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PubMed1989

Progressive resistance to doxorubicin in mouse leukemia L1210 cells with multidrug resistance phenotype: reductions in drug-induced topoisomerase II-mediated DNA cleavage.

Cells selected for resistance to doxorubicin (DOX) express the multidrug resistance (MDR) phenotype, and resistance has been suggested to be due primarily to enhanced cellular efflux of drug. A progressively DOX-resistant (10- and 40-fold) L1210 mouse leukemia model system, which does not exhibit enhanced DOX efflux as a primary mechanism of resistance, was found to display the MDR phenotype, based on overexpression of P-glycoprotein in western blots and cross-resistance to vinca alkaloids. Cross-resistance to another topoisomerase II inhibitor, etoposide (VP-16), was similar to that of DOX (10- and 40-fold), whereas resistance to N-[4-(9-acridinylamino)-3-methoxyphenyl]methanesulfonamide (m-AMSA) was 5-fold lower. In contrast, no cross-resistance to camptothecin, an inhibitor of topoisomerase I, was observed. Topoisomerase II decatenation activity in nuclear extracts from 10- and 40-fold DOX-resistant cells was 2- and 4-fold lower, respectively, when compared to sensitive cells. In these cells, however, marked reductions in m-AMSA- and VP-16-induced topoisomerase II mediated DNA cleavage were found to exceed decreases in the catalytic activity of the enzyme. Results from this study demonstrated that, in progressively DOX-resistant L1210 mouse leukemia cells with the MDR phenotype, a better relation existed between the degree of resistance and reduced VP-16- and m-AMSA-induced topoisomerase II mediated DNA cleavage, than between increases in P-glycoprotein and concomitant reduction in DOX accumulation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1986

Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins.

We have established four cell lines derived from the human KB carcinoma cell line which express high-level multiple drug resistance. One of these lines was selected for resistance to colchicine, one was selected for resistance to colchicine in the presence of the tumor promoter, mezerein, one for resistance to vinblastine, and one for resistance to adriamycin. All of these cell lines are cross-resistant to the other selective agents. The development of multidrug resistance in these cultured human carcinoma cells is associated with a limited number of specific protein alterations revealed by high resolution two-dimensional gel electrophoresis and Western blot analysis. These protein alterations in multidrug-resistant lines include the decreased prevalence of members of a family of proteins of molecular mass 70,000 to 80,000 daltons, pI 4.8-5.0, the increased synthesis of a protein of molecular mass 21,000 daltons, pI 5.0, in the colchicine-resistant cell lines only, and the increased expression of a 170,000-dalton protein in membrane preparations from all of the resistant cells. The loss of the 70,000- to 80,000-dalton proteins in the multidrug-resistant lines, which can also be demonstrated by immunoprecipitation of these proteins with specific antisera, is associated with a loss of translatable mRNA for these proteins. These studies suggest that only a limited number of protein changes occur in multidrug-resistant cell lines.

Animals↗
PubMed1979

[Yeast resistance to polyene antibiotics. I. Production of Saccharomyces cerevisiae mutants resistant to nystatin and their genetic analysis].

239 nistatin-resistant mutants were selected after UV-irradiation of yeasts. Phenotypical analysis has revealed two main groups of the mutants: 1) resistant to nistatin and resistant or sensitive (in different combinations) to haptaens; 2) resistant to nistatin and having an increased resistance to haptens. It is found that the sensitivity dominates over the resistance and hyper-resistance. Genetic analysis of the mutant collection has shown that the resistance to nistatin is determined by 5 nuclear genes (hysr). Hyper-resistance is controlled by mutations in other genes, which are not connected with stable phenotype. Genes of hyper-resistance can be considered as minus-modificators of pleiothrophic cross-resistance, characteristic of hysr genes. Plus-modificator genes of polyenic resistance are described. The gene hysr1 is linked with its chromosome.

Crosses, Genetic↗
PubMed1982

Bacterial antibiotic resistance: frequency of gentamicin-resistant strains of Escherichia coli in the fecal microflora of commercial turkeys.

