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PubMed1989

Resistance to drugs associated with the multidrug resistance phenotype following selection with high-concentration methotrexate.

To study patterns of resistance at extreme but nevertheless clinically relevant drug concentrations, we developed a series of methotrexate-selected CCRF-CEM sublines, all of which were highly resistant to this antifolate (relative resistance, 10(2)- to greater than 10(5)-fold). The least methotrexate-resistant subline was completely sensitive to drugs associated with the multidrug resistance phenotype. However, more highly methotrexate-resistant sublines were significantly cross-resistant to vincristine, vinblastine, and dactinomycin (maximum relative resistance, 40-fold). These sublines were not cross-resistant to doxorubicin, daunorubicin, and teniposide. Regression analysis indicated that relative resistance to methotrexate was correlated with relative resistance to vincristine (r = 0.96) and vinblastine (r = 0.99). Such cross-resistance in highly methotrexate-resistant cells may have important clinical implications.

Antineoplastic Agents↗
PubMed2001

Carrier rate of zidovudine-resistant HIV-1: the impact of failing therapy on transmission of resistant strains.

OBJECTIVE: Because maintenance of treatment success in HIV-1 infection requires viruses to remain therapy sensitive in drug-naive seropositive persons, we looked at the primary infections caused by drug-resistant HIV-1 over time. Furthermore, to study the coverage rate of therapy and therapy failure in relation to the transmission of resistant viruses a mathematical model was developed. DESIGN: The reverse transcriptase and protease genes of viruses were analysed in newly infected people in the period 1990-1998 in the Amsterdam Cohort Study on HIV infection and AIDS in homosexual men. METHODS: The mathematical model was based on the coverage of drug regimens selecting zidovudine (ZDV) resistance, the lag time in which resistance is gained or lost, the death rate of people infected with resistant virus, and the replacement of resistance-selecting regimens by more potent treatments that substantially reduce viral load and mortality. RESULTS: Of 43 individuals with a primary HIV-infection, three (7%) harboured ZDV-resistant viruses. The first of the ZDV-resistant strains was transmitted in 1995, the last two in 1996. The build-up of ZDV resistance was described by the mathematical model indicating that the equilibrium level of resistance due to treatment depends only on the treatment rate and the outflow rate of patients with resistance virus. CONCLUSIONS: Our model indicates that the frequency of viral resistance in a population is determined largely by the number of individuals on insufficient or failing therapy and is influenced only modestly by secondary transmission of ZDV-resistant strains.

Anti-HIV Agents↗
PubMed2002

[Drug resistance of enterohemorrhagic Escherichia coli O157 and a possible relation of plasmids to the drug-resistance].

Antimicrobial susceptibility was examined using 89 enterohemorrhagic Escherichia coli O157 isolates obtained from diarrhea patients in Aichi Prefecture, Japan between June 1996 and June 1997. Among the 89 isolates, 15 (16.9%) were found to be resistant to 6 of 9 antibiotics examined. These 6 antibiotics were ampicillin (ABPC), cefaloridine (CER), chloramphenicol (CP), kanamycin (KM), streptomycin (SM), and tetracycline (TC). Among the 15 drug-resistant isolates, 7 were resistant to 4 drugs (ABPC, CER, SM, TC), 3 were resistant to 3 (ABPC and 2 of CER, SM, TC), 2 were resistant to 2 (SM, TC), one each to KM or SM. Another isolate showed resistance to 5 drugs (ABPC, CP, KM, SM, TC). Selected 13 drug-sensitive and selected 12 multi-drug resistant isolates were tested for the presence of plasmids. All of the drug-sensitive isolates had 54 MDa plasmid and the majority (8/13) had 2.0 MDa plasmids, whereas; all of the drug-resistant isolates except one (1/12) had 54 MDa plasmid and the majority had 8.0 MDa (9/12) and 4.2 MDa (11/12) plasmids. The first transformation test revealed that plasmids of 8.0 MDa (3/4) and 46 MDa (1/4) were transferred to a donor cell with ABPC resistance. 54 MDa plasmid was transferred to a donor cell with both of ABPC and TC resistance. In the second transformation test, only the 8.0 MDa plasmid was confirmed to be transferred to a donor cell with ABPC resistance. Accordingly, it was indicated that the ABPC resistant gene was carried on 8.0 MDa plasmid, and it was suggested that resistant genes for ABPC and TC, and ABPC were carried on 54 MDa, and on 46 MDa plasmids, respectively.

