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PubMed1984

Cross-resistance of vincristine-resistant sublines of P388 leukemia to mitoxantrone with special emphasis on the relationship between in vitro and in vivo cross-resistance.

In vitro and in vivo cross-resistance to mitoxantrone of two vincristine-resistant sublines of P388 leukemia with different degrees of resistance in vitro was compared with that to adriamycin. A subline with a lower degree of resistance to vincristine exhibited approximately the same responses in vivo to mitoxantrone and adriamycin as the original P388 leukemic cell line, although it was evidently cross-resistant in vitro to these agents. Another subline having a higher degree of resistance to vincristine showed a 25-fold cross-resistance in vitro and gave no response in vivo to adriamycin. With mitoxantrone, on the other hand, this subline was solidly resistant as compared with the sensitive line but still retained significant responsiveness in vivo irrespective of a 150-fold cross-resistance in vitro. These results suggest that cross-resistance on a cellular basis does not necessarily correspond to in vivo cross-resistance. The relationship between in vitro and in vivo cross-resistance is discussed.

Animals↗
PubMed1991

Understanding "insulin resistance": both glucose resistance and insulin resistance are required to model human diabetes.

A mathematical model of normal glucose/insulin homoeostasis has been based on the known, experimentally determined responses of the liver and periphery to different glucose/insulin concentrations. Different defects of glucose resistance and insulin resistance have been applied to the model to investigate the degree to which these abnormalities could successfully predict the range of fasting glucose and insulin values found in normal, obese, and diabetic subjects. Modeling glucose resistance or insulin resistance at the liver or the periphery alone did not increase the plasma glucose to levels observed in diabetes, even when associated with marked deficiency of beta-cell function. A defect of either glucose resistance or insulin resistance affecting both periphery and liver allowed a wider range of basal glucose and insulin concentration values, but resulted in unphysiologically low hepatic glucose output: with modeling insulin resistance, hyperglycemia suppressed glucose output, whereas with glucose resistance, raised insulin levels suppressed hepatic glucose output. A wide range of glucose and insulin values, with appropriate basal hepatic glucose output, could only be modeled by insulin resistance at both the liver and periphery with additional glucose resistance at the liver. The modeling results are in accord with investigative studies that suggest secondary hepatic and peripheral glucose resistance in response to hyperglycemia. Modeling provides a systematic means of examining the likely effect of different putative defects in a complex physiological system.

Diabetes Mellitus↗
PubMed1997

[Expression of ATP binding cassette superfamily (multidrug resistance-1, multidrug resistance-associated protein, human canalicular multispecific organ anion transporter) mRNA in etoposide and m-AMSA resistant cell lines].

The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. To further understand resistance to topoisomerase (topo) II inhibitors, 50 sublines were isolated as single clones from parental cells by exposure to etoposide or m-AMSA. Subsequently, a population of cells from each sublines was exposed to three-fold higher drug concentrations allowing 16 stable sublines to be established at higher extracellular drug concentration. Quantitative aspects of MRP and C-MOAT were studied by Northern blotting in 66 resistant cell lines. Increased MRP mRNA was observed in 48.5% of resistant cell lines (64.7% of etoposide resistant cells and 31.3% of m-AMSA resistant cell lines). Increased C-MOAT mRNA was also observed in 39.4% of resistant cell lines (41.2% in etoposide resistant cell lines and 37.5% in m-AMSA resistant cell lines). To characterize the function of C-MOAT, cellular accumulation assay for 3H-etoposide was performed in three resistant cell lines which overexpress C-MOAT but do not express MRP. Accumulation of etoposide was reduced in the cell lines. Our findings suggest that increased MRP and O-MOAT mRNA seems to be an important mechanism of resistance to topo II inhibitors.

ATP-Binding Cassette Transporters↗
PubMed2001

The drug resistance proteins, multidrug resistance-associated protein and P-glycoprotein, do not confer resistance to Fas-induced cell death.