The relationship of subtherapeutic feeding and parenteral injection of antibiotics to the presence of antibiotic resistant strains of Escherichia coli in the fecal microflora of commercial turkeys has been investigated. Cloacal swabs collected from 137 commercial turkeys were examined for E coli resistant to gentamicin. Gentamicin-resistant E coli organisms were isolated and tested for resistance to ampicillin, chloramphenicol, kanamycin, streptomycin, and tetracycline. Strains of E coli resistant to gentamicin were identified in 118 of 137 (86.1%) specimens evaluated. There were 5 different antibiotic resistance patterns exhibited by the gentamicin-resistant strains of E coli. All strains showed a common antibiotic resistance pattern of gentamicin, kanamycin, and streptomycin. The results of the antibiotic susceptibility tests were compared to the known history of antibiotic usage in each flock. There was no significant correlation between the use of subtherapeutic concentrations of antibiotics and the frequency of gentamicin resistant E coli. However, the frequency of gentamicin-resistant E coli was closely related to the age of the bird, with birds less than 12 weeks of age being most likely to harbor E coli resistant to gentamicin. This age-dependent frequency of gentamicin-resistant E coli was associated with the common practice of dipping eggs in gentamicin and injecting newly hatched poults with gentamicin, but not with the feeding of subtherapeutic concentrations of antibiotics.

Age Factors↗
PubMed1980

Mechanism of intrinsic penicillin-resistance in Staphylococcus aureus. Binding of penicillin G to the cytoplasmic membrane of resistant staphylococci.

In staphylococci (and other gram-positive bacteria) the phenotypical expression of intrinsic penicillin resistance as well as the frequency of this resistance are unknown. A permeability barrier in the cell wall, as it was established in gram-negative bacteria, is unlikely in staphylococci and was excluded by experiments with whole cells. Assuming that in staphylococci intrinsic resistance is also located in the cell envelope, the cytoplasmic membrane should be the site of responsibility. Therefore the binding of (14C)-penicillin G to the isolated membrane fraction of four staphylococcal strains resistant to penicillin G was studied. Two strains showed an additional resistance to methicillin, one of them was penicillinase-negative. Compared with two sensitive strains the penicillin binding was greatly reduced in the membranes of the resistant ones. This was not due to a loss of specific receptors. The maximum specific binding capacity of about 20 nmol of (14C)-penicillin G/g membrane protein was found in the resistant strains as well as in the sensitive controls. Furthermore penicillin G irreversibly bound also in the resistant bacteria. Differences, however, were found regarding the affinity of the binding sites for penicillin. In all resistant strains it was reduced by a factor of about 500. Our findings confirm the assumption that in staphylococci the mechanism of intrinsic penicillin resistance is located in the cytoplasmic membrane. They can best be explained when considering that not the penicillin binding components themselves but the membrane structure in their environment is altered thus preventing the access of the antibiotic to its site of action in the membrane. In addition, the homogeneity of our results indicates that intrinsic resistance to penicillin G is, contrary to current opinion, a general phenomenon in resistant staphylococci.

Binding Sites↗
PubMed1994

Human larynx carcinoma cells resistant to cis-diamminedichloroplatinum(II): cross-resistance patterns.

In our previous study we developed two lines of human larynx carcinoma HEp2 cells resistant to cis-diamminedichloroplatinum(II) (CDDP) due to acute (CA3 cells), or continuous (CK2 cells) treatments with increased CDDP concentrations. CA3 line was 2.3-fold resistant, and CK2 line 3.7-fold resistant to CDDP as compared to the parental cells. In this study the sensitivity of CDDP resistant and parental cells to several antitumor drugs was examined using clonogenic survival assay. CK2 cells were 1.7-fold more resistant to vincristine than parental cells, while CA3 cells exhibited resistance to vincristine only at higher concentrations of this drug. Verapamil, an inhibitor of P-glycoprotein, was not able to reverse the resistance of CK2 cells to vincristine, indicating that this cross-resistance did not involve P-glycoprotein. As compared to the parental cells, CK2 cells were 2.1-fold resistant, and CA3 cells 1.7-fold resistant to mitomycin C. CK2 cells were 2-fold more resistant to 5-fluorouracil than the parental cells, while CA3 cells did not exhibit any change in the sensitivity to this drug. CA3 cells were 0.4-fold sensitive to epoxide and 0.53-fold sensitive to doxorubicin, while CK2 cells had the same sensitivity to these drugs as the parental cells. Our results showed that treatment schedule determines the response of CDDP resistant human larynx carcinoma cells to additional drugs, suggesting the complexity of the judicious choice of the drugs in the combined modality treatments of cancer.

Antineoplastic Agents↗
PubMed1993

Pyrethroid resistance in German cockroaches (Dictyoptera: Blattelidae): resistance levels and underlying mechanisms.