Ampicillin↗
PubMed1982

Candida albicans resistance to 5-fluorocytosine: frequency of partially resistant strains among clinical isolates.

Resistance to 5-fluorocytosine was studied in 137 independent Candida albicans clinical isolates. Seventy-eight isolates (57%) were susceptible; 51 isolates (37%) were partially resistant; 8 isolates (6%) were highly resistant. All partially resistant isolates gave rise to variants which were highly resistant. Some susceptible isolates gave rise to variants which were highly resistant; two such isolates were shown to be heterozygous for resistance, and these isolates define a new type of heterozygote. A partially resistant isolate gave rise to resistant variants which were auxotrophic for lysine; this result was interpreted as preliminary evidence that the allele which determined resistance was linked to an allele which determined auxotrophy for lysine. It is suggested that heterozygotes constitute a source of preexisting mutant alleles which determine resistance, and that 5-fluorocytosine treatment of infections due to heterozygotes may result in significant selection for resistant variants. A simple screening procedure is described by which partially resistant strains may be recognized.

Candida albicans↗
PubMed1994

Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: active efflux as a contributing factor to beta-lactam resistance.

Wild-type strains of Pseudomonas aeruginosa are more resistant to various beta-lactam antibiotics as well as other agents than most enteric bacteria. Although resistance to compounds of earlier generations is explained by the synergism between the outer membrane barrier and the inducible beta-lactamase, it was puzzling to see significant levels of resistance to compounds that do not act as inducers or are not hydrolyzed rapidly by the chromosomally encoded enzyme. This intrinsic-resistance phenotype becomes enhanced in those strains with the so-called intrinsic carbenicillin resistance. In the accompanying paper (X.-Z. Li, D. M. Livermore, and H. Nikaido, Antimicrob. Agents Chemother. 38:1732-1741, 1994), we showed that active efflux played a role in the resistance, to various non-beta-lactam agents, of P. aeruginosa strains in general and that the efflux was enhanced in intrinsically carbenicillin-resistant strains. We show in this paper that, in comparison with the drug-hypersusceptible mutant K799/61, less benzylpenicillin was accumulated in wild-type strains of P. aeruginosa and that the accumulation levels were even lower in intrinsically carbenicillin-resistant strains. Deenergization by the addition of a proton conductor increased the accumulation level to that expected for equilibration across the cytoplasmic membrane. In intrinsically carbenicillin-resistant isolates, there was no evidence that either nonspecific or specific permeation rates of beta-lactams across the outer membrane were lowered in comparison with those of the more susceptible isolates. Furthermore, these carbenicillin-resistant isolates were previously shown to have no alteration in the level or the inducibility of beta-lactamase and in the affinity of penicillin-binding proteins. These data together suggest the involvement of an active efflux mechanism also in the resistance to beta-lactams. Hydrophilic beta-lactams with more than one charged group did not cross the cytoplasmic membrane readily. Yet one such compound, ceftriaxone, appeared to be extruded from the cells of more-resistant strains, although with this compound effects of proton conductors could not be shown. We postulate that wild-type strains of P. aeruginosa pump out such hydrophilic beta-lactams either from the periplasm or from the outer leaflet of the lipid bilayer of the cytoplasmic membrane, in a manner analogous to that hypothesized for multidrug resistance protein of human cancer cells (M.M. Gottesman and I. Pastan, Annu. Rev. Biochem. 62:385-427, 1993).