BACKGROUND: Multidrug resistance (MDR) is mediated by the drug resistance proteins, the multidrug resistance-associated protein (MRP) and P-glycoprotein, both of which confer resistance by the active efflux of chemotherapeutic drugs from the cell. Reduced Fas (CD95/APO-1) expression and resistance to Fas-mediated apoptosis have also been correlated with P-glycoprotein-mediated MDR. METHODS: We investigated cell surface Fas expression (using anti-Fas monoclonal antibody DX2.1) in a series of MRP-expressing drug-resistant leukemia sublines, and P-glycoprotein-expressing leukemia sublines, and their susceptibility to apoptosis induced by anti-Fas treatment (CH-11 monoclonal antibody). Caspase-3 activation was detected by Western blot and apoptosis was determined by flow cytometry with 7-aminoactinomycin D (7-AAD) staining of cells. RESULTS: Fas expression was not reduced in either the MRP- or P-glycoprotein-expressing drug-resistant cell lines, although expression was reduced by 15% in one low-level drug-resistant subline. Expression of MRP or P-glycoprotein did not confer resistance to caspase-3 activation or to anti-Fas-induced cell death. CONCLUSIONS: MDR mediated by the drug transport proteins MRP and P-glycoprotein does not correlate with resistance to Fas-mediated cell death or resistance to caspase-3 activation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Changes in muntjac fibroblasts associated with the acquisition of cadmium resistance. A pre-resistance, transitional and post-resistance study.

A series of cell lines with different levels of resistance to continuous cadmium exposure has been developed from an immortal but non-transformed muntjac fibroblast cell line. Concentrations accepted in their culture medium range from 0.1 microM for the cadmium sensitive parent line to 5 microM for the intermediate "cadmium-tolerant" line, to 5, 10, 20 and 50 microM for the four "cadmium-resistant" lines. The present paper follows the morphological changes which accompanied the development of resistance through a 20-month pre-resistance period, a relatively abrupt 6-week transitional period and a 3-year post-resistance period, during which time levels of cadmium resistance were increased. Initial changes which led to the cadmium-tolerant CR5 cell line included (i) increased efficiency in autophagocytosing damaged cell components and in ridding the cell of residual waste materials, (ii) a reduction in fluid filled vacuoles and (iii) improved recycling and/or replacement of cadmium-damaged cell membrane. With the advent of cadmium resistance the intracellular damage necessitating these activities disappeared, yet the series of changes which occurred included a massive build-up of Golgi and the appearance of a trans-Golgi tubular network in addition to cytoskeletal and membrane changes. Though metallothionein levels are greater in the cadmium-resistant variants, their increase appears inadequate on their own to account for the high levels of resistance. The post-resistance changes which accompanied each step-up in cadmium resistance included further membrane and glycocalyx changes, in addition to continued increases in Golgi bodies and tubular network. This paper details the morphological changes which occurred throughout the 5-year period, tests the direct dependence of each on the presence of cadmium and examines their possible contribution to a cadmium protective mechanism.

Animals↗
PubMed2003

The 79,370-bp conjugative plasmid pB4 consists of an IncP-1beta backbone loaded with a chromate resistance transposon, the strA-strB streptomycin resistance gene pair, the oxacillinase gene bla(NPS-1), and a tripartite antibiotic efflux system of the resistance-nodulation-division family.

