyzed, preventing removal of secretions, which . Antimicrob Agents Chemother. 2003;47:1419-22. DOI: 10.1128/AAC.47.4.1419-1422.2003 (16.) Adam HJ, Schurek KN, Nichol KA, Hoban CJ, Baudry TJ, Laing NM, et al. Molecular characterization of increasing fluoroquinolone resistance in Streptococcus pneumoniae isolates in Canada, 1997 to 2005. Antimicrob Agents Chemother. 2007;51:198-207. DOI: 10.1128/AAC.00609-06 (17.) Morrissey I, Colclough A, Northwood J. TARGETed surveillance: susceptibility of Streptococcus pneumoniae isolated from community-acquired respiratory tract infections in 2003 to fluoroquinolones and other agents. Int J Antimicrob Agents. 2007;30:345-51. DOI: 10.1016/j.ijantimicag.2007.05.021 (18.) Whitney CG, Farley MM, Hadler J, Harrison LH, Bennett NM, Lynfield R, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine A conjugate vaccine is created by covalently attaching a poor antigen to a carrier protein, thereby conferring the immunological attributes of the carrier on the attached antigen. . N Engl J Med. 2003;348:1737-46. DOI: 10.1056/NEJMoa022823 (19.) Kyaw MH, Lynfield R, Schaffner W, Craig AS, Hadler J, Reingold A, et al. Effect of introduction of the pneumococcal conjugate vaccine Pneumococcal conjugate vaccine is a vaccine used to protect infants and young children against disease caused by the bacterium Streptococcus pneumoniae (pneumococcus). on drug-resistant Streptococcus pneumoniae. N Engl J Med. 2006;354:1455-63. DOI: 10.1056/NEJMoa051642 (20.) Beall B, McEllistrem MC, Gertz RE Jr, Wedel S we·del intr.v. we·deled, we·del·ling, we·dels To ski on snow by means of wedeln. [Back-formation from wedeln.] Verb 1. , Boxrud DJ, Gonzalez AL, et al. Pre- and postvaccination clonal compositions of invasive pneumococcal serotypes for isolates collected in the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area. in 1999, 2001, and 2002. J Clin Microbiol. 2006;44:999-1017. DOI: 10.1128/JCM.44.3.999-1017.2006 (21.) Munoz-Almagro C, Jordan I, Gene A, Latorre C, Garcia-Garcia JJ, Pallares R. Emergence of invasive pneumococcal disease caused by nonvaccine serotypes in the era of 7-valent conjugate vaccine. Clin Infect Dis. 2008;46:174-82. DOI: 10.1086/524660 (22.) Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; Eighteenth informational supplement. CLSI CLSI Clinical and Laboratory Standards Institute (Wayne, PA) CLSI Cisco Link Services Interface document M100-S18. Wayne (PA): The Institute; 2008. (23.) Ferrandiz MJ, Oteo J, Aracil B, Gomez-Garces JL, de la Campa AG. Drug efflux and parC mutations are involved in fluoroquinolone resistance in viridans group streptococci. Antimicrob Agents Chemother. 1999;43:2520-3. (24.) de la Campa AG, Balsalobre L, Ardanuy C, Fenoll A, Perez-Trallero E, Linares J. Fluoroquinolone resistance in penicillin-resistant Streptococcus pneumoniae clones, Spain. Emerg Infect Dis. 2004;10:1751-9. (25.) Balsalobre L, de la Campa AG. Fitness of Streptococcus pneumoniae fluoroquinolone-resistant strains with topoisomerase IV recombinant genes. Antimicrob Agents Chemother. 2008;52:822-30. DOI: 10.1128/AAC.00731-07 (26.) McGee L, McDougal L, Zhou J, Spratt BG, Tenover FC, George R, et al. Nomenclature nomenclature /no·men·cla·ture/ (no´men-kla?cher) a classified system of names, as of anatomical structures, organisms, etc. binomial nomenclature of major antimicrobial-resistant clones of Streptococcus pneumoniae defined by the pneumococcal molecular epidemiology network. J Clin Microbiol. 