Anti-Bacterial Agents↗
PubMed2001

Prevalence of molecular mechanisms of resistance to azole antifungal agents in Candida albicans strains displaying high-level fluconazole resistance isolated from human immunodeficiency virus-infected patients.

Molecular mechanisms of azole resistance in Candida albicans, including alterations in the target enzyme and increased efflux of drug, have been described, but the epidemiology of the resistance mechanisms has not been established. We have investigated the molecular mechanisms of resistance to azoles in C. albicans strains displaying high-level fluconazole resistance (MICs, > or =64 microg/ml) isolated from human immunodeficiency virus (HIV)-infected patients with oropharyngeal candidiasis. The levels of expression of genes encoding lanosterol 14alpha-demethylase (ERG11) and efflux transporters (MDR1 and CDR) implicated in azole resistance were monitored in matched sets of susceptible and resistant isolates. In addition, ERG11 genes were amplified by PCR, and their nucleotide sequences were determined in order to detect point mutations with a possible effect in the affinity for azoles. The analysis confirmed the multifactorial nature of azole resistance and the prevalence of these mechanisms of resistance in C. albicans clinical isolates exhibiting frank fluconazole resistance, with a predominance of overexpression of genes encoding efflux pumps, detected in 85% of all resistant isolates, being found. Alterations in the target enzyme, including functional amino acid substitutions and overexpression of the gene that encodes the enzyme, were detected in 65 and 35% of the isolates, respectively. Overall, multiple mechanisms of resistance were combined in 75% of the isolates displaying high-level fluconazole resistance. These results may help in the development of new strategies to overcome the problem of resistance as well as new treatments for this condition.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Mechanism and suppression of lysostaphin resistance in oxacillin-resistant Staphylococcus aureus.

The potential for the development of resistance in oxacillin-resistant Staphylococcus aureus (ORSA) to lysostaphin, a glycylglycine endopeptidase produced by Staphylococcus simulans biovar staphylolyticus, was examined in vitro and in an in vivo model of infection. Following in vitro exposure of ORSA to subinhibitory concentrations of lysostaphin, lysostaphin-resistant mutants were idenitifed among all isolates examined. Resistance to lysostaphin was associated with a loss of resistance to beta-lactams and a change in the muropeptide interpeptide cross bridge from pentaglycine to a single glycine. Mutations in femA, the gene required for incorporation of the second and third glycines into the cross bridge, were found following PCR amplification and nucleotide sequence analysis. Complementation of lysostaphin-resistant mutants with pBBB31, which encodes femA, restored the phenotype of oxacillin resistance and lysostaphin susceptibility. Addition of beta-lactam antibiotics to lysostaphin in vitro prevented the development of lysostaphin-resistant mutants. In the rabbit model of experimental endocarditis, administration of a low dose of lysostaphin for 3 days led predictably to the appearance of lysostaphin-resistant ORSA mutants in vegetations. Coadministration of nafcillin with lysostaphin prevented the emergence of lysostaphin-resistant mutants and led to a mean reduction in aortic valve vegetation counts of 7.5 log(10) CFU/g compared to those for untreated controls and eliminated the isolation of lysostaphin-resistant mutants from aortic valve vegetations. Treatment with nafcillin and lysostaphin given alone led to mean reductions of 1.35 and 1.65 log(10) CFU/g respectively. In ORSA, resistance to lysostaphin was associated with mutations in femA, but resistance could be suppressed by the coadministration of beta-lactam antibiotics.

Anti-Bacterial Agents↗
PubMed2001

Cross-resistance and stability of resistance to Bacillus thuringiensis toxin Cry1C in diamondback moth.