Plasmid pB4 is a conjugative antibiotic resistance plasmid, originally isolated from a microbial community growing in activated sludge, by means of an exogenous isolation method with Pseudomonas sp. B13 as recipient. We have determined the complete nucleotide sequence of pB4. The plasmid is 79,370 bp long and contains at least 81 complete coding regions. A suite of coding regions predicted to be involved in plasmid replication, plasmid maintenance, and conjugative transfer revealed significant similarity to the IncP-1beta backbone of R751. Four resistance gene regions comprising mobile genetic elements are inserted in the IncP-1beta backbone of pB4. The modular 'gene load' of pB4 includes (1) the novel transposon Tn 5719 containing genes characteristic of chromate resistance determinants, (2) the transposon Tn 5393c carrying the widespread streptomycin resistance gene pair strA-strB, (3) the beta-lactam antibiotic resistance gene bla(NPS-1) flanked by highly conserved sequences characteristic of integrons, and (4) a tripartite antibiotic resistance determinant comprising an efflux protein of the resistance-nodulation-division (RND) family, a periplasmic membrane fusion protein (MFP), and an outer membrane factor (OMF). The components of the RND-MFP-OMF efflux system showed the highest similarity to the products of the mexCD-oprJ determinant from the Pseudomonas aeruginosa chromosome. Functional analysis of the cloned resistance region from pB4 in Pseudomonas sp. B13 indicated that the RND-MFP-OMF efflux system conferred high-level resistance to erythromycin and roxithromycin resistance on the host strain. This is the first example of an RND-MFP-OMF-type antibiotic resistance determinant to be found in a plasmid genome. The global genetic organization of pB4 implies that its gene load might be disseminated between bacteria in different habitats by the combined action of the conjugation apparatus and the mobility of its component elements.

Bacterial Proteins↗
PubMed1989

Atypical multidrug resistance in a therapy-induced drug-resistant human leukemia cell line (LALW-2): resistance to Vinca alkaloids independent of P-glycoprotein.

Near diploid leukemic T-cells (LALW-2), exposed to cytotoxic drugs only as a consequence of therapy administered to the donor patient, have been maintained by serial xenograft in nude mice. In comparison with the leukemic line CCRF-CEM, using a growth inhibition assay, LALW-2 cells were resistant to Vinca alkaloids and actinomycin D (relative resistance, 200-fold or more), were slightly resistant to Adriamycin (relative resistance, 4-fold), and showed no resistance to daunorubicin or teniposide. By comparison, a vincristine-resistant CEM subline developed in our laboratory (CEM/VCR R) was resistant to all these agents by at least 30-fold. The VCR R subline served as a positive control, confirming the previously reported correlation between multidrug resistance and amplification of the P-glycoprotein gene. Comparison of CEM, CEM/VCR R, and LALW-2 cells establish that the P-glycoprotein gene was not amplified or overexpressed in the LALW-2 cells; neither could the gene product be detected by immunoblotting in extracts from these cells. The LALW-2 cells were further distinguished from CEM/VCR R cells due to the lack of increased vincristine efflux by the xenografted cells, an effect readily demonstrable in the CEM/VCR R cells. However, although LALW-2 cells efflux vincristine at the same rate as CCRF-CEM cells, the xenografted cells exhibited a reduced rate of vincristine accumulation. Uptake of daunorubicin by LALW-2 cells was not distinguished from that by CEM cells, consistent with similar 50% inhibitory dose levels for this drug in both cell populations, and differentiating both from CEM/VCR R cells. Thus, clinical resistance in this case appears to be an "atypical" form of multidrug resistance specifically distinguished by resistance to Vinca alkaloids and actinomycin D occurring in the absence of increased amounts of P-glycoprotein and manifesting decreased drug uptake.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1982

Resistance types in Enterobacter cloacae. Occurrence and resistance to Ampicillin, Carbenicillin, Cephalothin and Mecillinam. Transfer of ampicillin Resistance.

An investigation of the resistance types in Enterobacter cloacae is presented. The frequency of the different resistance types was determined. The strains were divided into three groups according to sensitivity to penicillin derivatives. The ampicillin-carbenicillin-sensitive (A-s/Ca-s) group 1 comprised 20% of the E. cloacae strains received in this laboratory. The ampicillin resistant-carbenicillin-sensitive (A-r/Ca-s) group 2 comprised 38.5% of the strains and the A-r/Ca-r group 3 comprised 41.5% of the strains. Group 3 contained a high proportion of multi-resistant strains. The log 2 IC50 against ampicillin, carbenicillin, cephalothin and mecillinam was determined for 28 strains. The group 3 strains were more ampicillin-resistant than the group 2 ones. Group 1 and 2 did not differ as regards carbenicillin sensitivity. The cephalothin resistance increased from group 1 to group 2 and further on to group 3. Mecillinam sensitivity did not differ between the three groups. The ability to transfer ampicillin resistance was investigated in the 24 A-r strains. The 8 group 2 strains were not able to transfer resistance, while 9 of 16 strains in groups 3 could transfer A-resistance with frequencies ranging from 10-0.2 to 10-5.7. Resistance to sulphonamide, tetracycline and streptomycin was also transferred, often with the same frequency as the ampicillin resistance.