2001;39:2565-71. DOI: 10.1128/JCM.39.7.2565-2571.2001 (27.) Tenover FC, Arbeit R, Goering RV, Mickelsen PA, Murray BE, Persing DH, et al. Interpreting chromosomal DNA restriction patterns produced by pulse-field gel electrophoresis: criteria for bacterial strain typing. J Clin Microbiol. 1995;33:2233-9. (28.) Enright MC, Spratt BG. A multilocus sequence typing scheme for Streptococcus pneumoniae: identification of clones associated with serious invasive disease. Microbiology. 1998;144:3049-60. (29.) Gonzalez I, Georgiou M, Alcaide al·cai·de also al·cay·de n. The commander or governor of a fortress in Spain or Portugal. [Spanish, from Arabic al-q F, Balas D, Linares J, de la Campa AG. Fluoroquinolone resistance mutations in the parC, parE, and gyrA genes of clinical isolates of viridans group streptococci. Antimicrob Agents Chemother. 1998;42:2792-8. (30.) Chen DK, McGeer A, de Azavedo JC, Low DE. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. N Engl J Med. 1999;341:233-9. DOI: 10.1056/ NEJM NEJM New England Journal of Medicine 199907223410403 (31.) Perez-Trallero E, Marimon JM, Iglesias L, Larruskain J. Fluoroquinolone and macrolide treatment failure in pneumococcal pneumonia Pneumococcal Pneumonia Definition Pneumococcal pneumonia is a common but serious infection and inflammation of the lungs. It is caused by the bacterium Streptococcus pneumoniae. and selection of multidrug-resistant isolates. Emerg Infect Dis. 2003;9:1159-62. (32.) Perez-Trallero E, Marimon JM, Gonzalez A, Ercibengoa M, Larruskain J. In vivo development of high-level fluoroquinolone resistance in Streptococcus pneumoniae in chronic obstructive pulmonary disease. Clin Infect Dis. 2005;41:560-4. DOI: 10.1086/432062 (33.) de Cueto M, Rodriguez JM, Soriano MJ, Lopez-Cerero L, Venero J, Pascual A. Fatal levofloxacin failure in treatment of a bacteremic bac·te·re·mi·a n. The presence of bacteria in the blood. bac  te·re patient infected with Streptococcus pneumoniae with a preexisting pre·ex·ist or pre-ex·ist v. pre·ex·ist·ed, pre·ex·ist·ing, pre·ex·ists v.tr. To exist before (something); precede: Dinosaurs preexisted humans. v.intr. parC mutation. J Clin Microbiol. 2008;46:1558-60. DOI: 10.1128/ JCM JCM Journal of Clinical Microbiology JCM Journal of Chinese Medicine JCM Japan Collection of Microorganisms JCM Joint Common Missile JCM Journal of Conceptual Modeling JCM Joint Commission Meeting JCM Journal of Composite Materials JCM Job Characteristics Model .02066-07 (34.) Reinert RR, Reinert S, van der Linden Linden, city, United States Linden, city (1990 pop. 36,701), Union co., NE N.J., in the New York metropolitan area; inc. 1925. During the first half of the 20th cent. M, Cil MY, Al-Lahham A, Appelbaum P. Antimicrobial susceptibility of Streptococcus pneumoniae in eight European countries from 2001 to 2003. Antimicrob Agents Chemother. 2005;49:2903-13. DOI: 10.1128/ AAC.49.7.2903-2913.2005 (35.) Linares J, de la Campa AG, Pallares R. Fluoroquinolone resistance in Streptococcus pneumoniae. N Engl J Med. 1999;341:1546-7. DOI: 10.1056/NEJM199911113412013 (36.) Perez-Trallero E, Garcia-Arenzana JM, Jimenez JA, Peris A. Therapeutic failure and selection of resistance to quinolones in a case of pneumococcal pneumonia treated with ciprofloxacin. Eur J Clin Microbiol Infect Dis. 1990;9:905-6. DOI: 10.1007/BF01967510 (37.) Lexau CA, Lynfield R, Danila R, Pilishvili T, Facklam R, Farley MM, et al. Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pediatric /pe·di·at·ric/ (pe?de-at´rik) pertaining to the health of children. pe·di·at·ric adj. Of or relating to pediatrics. pneumococcal conjugate vaccine. JAMA JAMA abbr. Journal of the American Medical Association . 