We tested toxins of Bacillus thuringiensis against larvae from susceptible, Cry1C-resistant, and Cry1A-resistant strains of diamondback moth (Plutella xylostella). The Cry1C-resistant strain, which was derived from a field population that had evolved resistance to B. thuringiensis subsp. kurstaki and B. thuringiensis subsp. aizawai, was selected repeatedly with Cry1C in the laboratory. The Cry1C-resistant strain had strong cross-resistance to Cry1Ab, Cry1Ac, and Cry1F, low to moderate cross-resistance to Cry1Aa and Cry9Ca, and no cross-resistance to Cry1Bb, Cry1Ja, and Cry2A. Resistance to Cry1C declined when selection was relaxed. Together with previously reported data, the new data on the cross-resistance of a Cry1C-resistant strain reported here suggest that resistance to Cry1A and Cry1C toxins confers little or no cross-resistance to Cry1Bb, Cry2Aa, or Cry9Ca. Therefore, these toxins might be useful in rotations or combinations with Cry1A and Cry1C toxins. Cry9Ca was much more potent than Cry1Bb or Cry2Aa and thus might be especially useful against diamondback moth.

Animals↗
PubMed1987

Biological and biochemical characterization of tunicamycin-resistant Leishmania mexicana: mechanism of drug resistance and virulence.

A parasitic protozoan, Leishmania mexicana amazonensis, was previously made resistant to tunicamycin (J.A. Kink and K.-P. Chang, Proc. Natl. Acad. Sci. USA 84:1253-1257, 1987). In the present study, six different tunicamycin-resistant variants were biologically and biochemically compared with their parental wild type to further delineate the mechanism of tunicamycin resistance and that of their virulence observed. In contrast to their parental wild type, all tunicamycin-resistant variants were found to grow and differentiate in tunicamycin-containing medium. The 50% lethal doses of tunicamycin for variants resistant to 10 or 80 micrograms of tunicamycin per ml were 20- and 100-fold higher, respectively, than that of the wild type. Specific activity of the microsomal N-acetylglucosamine-1-phosphate transferase was 4- to 12-fold higher in the tunicamycin-resistant cells than in their parental wild type and tunicamycin-sensitive revertants. The level of the enzyme activity is proportional to the degree of drug resistance. Inhibition kinetics studies showed that the enzyme from all groups was equally sensitive to the drug, with a 50% effective concentration of 1 to 1.3 micrograms of tunicamycin per ml. Thus, tunicamycin resistance of the variants is caused primarily by an increased level of their enzyme without alteration of its structure. Protein glycosylation determined by the incorporation of 2-D-[3H]mannose was about twofold higher in the tunicamycin-resistant variants than in their parental wild type. The increased glycosyltransferase activity in the latter apparently renders their protein glycosylation insensitive to the inhibition by tunicamycin. A major membrane glycoprotein of 63 kilodaltons (gp63) on the leishmania surface was found to be about threefold higher in the tunicamycin-resistant variants than in the wild type, as determined by immunoprecipitation with a monoclonal antibody specific for this antigen. Tunicamycin treatment of the wild type and tunicamycin-resistant variants caused changes in the electrophoretic mobility of this molecule, indicating a higher degree of its glycosylation in the latter cells. The tunicamycin-resistant variants parasitized macrophages in vitro more effectively than did the wild type, accounting for their virulence seen in mice. Thus, a high level of the glycosyltransferase enables the tunicamycin-resistant cells not only to overcome the inhibitory effect of tunicamycin on protein glycosylation but also to express their virulence, possibly by regulating N glycosylation of leishmanial proteins critical for leishmanias to establish intracellular parasitism.

Animals↗
PubMed1961

Episome-mediated transfer of drug resistance in Enterobacteriaceae. III. Transduotion of resistance factors.