Amdinocillin↗
PubMed1965

DRUG RESISTANCE OF STAPHYLOCOCCI. I. TRANSDUCTION OF TETRACYCLINE RESISTANCE WITH PHAGE LYSATES OBTAINED FROM MULTIPLY RESISTANT STAPHYLOCOCCI.

Mitsuhashi, Susumu (Gunma University, Maebashi, Japan), Hiroshi Oshima, Umeko Kawaharada, and Hajime Hashimoto. Drug resistance of staphylococci. I. Transduction of tetracycline resistance with phage lysates obtained from multiply resistant staphylococci. J. Bacteriol. 89:967-976. 1965.-Tetracycline resistance was found to be transduced with phage lysates obtained from multiply resistant strains of Staphylococcus aureus of human origin. With various combinations of multiply resistant donors and tetracycline (TC)-sensitive recipients, almost all of the strains were found to be competent donors. A greater percentage of group 1 staphylococci were competent recipients. Most of the TC(+) transductants were not lysogenic for the transducing phage and were unable to transduce TC resistance with their own phage lysates obtained by ultraviolet irradiation. However, the TC(+) transductants, lysogenized with transducing phage, were capable of transducing TC resistance, and some of the lysogenizations were accompanied by changes in phage type. These results suggest that the emergence of the multiply resistant staphylococci (consistently resistant to TC) can be accounted for by transduction among various strains accompanied sometimes by changes in phage typing pattern after lysogenization, and by selection through extensive use of antibiotics and chemotherapeutic agents.

Anti-Bacterial Agents↗
PubMed2006

Tetracycline-resistance in lactose-positive enteric coliforms originating from Belgian fattening pigs: degree of resistance, multiple resistance and risk factors.

Between March and October 2003 a field study was conducted in 50 randomly selected pig herds to assess the degree of tetracycline-resistance in lactose-positive enteric coliforms (LPEC) originating from fattening pigs and to evaluate the combined effects of various husbandry conditions on the development and persistence of antimicrobial-resistant bacteria. Data on housing, management and antimicrobial-drug consumption were collected, as well as faecal samples at three production stages: end of the nursery period (mean age: 72 days), end of the grower period (mean age: 125 days) and end of the finisher period (mean age: 186 days). The degree of tetracycline-resistant LPEC was determined by means of an agar dilution method. Tetracycline-resistant LPEC were found in every herd. The overall degree of tetracycline-resistance in LPEC was 56.8% (S.D. 22.4%). Only a very weak relation was found between the degrees of TETR in the different production stages within the same herd, indicating that the degree of TETR is mainly associated with the production stage rather than with the farm as a whole. The risk factor analysis showed that besides the antimicrobial-drug use, other factors like inside pen hygiene can influence the development and maintenance of antimicrobial-resistant bacteria in the gastrointestinal tracts of pigs. It was also observed that tetracycline-resistance in commensal Escherichia coli is often linked with resistance to other antimicrobial drugs like ampicillin and trimethoprim-sulphonamides. These results illustrate that the epidemiology of antimicrobial resistance is influenced by antimicrobial-drug use, cross-resistance development and non-antimicrobial risk factors.

Animal Husbandry↗
PubMed1998

The independent evolution of resistance to ciprofloxacin, rifampicin, and fusidic acid in methicillin-resistant Staphylococcus aureus in Australian teaching hospitals (1990-1995). Australian Group for Antimicrobial Resistance (AGAR).