Thirty strains of Blattella germanica (L.) reported to be pyrethroid resistant were collected from three continents. Greater than 2-fold resistance to the pyrethroids cyfluthrin, fenvalerate, cypermethrin, and lambda cyhalothrin appeared in 15 of these strains. Twelve of these strains were also resistant to chlorpyrifos and propoxur. All the field strains tested were heterogeneous with regard to resistance. Possible resistance mechanisms detected in these populations included elevated levels of cytochrome P450, general esterase and glutathione S-transferase, and nerve insensitivity (kdr-type resistance). The elevated esterases and oxidase-based resistance were the most prevalent; 11 and 10 strains, respectively, had evidence of these mechanisms. Resistance was synergized by piperonyl butoxide in some strains. In some strains, elevated esterases, although present, were primarily correlated with organophosphate resistance. Pyrethroid insecticides may still be effective against many of these populations because of the low levels of resistance detected. However, potential exists for more serious resistance problems to develop if only pyrethroids are used. Because many of these strains are already resistant to organophosphorus and carbamate insecticides, prospects for the future chemical control of these populations must be carefully considered.

Animals↗
PubMed1997

Selection for drug resistance results in resistance to Fas-mediated apoptosis.

Recent evidence has supported the hypothesis that chemotherapeutic drugs and radiation induce an apoptotic pathway that requires the active participation of the cell. One pathway of apoptosis in malignant lymphoid cells is mediated by the Fas antigen. We studied the human myeloma (8226) and T-cell leukemia (CEM) cell lines selected for resistance to the anthracenes, doxorubicin or mitoxantrone, by continuous culture in the presence of either agent. We found that these drug-resistant cell lines were also resistant to Fas-mediated apoptosis in a dose-dependent manner. The degree of resistance to Fas-mediated apoptosis correlated directly with the level of resistance to chemotherapeutic drugs. These observations indicate that, as cancer cell lines develop mechanisms of drug resistance, they may also develop mechanisms of resistance to physiologic signals of apoptosis. Two mechanisms of resistance to Fas-mediated apoptosis were observed in these cell lines. One mechanism was associated with a dose-dependent reduction in the surface expression of Fas antigen. Analysis of RNA by reverse transcriptase-polymerase chain reaction assays showed that the reduction of Fas antigen expression occurred at the level of transcription. A second mechanism of drug resistance showed no decrease of Fas antigen expression; however, the apoptotic response was diminished. In this situation, removal of the chemotherapeutic agent resulted in a partial reversion to chemosensitivity and re-expression of the Fas antigen, but these cell lines did not regain the ability to undergo apoptosis in response to cross-linking by anti-Fas antibody. These findings support the hypothesis that apoptosis mediated by both chemotherapeutic agents and physiologic stimuli may share a common downstream effector. The demonstration that selection for drug resistance in hematopoietic cell lines results in a simultaneous resistance to Fas-mediated apoptosis may have clinical implications in the development of strategies for the treatment of resistant disease. Further analysis of the molecular mechanisms of Fas expression and function will facilitate the design of biological response modifying agents for the treatment of malignancy.

Antibodies, Monoclonal↗
PubMed2026

Development of linezolid and daptomycin resistance in vancomycin resistant Enterococcus faecium during antibiotic treatment.

The increasing incidence of vancomycin-resistant enterococci (VRE) over the past decade has reduced treatment options largely to linezolid and daptomycin. However, the emergence of resistance to both agents further complicates the management of VRE infections. While the mechanisms of linezolid resistance are relatively well understood, those underlying daptomycin resistance remain less clearly defined. In this study, we analyzed genomic changes associated with the development of linezolid and daptomycin resistance in initially susceptible isolates following treatment at a Danish university hospital. Phenotypic susceptibility testing and whole-genome sequencing were performed on eight isolates obtained from the same patient. We identified two distinct Enterococcus faecium clones with different mechanisms of linezolid resistance. Linezolid resistance was associated with a G2576T mutation in the 23S rRNA gene (ST80 clone) and the presence of the poxtA gene (ST3082 clone). The ST80 clone also developed daptomycin resistance during therapy. We found that daptomycin resistance might result from either a G173R substitution in a gene annotated as an "ABC transporter ATP-binding protein (LolD)" or a nonsense mutation (Q58*) in phosphoketolase, with both alterations potentially acting synergistically, but further studies are warranted to confirm if these mutations can confer resistance. Together with these findings, the study demonstrates that a single patient may harbor multiple E. faecium clones simultaneously, highlighting the risk of treatment failure if all clones are not accurately identified.

Daptomycin↗
PubMed1984

Life history of cells mediating natural resistance to tumor cells and bone-marrow transplants: the respective roles of cell lineage commitment and host environment in determining strain characteristics of natural resistance to foreign marrow grafts.