Watanabe, Tsutomu (Keio University, Tokyo, Japan), and Toshio Fukasawa. Episome-mediated transfer of drug resistance in Enterobacteriaceae. III. Transduction of resistance factors. J. Bacteriol. 82:202-209. 1961.-Transmissible multiple drug resistance of Enterobacteriaceae, which includes resistance to streptomycin (SM), chloramphenicol (CM), tetracycline (TC), and sulfonamide (Su), was found to be transduced in the systems of Salmonella typhimurium strain LT-2 with phage P-22 and Escherichia coli strain K-12 with phage P1kc. No linked chromosomal markers to the resistance factors have so far been found in the substrains of K-12. The transductants of K-12 were all found to be able to transfer their resistance factors by conjugation, whereas a majority of those of LT-2 could not transfer their resistance factors by conjugation. The resistance factors were segregated rarely in K-12 and consistently in LT-2. Defective resistance factors could be transferred by conjugation to the transductants of LT-2. The transductants thus made resistant to the four drugs were able to transfer only the resistance factors which had been introduced by conjugation and none of those which had been transduced. The patterns of segregation of the resistance factors by transduction suggested that they are located in the following sequence; Su-----Sm-----Cm-----Tc, and they were assumed to be carried by an episome "resistance transfer factor" which is considered to be located at the distal end of Tc.

Anti-Bacterial Agents↗
PubMed2001

Cross-resistance, inheritance, and biochemistry of mitochondrial electron transport inhibitor-acaricide resistance in Tetranychus urticae (Acari: Tetranychidae).

Resistance of the twospotted spider mite, Tetranychus urticae Koch, to acaricides acting as mitochondrial electron transport inhibitors (METIs) is an increasing problem. Because of their high levels of cross-resistance to all commercially available METI-acaricides, a Japanese strain (AKITA) and an English strain (UK-99) of T. urticae were investigated in detail. Larvae of both strains, AKITA and UK-99, showed 1,100- and 480-fold resistance against pyridaben, 870- and 45-fold resistance against fenpyroximate, and 33- and 44-fold resistance against tebufenpyrad, respectively, in a foliar spray application bioassay compared with the susceptible strain GSS. These resistance factors remained stable even when maintained in the laboratory without further selection. Furthermore, strain AKITA showed cross-resistance to dicofol. The METI resistant strains AKITA and UK-99 showed 2.4- and 1.7-fold enhanced O-ethoxycoumarin O-deethylation (cytochrome P450) activity. Increased oxidative metabolism of the METI-acaricides in the resistant strains could be partially suppressed in vivo by the monooxygenase-inhibitor piperonyl butoxide. Reciprocal crosses of homozygous, diploid females and hemizygous, haploid males of strains GSS (susceptible) and AKITA (resistant) revealed that resistance to pyridaben and fenpyroximate was inherited incompletely dominant with slight differences between maternal and paternal inheritance. This is the first attempt to mechanistically describe METI-acaricide resistance in T. urticae. The implications for resistance management strategies are discussed.

Animals↗
PubMed1980

Increase in the calculated resistance of anatomically fixed stenosis in vitro in association with decrease in distal resistance.

The effects of changes in distal resistance on stenotic resistance were studied in vitro. Physiological saline was passed through the left carotid artery obtained from the dog, flexible rubber tubing, or through solid polyethylene tubing with a constant perfusion pressure or with a constant flow rate. Various stenotic resistances were established using a screw type constrictor and the distal resistance was varied by allowing physiological saline to pass through either a 23 gauge hypodermic needle (high peripheral resistance) or 23 and 20 gauge needles (low peripheral resistance ). For arteries with anatomically fixed stenosis, the calculated resistance was increased in association with reduction of the distal resistance. The stenotic resistance in the flexible rubber tubing changed in the same manner as that of the carotid artery, while the solid polyethylene tubing showed no significant stenotic resistance changes due to altering the distal resistance. These findings suggest that the stenotic resistance change of the artery correlates with the elasticity of the vessel wall and also indicate that resistance values were of little usefulness for evaluating the effects of vasodilating stimuli on the vessel segment with a significant stenosis.

Animals↗
PubMed2000

Overcoming of multidrug resistance by introducing the apoptosis gene, bcl-Xs, into MRP-overexpressing drug resistant cells.