Methicillin-resistant Staphylococcus aureus (MRSA) is endemic in teaching hospitals in eastern Australian states, with prevalence rates averaging 25-30% of all S. aureus. Between 1990 and 1995, 1467 non-duplicate MRSA isolates from clinically infected sites were tested in Sydney, Melbourne, and Brisbane as part of a national survey of staphylococcal susceptibility. We reviewed the differing evolution of resistance to ciprofloxacin, rifampicin, and fusidic acid. Despite similarities in community and hospital antibiotic use and MRSA prevalence rates, trends in resistance to the oral antibiotics in these cities have progressed independently of each other. In the 1995 survey in individual hospitals in Melbourne, 16-24% of strains were ciprofloxacin-resistant, compared with 80-100% in Sydney and 30-44% in Brisbane. There was great diversity of phage type patterns for ciprofloxacin-resistant strains, suggesting heterogeneous development of resistance. Rifampicin resistance was more closely associated with distinct dominant epidemic phage types, common to institutions in the same city, but without spread to the other cites. Between 1990 and 1995, these comprised 30-60% of all MRSA in Brisbane, compared with 5-10% in Melbourne and < 25% in Sydney. Fusidic acid resistance was uncommon and sporadic (< 5%), and was distributed equally between methicillin-resistant and methicillin-susceptible strains. Resistance to the oral agents in MRSA is due to a complex mix of antibiotic selection pressures and cross-infection with local and epidemic strains in closely related institutions. Each of these mechanisms can predominate, dependent on local factors and the antibiotics used.

Anti-Bacterial Agents↗
PubMed2006

The tetracycline resistance determinant Tet 39 and the sulphonamide resistance gene sulII are common among resistant Acinetobacter spp. isolated from integrated fish farms in Thailand.

OBJECTIVES: To determine the genetic basis for tetracycline and sulphonamide resistance and the prevalence of class I and II integrons in oxytetracycline-resistant Acinetobacter spp. from integrated fish farms in Thailand. METHODS: A total of 222 isolates were screened for tetracycline resistance genes [tet(A), tet(B), tet(H), tet(M) and tet(39)] and class II integrons by PCR. One hundred and thirty-four of these isolates were also sulphonamide resistant and these isolates were screened for sulphonamide resistance genes (sulII and sulIII) as well as class I integrons. Plasmid extraction and Southern blots with sulII and tet(39) probes were performed on selected isolates. RESULTS: The recently identified tetracycline resistance gene tet(39) was demonstrated in 75% (166/222) of oxytetracycline-resistant Acinetobacter spp. from integrated fish farms in Thailand. Isolates that were also sulfamethoxazole-resistant contained sulII (96%; 129/134) and/or sulI (14%; 19/134) (as part of class I integrons). sulII and tet(39) were located on plasmids differing in size in the isolates tested. CONCLUSIONS: The study shows tet(39) and sulII to be common resistance genes among clonally distinct Acinetobacter spp. from integrated fish farms and these bacteria may constitute reservoirs of resistance genes that may increase owing to a selective pressure caused by the use of antimicrobials in the overlaying animal production.

Acinetobacter↗
PubMed1994

Mupirocin resistance among consecutive isolates of oxacillin-resistant and borderline oxacillin-resistant Staphylococcus aureus at a university hospital.

Mupirocin resistance was determined in consecutive oxacillin-resistant and borderline oxacillin-resistant Staphylococcus aureus clinical isolates collected over 14 months at a university hospital during 1991 and 1992. Twenty of 86 (23%) oxacillin-resistant and borderline oxacillin-resistant S. aureus isolates were mupirocin resistant; 80% were high-level resistant. Prior mupirocin use was a significant risk factor (relative risk, 6.08; 95% confidence interval, 3.7 to 9.99). Seven of 20 resistant isolates were distinct strains, as determined by pulsed-field gel electrophoresis typing. Two instances of clonal dissemination of a single strain occurred, but several other distinct mupirocin-resistant strains were documented. Mupirocin resistance was unexpectedly common among these isolates.

DNA, Bacterial↗
PubMed1996

Single amino acid changes in the DNA polymerase confer foscarnet resistance and slow-growth phenotype, while mutations in the UL97-encoded phosphotransferase confer ganciclovir resistance in three double-resistant human cytomegalovirus strains recovered from patients with AIDS.