2005;294:2043-51. DOI: 10.1001/ jama.294.16.2043 (38.) Ardanuy C, Tubau F, Pallares R, Calatayud L, Dominguez MA, Rolo D, et al. Epidemiology of invasive pneumococcal disease among adult patients in Barcelona before and after pediatric 7-valent conjugate vaccine introduction, 1997-2007. Clin Infect Dis. 2009;48:57-64. DOI: 10.1086/594125 (39.) Murray TS, Baltimore RS. Pediatric uses of fluoroquinolone antibiotics. Pediatr Ann. 2007;36:336-42. (40.) Rozen DE, McGee L, Levin BR, Klugman KP. Fitness costs of fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007;51:412-6. DOI: 10.1128/AAC.01161-06 DOI: 10.3201/eid1506.080684 Adela G. de la Campa, Carmen Carmen throws over lover for another. [Fr. Lit.: Carmen; Fr. Opera: Bizet, Carmen, Westerman, 189–190] See : Faithlessness Carmen the cards repeatedly spell her death. [Fr. Ardanuy, Luz Balsalobre, Emilio Perez-Trallero, Jose M. Marimon, Asuncion Fenoll, and Josefina Linares Address for correspondence: Adela G. de la Campa, Unidad de Genetica Bacteriana, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain; email: agcampa@isciii.es Author affiliations: Instituto de Salud Carlos III, Madrid, Spain (A.G. de la Campa, L. Balsalobre, A. Fenoll); Ciber Enfermedades Respiratorias, Mallorca, Spain (A.G. de la Campa, C. Ardanuy, L. Balsalobre, E. Perez-Trallero, J. M. Marimon, J. Linares); Hospital Universitary de Bellvitge, Barcelona, Spain (C. Ardanuy, J. Linares); and Hospital Donostia, San Sebastian, Spain (E. Perez-Trallero, J.M. Marimon)
Table 1. Comparison of 2 surveillance studies on ciprofloxacin-
resistant Streptococcus pneumoniae isolates in Spain, 2002 and
2006 *
No. ciproflaxin resistant/
no. isolates (%)
Characteristic 2002 2006
Ciproflaxin resistance
Global 75/2,882 (2.6) 98/4,215 (2.3)
Low-level (MICs 4-8 [micro]g/mL) 14/75 (18.7) 30/98 (30.6)
High-level (MICs [greater than 61/75 (81.3) 68/98 (69.4)
or equal to] 16 [micro]g/mL)
In persons <15 years of age 0/978 (0) 2/1,446 (0.14)
In persons 15-64 years of age 22/1,166 (1.9) 34/1,455 (2.3)
In persons >64 years of age 53/738 (7.2) 62/1,314 (4.7)
PCV7 serotypes 49/75 (65.3) 35/98 (35.7)
Other antimicrobial drug resistance No. resistant/no. ciproflaxin-
resistant isolates (%)
Penicillin MIC [greater than or 55/75 (73.3) 44/98 (44.9)
equal to] 0.12 [micro]g/mL
Erythromycin MIC [greater than 53/75 (70.7) 53/98 (54.1)
or equal to] 0.5 [micro]g/mL
Clindamycin MIC [greater than 47/75 (62.7) 45/98 (45.9)
or equal to] 1 [micro]g/mL
Chloramphenicol MIC [greater 33/75 (44.0) 11/98 (11.2)
than or equal to] 8 [micro]g/mL
Tetracycline MIC [greater than 52/75 (69.3) 39/98 (39.8)
or equal to] 4 [micro]g/mL
Cotrimoxazole MIC [greater than 51/75 (68.0) 47/98 (47.8)
or equal to] 4/76
[micro]g/mL ([dagger])
Multidrug resistance ([greater than 55/75 (73.3) 48/98 (49.0)
or equal to] 3 drugs)
Characteristic p value
Ciproflaxin resistance
Global NS
Low-level (MICs 4-8 [micro]g/mL) NS
High-level (MICs [greater than NS
or equal to] 16 [micro]g/mL)
In persons <15 years of age NS
In persons 15-64 years of age NS
In persons >64 years of age 0.02
PCV7 serotypes <0.001
Other antimicrobial drug resistance
Penicillin MIC [greater than or <0.001
equal to] 0.12 [micro]g/mL
Erythromycin MIC [greater than 0.03
or equal to] 0.5 [micro]g/mL
Clindamycin MIC [greater than 0.03
or equal to] 1 [micro]g/mL
Chloramphenicol MIC [greater <0.001
than or equal to] 8 [micro]g/mL
Tetracycline MIC [greater than <0.001
or equal to] 4 [micro]g/mL
Cotrimoxazole MIC [greater than 0.008
or equal to] 4/76
[micro]g/mL ([dagger])
Multidrug resistance ([greater than <0.001
or equal to] 3 drugs)
* NS, not significant; PCV7, 7-valent conjugate pneumococcal vaccine.