Multidrug resistance associated protein (MRP) is one of drug transport membranes that confer multidrug resistance in cancer cells. Multidrug resistance has been known to be associated with resistance to apoptosis. In this study, using MRP overexpressing multidrug resistant nasopharyngeal cancer cells, we examined the expression of apoptosis related genes including p53, p21WAF1, bax and bcl-Xs between drug sensitive KB and its resistant KB/7D cells. We also examined whether the introduction of apoptosis related gene could increase the sensitivity to anticancer drugs in association with apoptotic cell death. The relative resistances to anticancer drugs in KB/7D cells evaluated by IC50 values were 3.6, 61.3, 10.4 and 10.5 to adriamycin (ADM), etoposide (VP-16), vincristine (VCR) and vindesine (VDS), respectively. The resistance to anticancer drugs in KB/7D cells was associated with the attenuation of internucleosomal DNA ladder formation in apoptosis. Of important, the mRNA expression of bcl-Xs gene in KB/7D cells was decreased in one-fourth as compared to that of KB cells among the apoptosis genes. The mRNA expression of bcl-Xs gene in a bcl-Xs transfected clone (KB/7Dbcl-Xs) was increased about 2-fold compared to that of KB/7Dneo cells, while the mRNA expression of MRP gene was not significantly different in KB/7bcl-Xs and KB/7Dneo cells. The sensitivities to anticancer drugs including ADM, VCR and VDS except VP-16 were increased in KB/7Dbcl-Xs cells, in turn, the relative resistance in KB/7Dbcl-Xs cells was decreased to 1.4, 4.0, and 3.0 in ADM, VCR and VDS, respectively, as compared to those of KB/7Dneo cells. Of interest, the studies on the accumulation of [3H]VCR showed that the decrease of [3H]VCR accumulation in KB/7Dbcl-Xs was not significantly different from that of KB/7Dneo cells. Collectively, these results indicated that the mechanism(s) of drug resistance in KB/7D cells could be explained at least by two factors: a) reduced drug accumulation mediated by MRP; b) resistance to apoptosis due to the decreased expression of the bcl-Xs gene. These results also indicated that the multidrug resistance mediated by MRP might be partially overcome by introducing apoptosis gene into drug resistant cells without modulation of MRP function in drug accumulation.

ATP-Binding Cassette Transporters↗
PubMed2002

Risk factors for Helicobacter pylori resistance in the United States: the surveillance of H. pylori antimicrobial resistance partnership (SHARP) study, 1993-1999.

BACKGROUND: Pretreatment antimicrobial resistance has an important impact on the efficacy of many Helicobacter pylori treatment regimens. OBJECTIVE: To estimate the prevalence of H. pylori resistance to antimicrobials in the United States, to characterize risk factors associated with H. pylori antimicrobial resistance, and to explore the association between drug utilization and antimicrobial resistance patterns over time. DESIGN: Meta-analysis using patient-level data. SETTING: 20 nationwide trials of H. pylori eradication. PATIENTS: 3624 men and women, each of whom contributed one isolate. MEASUREMENTS: Rates of H. pylori resistance to clarithromycin, metronidazole, and amoxicillin, according to geographic region, age, sex, study year, ethnicity, ulcer status, test method, and study. RESULTS: Overall resistance to clarithromycin, metronidazole, and amoxicillin was 10.1% (95% CI, 9.1% to 11.1% [360 of 3571 patients]), 36.9% (CI, 35.1% to 38.7% [1063 of 2883 patients]), and 1.4% (CI, 1.0% to 1.8% [48 of 3486 patients]), respectively. In multivariable analyses, multiple risk factors were associated with resistance to individual agents. Clarithromycin resistance was significantly associated with geographic region (P = 0.050), older age (P < 0.001), female sex (P < 0.001), inactive ulcer disease (P < 0.001), and study (P = 0.010). Metronidazole resistance was significantly associated with female sex (P < 0.001), earlier year of study enrollment (P = 0.036), Asian ethnicity (P < 0.001), use of an epsilometer test (P = 0.002), and study (P < 0.001). Amoxicillin resistance was low and was not significantly associated with any risk factor. In the 1990s, when rates for use of oral macrolides and metronidazole were relatively stable, clarithromycin resistance rates were stable and metronidazole resistance rates varied. CONCLUSIONS: Clinicians should consider risk factors for antimicrobial resistance when deciding which patients should have susceptibility testing and when choosing appropriate H. pylori treatments in the empirical setting.