Three human cytomegalovirus (HCMV) strains (VR4760, VR4955, and VR5120) showing double resistance to ganciclovir (GCV) and foscarnet (PFA) were isolated from three patients with AIDS who underwent multiple sequential courses of therapy with GCV and PFA (A. Sarasini, F. Baldanti, M. Furione, E. Percivalle, R. Brerra, M. Barbi, and G. Gerna, J. Med. Virol., 47:237-244, 1995). We previously demonstrated that the three strains were genetically unrelated and that each of them was present as a single viral population in vivo. Thus, in each of the three cases, a single viral strain was resistant to both GCV and PFA. In the present paper, we report the characterization of the molecular bases of the double resistance and demonstrate that the PFA resistance is associated with a slower replication of HCMV strains in cell cultures. Sequencing of the UL97 and UL54 genes, GCV anabolism assays, and marker transfer experiments showed that GCV resistance was due to single amino acid changes in the UL97 gene product (VR4760, Met-460 --> Ile; VR4955, Ala-594 --> Val; VR5120, Leu595 --> Ser), while single amino acid changes in domain II of the DNA polymerase (VR4760 and VR5120, Val-715 --> Met; VR4955, Thr-700 --> Ala) were responsible for both the PFA resistance and the slow-growth phenotype. Thus, in these three cases, double resistance to GCV and PFA was not due to a single mutation conferring cross-resistance or to the presence of a mixture of strains with different drug susceptibilities. The HCMV DNA polymerase recombinant strains carrying the mutations conferring PFA resistance were sensitive to GCV and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). In addition, the same UL54 mutations were responsible for the slow growth of the clinical isolates, since the recombinant strains showed a marked delay in immediate-early antigen plaque formation and a reduction of infectious virus yield compared with AD169, from which they were derived. These results may have some important implications for the successful isolation, propagation, and characterization of PFA-resistant strains from clinical samples containing mixed viral populations.

AIDS-Related Opportunistic Infections↗
PubMed1998

Relationship between major vault protein/lung resistance protein, multidrug resistance-associated protein, P-glycoprotein expression, and drug resistance in childhood leukemia.

Cellular drug resistance is related to a poor prognosis in childhood leukemia, but little is known about the underlying mechanisms. We studied the expression of P-glycoprotein (P-gp), multidrug resistance (MDR)-associated protein (MRP), and major vault protein/lung resistance protein (LRP) in 141 children with acute lymphoblastic leukemia (ALL) and 27 with acute myeloid leukemia (AML) by flow cytometry. The expression was compared between different types of leukemia and was studied in relation with clinical risk indicators and in vitro cytotoxicity of the MDR-related drugs daunorubicin (DNR), vincristine (VCR), and etoposide (VP16) and the non-MDR-related drugs prednisolone (PRD) and L-asparaginase (ASP). In ALL, P-gp, MRP, and LRP expression did not differ between 112 initial and 29 unrelated relapse samples nor between paired initial and relapse samples from 9 patients. In multiple relapse samples, LRP expression was 1.6-fold higher compared with both initial (P = .026) and first relapse samples (P = .050), which was not observed for P-gp and MRP. LRP expression was weakly but significantly related to in vitro resistance to DNR (Spearman's rank correlation coefficient 0.25, P = .016) but not to VCR, VP16, PRD, and ASP. No significant correlations were found between P-gp or MRP expression and in vitro drug resistance. Samples with a marked expression of two or three resistance proteins did not show increased resistance to the tested drugs compared with the remaining samples. The expression of P-gp, MRP, and LRP was not higher in initial ALL patients with prognostically unfavorable immunophenotype, white blood cell count, or age. The expression of P-gp and MRP in 20 initial AML samples did not differ or was even lower compared with 112 initial ALL samples. However, LRP expression was twofold higher in the AML samples (P < .001), which are more resistant to a variety of drugs compared with ALL samples. In conclusion, P-gp and MRP are unlikely to be involved in drug resistance in childhood leukemia. LRP might contribute to drug resistance but only in specific subsets of children with leukemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Fenpyroximate resistance in Tetranychus urticae (Acari: Tetranychidae): cross-resistance and biochemical resistance mechanisms.