Ciproflaxin resistance is defined by Chen et al. (30) as an MIC
[greater than or equal to] 4 [micro]g/mL.
([dagger]) MIC is 4 [micro]g/mL for trimethoprim and 76 [micro]g/mL
for sulfamethoxazole.
Table 2. Fluoroquinolone MICs of 30 low-level resistant Streptococcus
pneumoniae isolates and 5 laboratory strains and amino acid changes
in their DNA topoisomerase IV and gyrase genes, Spain, 2006 *
Amino acid substitution
parC
No.
isolates S79 S80 D83
1 -- -- --
3 -- -- --
1 -- ([double -- ([double -- ([double
dagger]) dagger]) dagger])
9 F -- --
3 F -- --
1 F -- --
1 F ([double -- ([double -- ([double
dagger]) dagger]) * dagger])
5 Y -- --
1 Y -- --
1 -- -- N
1 -- -- N
1 -- -- Y
1 -- -- Y
1 -- -- --
Laboratory strains ([section])
R6
R[6.sup.CS80P] -- P --
T1 F -- --
T[1.sup.AS81V] F -- --
T[1.sup.AE85G] F -- --
Amino acid substitution
parE
No.
isolates D435E 474
1 -- --
3 -- --
1 -- ([double dagger]) -- ([double dagger])
9 -- --
3 -- --
1 -- --
1 -- ([double dagger]) -- ([double dagger])
5 -- --
1 -- --
1 -- --
1 -- --
1 -- --
1 -- --
1 N --
Laboratory strains ([section])
R6
R[6.sup.CS80P] -- --
T1 -- --
T[1.sup.AS81V] -- --
T[1.sup.AE85G] -- --
Amino acid substitution
gyrA
No.
isolates S81 E85
1 -- --
3 -- --
1 -- ([double dagger]) -- ([double dagger])
9 -- --
3 -- --
1 -- ([double dagger]) -- ([double dagger])
1 -- ([double dagger]) -- ([double dagger])
5 -- --
1 -- --
1 -- --
1 -- --
1 -- --
1 -- --
1 -- --
Laboratory strains ([section])
R6
R[6.sup.CS80P] -- --
T1 -- --
T[1.sup.AS81V] V --
T[1.sup.AE85G] -- G
MIC, [micro]g/mL
No. Efflux
isolates CIP LVX MXF phenotype ([dagger])
1 4 1 0.12 None
3 4-8 2 0.5 CIP
1 8 4 0.5 CIP
9 4-8 1-2 0.25-0.50 None
3 4-8 2 0.12-0.25 CIP
1 8 1 0.12 None
1 8 2 0.12 CIP,
5 4-8 2 0.12-0.25 None
1 4 2 0.25 CIP
1 16 4 0.5 None
1 4 2 0.12 CIP
1 4 1 0.5 None
1 8 2 0.5 CIP
1 8 2 0.12 None
Laboratory strains ([section])
R6 0.5 0.25 0.12 None
R[6.sup.CS80P] 2 1 0.25 None
T1 4 2 0.12 None
T[1.sup.AS81V] 32 32 4 None
T[1.sup.AE85G] 32 8 2 None
* par, topoisomerase gene; gyr, gyrase gene; CIP, ciprofloxacin;
LVX, levofloxacin; MXF, moxifloxacin. Only changes involved in
resistance are shown. --, no change. Additional amino acid changes
not involved in resistance were parC D78N (1 isolate), parC K137
N (9), parC N91D (2 with mosaic parC genes), parE I460V (17),
parE I476F (1), gyrA S114G (2 with mosaic gyrA genes), and gyrA
N150H (1 with a mosaic gyrA gene).