Adolescent↗
PubMed2001

[A study on the resistance of Staphylococcus aureus and the mechanisms of its resistance to fluoroquinolone].

OBJECTIVE: To investigate the resistance of Staphylococcus aureus(SA) and the mechanisms of its resistance to fluoroquinolones (FQ). METHODS: The susceptibility of SA (200 strains) to 12 antibiotics was detected by disc diffusion, The minimal inhibitory concentrations (MICs) of 52 strains to three FQ were determined by agar dilution method. 52 strains resistant to ciprofloxacin (MIC> or =4 mg/L) were studied for the presence of point mutations in the gyrA gene and grlA gene by polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) method and for the expression of norA gene by reserpine reverse test respectively. RESULTS: 34% of the strains were resistant to oxacillin(methicillin resistant Staphylococcus aureus, MRSA) and other antimicrobials as well, but no vancomycin resistant strain was found. The resistance rate of MRSA to ciprofloxacin was 79.4% and cross-resistance existed. It was found that 42 strains (80.8%) had a mutation at gyrA codon 84 (TCA-->TTA or GCA). Mutations at grlA codon 80 (TCC-->TAC or TTC) and codon 84 (GAA-->AAA)were observed in 10 (19.2%) and 14 strains(26.9%) respectively.Strains containing mutations in gyrA or both gyrA and grlA gene showed a higher level of ciprofloxacin resistance than those with alternation in grlA gene but with wild type gyrA or non-gyrA mutants (P < 0.01). Decreased MICs to ciprofloxacin, norfloxacin and levofloxacin in reserpine reverse test indicated the presence of norA phenotype. CONCLUSIONS: It is clear that emergence of resistant SA strains will continue to be a problem, especially in MRSA which was resistant to most of the antibiotics. Fluoroquinolones are not the choice for MRSA now. The resistance to fluoroquinolones in clinical isolates of SA are due to the mutations of the gyrA and grlA gene encoding the target enzyme of fluoroquinolones and cell membrane resistance. Mutations of grlA gene may differ in different districts.

Anti-Infective Agents↗
PubMed2004

The role of aquatic ecosystems as reservoirs of antibiotic resistant bacteria and antibiotic resistance genes.

The widespread and indiscriminate use of antibiotics has led to the development of antibiotic resistance in pathogenic, as well as commensal, microorganisms. Resistance genes may be horizontally or vertically transferred between bacterial communities in the environment. The recipient bacterial communities may then act as a reservoir of these resistance genes. In this study, we report the incidence of antibiotic resistance in enteric bacteria isolated from the Mhlathuze River and the distribution of genetic elements that may be responsible for the observed antibiotic resistance. The resistance of the enteric bacteria isolated over a period of one year showed that resistance to the older classes of antibiotics was high (94.7% resistance to one antibiotic and 80.8% resistance to two antibiotics). Furthermore, antibiotic resistance data of the environmental isolates showed a strong correlation (r = 0.97) with data obtained from diarrhoea patients. PCR based methods demonstrated that class 1 integrons were present in >50% of the environmental bacterial isolates that were resistant to multiple antibiotics. This class of integrons is capable of transferring genes responsible for resistance to beta-lactam, aminoglycoside, sulfonamide and quaternary ammonium antimicrobial agents. Conjugate plasmids were also isolated, but from a small percentage of isolates. This study showed that the Mhlathuze River (a) is a medium for the spread of bacterial antibiotic resistance genes, (b) acts as a reservoir for these genes and (c) due to socio-economic pressures, may play a role in the development and evolution of these genes along this river system.

DNA, Bacterial↗
PubMed2006

Predictive efficacy of nalidixic acid resistance as a marker of fluoroquinolone resistance in Salmonella enterica var Typhi.