A field colony of the Two-spotted spider mite, Tetranychus urticae (Koch), resistant to fenpyroximate was further selected with fenpyroximate 5SC for 20 generations at a selection pressure of 30-50% mortality (designated as FR-20 strain). Resistance and cross-resistance levels of the FR-20 strain to 18 acaricides were determined using a spray method. The FR-20 strain was extremely resistant to fenpyroximate [resistance ratio (RR) 252]. The strain exhibited extremely strong positive cross-resistance to acrinathrin (RR 196), and high levels of resistance to benzoximate (RR 55) and propargite (RR 64). Moderate levels of cross-resistance (RR 11-40) to abamectin, fenbutatin oxide, fenpropathrin, pyridaben, pyridaben + bifenthrin and tebufenpyrad were observed. The FR-20 strain showed low levels of resistance (RR < 10) to azocyclotin, bromopropylate, chlorfenapyr, chlorfenapyr + bifenthrin, chlorfenapyr + pyridaben, dicofol, fenazaquin and milbemectin. Synergist experiments with different metabolic inhibitors revealed that piperonyl butoxide had the greatest effect on the efficacy of fenpyroximate, followed by iprobenfos and triphenyl phosphate. In a comparative assay with detoxifying enzymes, the FR-20 strain showed 2.5-fold higher activity in p-nitroanisole-O-demethylation, and 2.5- and 2.2-fold higher activities in alpha- and beta-naphthyl acetate hydrolysis, respectively. These results suggested that enhanced activities of both mixed-function oxidases and esterases likely contribute to the fenpyroximate resistance of the FR-20 strain of T urticae.

Animals↗
PubMed2001

Development and application of a genotypic AZT resistance assay: quantitative assessment of the resistance profile of clinical samples and the relative predictive ability of a resistance index.

OBJECTIVES: To develop and validate a rapid, genotypic, quantitative AZT resistance assay, and to evaluate the predictive ability of a resistance index. METHODS: AZT resistance profiles of paired samples from HIV-infected patients were determined by a ligase chain reaction (LCR) assay. AZT resistance levels and surrogate markers of HIV disease progression (viral load and CD4 counts) were used to compare AZT-naive and AZT-experienced patients. The ability of a "mutant/wild-type HIV-1 quasi-species" index to predict viral load was assessed. RESULTS: AZT resistance, evident at baseline in both AZT-experienced and AZT-naive patients, increased over 6 months of treatment. The resistance profile of AZT-naive patients differed from that of AZT-experienced patients ( p <.05); viral load and CD4 counts were similar. The relative predictive ability (for subsequent viral load) of the resistance index was similar to or higher than that of baseline viral load or CD4 count. CONCLUSIONS: This assay used to detect AZT resistance could be adapted for use with other antiretrovirals. The predictive ability of the proposed resistance index was equal to or surpassed that of viral load and CD4 count, lending further support to the use of resistance assays in selecting drug regimens both before and during antiretroviral therapy.

Anti-HIV Agents↗
PubMed1996

Correlation of molecular resistance mechanisms and phenotypic resistance levels in streptomycin-resistant Mycobacterium tuberculosis.

Quantitative susceptibility testing of clinical isolates of streptomycin-resistant Mycobacterium tuberculosis demonstrated that there is a close correlation between the molecular resistance mechanism and the in vitro activity of streptomycin: mutations in rpsL were mainly associated with high-level resistance, mutations in rrs were associated with an intermediate level of resistance, and streptomycin-resistant isolates with wild-type rpsL and rrs exhibited a low-level resistance phenotype. Investigations of streptomycin-resistant isolates with wild-type rpsL and rrs revealed that (i) there is no cross-resistance to other drugs and (ii) a permeability barrier may contribute to resistance, because resistance was significantly lowered in the presence of a membrane-active agent.

Antibiotics, Antitubercular↗