([dagger]) An isolate was considered to have an efflux phenotype
for the indicated fluoroquinolone when a [greater than or equal
to] 2-fold decrease in its MIC in the presence of reserpine was
observed.
([double dagger]) Indicates that the residue is located in a
recombinant gene.
([section]) R[6.sup.CS80P], R6 derivative carrying parC S80P;
T[1.sup.AS81V], T1-derivative carrying gyrA S81V; T[1.sup.AE85G],
T1-derivative carrying gyrA E85K.
Table 3. Fluoroquinolone MICs of 68 high-level resistant Streptococcus
pneumoniae isolates and amino acid changes in their DNA topoisomerase
IV and gyrase genes, Spain, 2006 *
Amino acid substitution
parC
No.
isolates S79 S80 D83
4 F -- --
21 F -- --
1 F -- --
1 F -- --
3 F -- --
1 F -- --
2 F -- --
1 Y ([double -- ([double -- ([double
dagger]) dagger]) dagger])
8 Y -- --
1 Y -- --
1 Y -- --
1 Y -- --
1 v P --
1 -- -- H
1 -- -- Y
2 -- -- Y
1 -- -- N
3 -- -- --
1 -- ([double -- ([double -- ([double
dagger]) dagger]) dagger])
1 F -- G
2 F -- G
1 F -- G
1 F -- H
2 F -- N
2 F -- --
1 F -- --
1 F -- --
1 F -- --
1 F -- --
Amino acid substitution
parE
No.
isolates D435E 474
4 -- --
21 -- --
1 -- --
1 -- --
3 -- --
1 -- --
2 -- --
1 -- ([double dagger]) -- ([double dagger])
8 -- --
1 -- --
1 -- --
1 -- --
1 -- --
1 -- --
1 -- --
2 -- --
1 -- --
3 N --
1 N ([double dagger]) -- ([double dagger])
1 -- --
2 -- --
1 -- --
1 -- --
2 -- --
2 N --
1 N --
1 -- K
1 -- --
1 -- --
Amino acid substitution
gyrA
No.
isolates S81 E85
4 F --
21 F --
1 L --
1 V --
3 Y --
1 -- G
2 -- K
1 F ([double dagger]) -- ([double dagger])
8 F --
1 F --
1 Y --
1 -- K
1 F --
1 F --
1 F --
2 F --
1 -- K
3 F --
1 F ([double dagger]) -- ([double dagger])
1 F --
2 F --
1 L --
1 F --
2 F --
2 F --
1 -- K
1 F --
1 F A
1 F K
MIC, [micro]g/mL
No. Efflux
isolates CIP LVX MXF phenotype ([dagger])
4 64 16-32 4 CIP
21 32-128 16-32 2-8 None
1 64 32 2 None
1 64 32 4 CIP
3 64-128 16-32 4 None
1 32 16 4 None
2 32-64 16-32 2-4 None
1 64 32 4 None
8 32-64 16-32 2-4 None
1 64 32 4 CIP, LVX
1 64 32 4 None
1 32 16 2 None
1 16 4 0.5 None
1 32 16 2 CIP
1 32 16 2 CIP
2 32 8-16 2-4 None
1 16 8 2 None
3 16 8 0.5-2 None
1 16 4 0.5 CIP
1 64 32 4 CIP, LVX
2 32-64 32 4 None
1 64 64 16 None
1 64 32 4 None
2 32-64 16-32 4 None
2 64-128 32-128 4-32 None
1 16 32 4 None
1 64 32 4 None
1 64 16 4 None
1 32 32 4 None
* par, topoisomerase gene; gyr, gyrase gene; CIP, ciprofloxacin;
LVX, levofloxacin; MXF, moxifloxacin. Only changes involved in
resistance are shown. --, no change. Additional amino acid changes
not involved in resistance were parC D83E (1), parC K137 N (24),
parC N91D (2 with mosaic parC genes), parE I460V (47), and gyrA
S114G (2 with mosaic gyrA genes).
([dagger]) An isolate was considered to have an efflux phenotype
for the indicated fluoroquinolone when a [greater than or equal to]
2-fold decrease in its MIC in the presence of reserpine was observed.
([double dagger]) Indicates that the residue is located in a
recombinant gene.
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