BACKGROUND AND OBJECTIVES: Resistance in Salmonella enterica var Typhi (S. Typhi) to chloramphenicol, amoxicillin and co-trimoxazole has posed a challenge to treatment of typhoid fever. Ciprofloxacin has been the empirical therapy of choice, but the recent increase in minimum inhibitory concentration (MIC) to ciprofloxacin in S. Typhi, not detectable by disc diffusion (DD) tests, may result in delayed response and serious complications. Nalidixic acid (NA) resistance has been used as an indirect evidence of increased ciprofloxacin MIC in S. Typhi. We evaluated the predictive value of NA resistance for fluoroquinolone resistance in clinical isolates of S. Typhi. METHODS: A total of 70 clinical isolates of S. Typhi were tested for antimicrobial susceptibility according to the National Committee for Clinical Laboratory Standards (NCCLS) method. MIC to fluoroquinolones was carried out by the agar dilution method. RESULTS: Thirteen (18.6 %) isolates were resistant to amoxicillin, chloramphenicol and cotrimoxazole; all were sensitive to ciprofloxacin and cefotaxime. Fifty (71.4%) were resistant to NA. Nineteen (27.1 %) isolates were resistant to ciprofloxacin by MIC tests. The MIC for ciprofloxacin was 0.03-4 microg/ml for NA(S) and 0.25-4 microg/ml for NA(R) isolates. NA susceptibility showed a predictive value of 95 per cent for ciprofloxacin susceptibility while NA resistance had a predictive value of 36 per cent for ciprofloxacin resistance. Thirty isolates studied were sensitive to gatifloxacin; MIC values were 0.03-0.5 microg/ml for NA(S) and 0.25-0.5 microg/ml for NA(R) isolates. INTERPRETATION AND CONCLUSION: NA susceptibility was a good marker for fluoroquinolone susceptibility but NA resistance had a poor predictive value for ciprofloxacin resistance. NA resistant isolates should be tested for ciprofloxacin MIC before deciding a change in therapeutic regimen. Higher MIC for gatifloxacin was also noticed in NA resistant isolates.

Biomarkers↗
PubMed1986

Augmentation of 1-beta-D-arabinofuranosylcytosine resistance in human KB epidermoid carcinoma cells upon induction of a second resistance to vincristine.

Human KB epidermoid carcinoma cells (KB/p) and their variant cells (KB/ara-C) resistant to 1-beta-D-arabinofuranosylcytosine (ara-C) that were not cross-resistant to vincristine (VCR) were exposed to increasing concentrations of VCR to establish VCR resistant cells (KB/VCR) and doubly resistant variant cells (KB/ara-C/VCR). KB/VCR and KB/ara-C/VCR cells showed a similar increase in resistance to VCR (about 337- to 460-fold) over that of the parent KB/p cells. KB/ara-C showed a 911-fold increase in resistance to ara-C, while KB/ara-C/VCR showed a 60,837-fold increase in resistance to ara-C compared with the parent cells. The concentration of ara-C required for 50% inhibition of KB/ara-C/VCR cells was much higher (67-fold) than that for KB/ara-C cells, although the concentration of ara-C required for 50% inhibition of KB/VCR cells was 12-fold that for KB/p cells. Thus the acquisition of resistance to a second drug by these human KB cells augmented their resistance to the first drug. Induction of resistance to ara-C or VCR resulted in marked decrease in cellular uptake of the respective drugs, but there was no difference in cellular uptakes of ara-C by KB/ara-C and KB/ara-C/VCR or of VCR by KB/VCR and KB/ara-C/VCR. KB/VCR and KB/ara-C/VCR cells were cross-resistant to vinblastine, colchicine, vindesine, etoposide, mitomycin C, and Adriamycin. Cells of the two groups (KB/p and KB/ara-C; KB/VCR and KB/ara-C/VCR) differed in sizes and doubling times. In the absence of ara-C, the resistance of KB/ara-C cells to ara-C was stable for at least 1 year, whereas in the absence of VCR resistance to VCR was almost completely lost within 1 month.

Antineoplastic Agents↗