A class of cells present in the blood and lymphoid tissues of mammals produces rapid cytolysis of tumor cells on first contact. Abundant evidence suggests that such natural killer (NK) cells play a role in tumor immunosurveillance in vivo. A similarly prompt and spontaneous activity can cause the rejection of foreign marrow transplants. These phenomena are known collectively as natural resistance. The cells mediating natural resistance are lymphoid in morphology, but are neither T nor B lymphocytes. Kinetically, NK cells and cells mediating natural resistance to foreign marrow grafts are themselves nondividing but are rapidly renewed from radiosensitive proliferating precursors in the bone marrow. They appear to have no long-lived (memory) component. Newly formed NK cells have a short residence time in the spleen. Other general properties of the natural-resistance cell lineage, including strain variation, ontogeny, and cell phenotype, are reviewed in this article. The present study aimed to examine the respective roles of cell lineage commitment and of the host environment in determining strain characteristics of natural resistance to foreign marrow grafts. Chimeras produced by inoculating mice of a strain that normally has little or no natural resistance with bone marrow from adult mice of a highly resistant strain develop resistance to a third-party marrow allograft. Such chimeras do not develop the full rejection capacity of the high-resistance strain, however; and chimeras created by inoculating marrow from infant mice develop less resistance than those reconstituted by bone marrow from adult mice. The results demonstrate that the ability to reject foreign marrow grafts develops as an intrinsic property of the natural-resistance cell lineage. The host environment may provide an additional influence, however, particularly in the initial development of natural resistance in early postnatal life.

Animals↗
PubMed2000

Multidrug-resistant Pathogens: Mechanisms of Resistance and Epidemiology.

Resistance to antimicrobial agents among bacteria and fungi is a persistent problem complicating the management of critically ill patients. To understand the issues involved in resistance in critical care, it is essential to understand the epidemiology and mechanisms of resistance. beta-lactam resistance in pneumococci, and penicillin and chloramphenicol resistance in Neisseria meningitidis, have complicated the management of meningitis. Vancomycin resistance in enterococci and methicillin resistance in Staphylococcus aureus have disseminated among hospitals, nursing homes and, in some cases, community patients. Glycopeptide resistance in S. aureus has recently been described in clinical isolates; the potential for spread of this resistance trait is concerning. Resistance to broad-spectrum cephalosporins is a persistent challenge in the management of infections caused by Pseudomonas areuginosa, and Enterobacter species, as well as other Enterobacteriaceae. Azole resistance in Candida species. has also complicated the treatment of nosocomial infections. Resistance to antimicrobial drugs is a persistent and emerging problem and presents major therapeutic challenges.

Journal Article↗
PubMed2026

Mechanisms of cefiderocol resistance in carbapenem-resistant Acinetobacter baumannii: a Swiss 2023-2025 collection.

OBJECTIVES: The numbers of infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) are increasing globally and present a significant burden on healthcare systems. This study describes the CRAB isolates received at the Swiss National Reference Centre for Emerging Antibiotic Resistance (NARA) over a 3-year period, from January 2022 to December 2025, and aimed to characterize the prevalence and mechanisms of FDC resistance. METHODS: Two-hundred and thirty-four non-duplicate CRAB isolates were submitted to NARA over the study period from hospitals and laboratories across Switzerland. Susceptibility testing was performed by disk diffusion and broth microdilution, according to EUCAST methodology. Whole-genome sequencing was performed on 11 isolates. ADC alleles were cloned into vector pVRL1 and transformed into Escherichia coli Top10. RESULTS: All isolates exhibited resistance to the carbapenems, and most were resistant to cephalosporins. Most isolates harboured an acquired class D carbapenemase, most frequently OXA-23 (181/234; 77.4%). One quarter of isolates were resistant to cefiderocol (FDC), exhibiting MICs ranging from 4->32 mg/L. Whole genome sequencing analyses, performed on 11 FDC-resistant isolates, identified that FDC resistance was due a combination of mechanisms including NDM and PER-production, mutations within the iron transporters, piuA and pirA, and the overexpression of ADC variants. CONCLUSIONS: This study showed that OXA-23 was the dominant mechanism of carbapenem-resistance in CRAB in Switzerland. Almost one quarter of CRAB isolates were resistant to "last resort" antimicrobial, FDC. The mechanisms of FDC resistance identified in this study emphasise that resistance to this antimicrobial is often complex and multifactorial, requiring high-resolution methods, including WGS, to identify.

Acinetobacter baumannii↗
PubMed2005

Measurement of peripheral muscle resistance in rats with chronic ischemia-induced paraplegia or morphine-induced rigidity using a semi-automated computer-controlled muscle resistance meter.

In experimental and clinical studies, an objective assessment of peripheral muscle resistance represents one of the key elements in determining the efficacy of therapeutic manipulations (e.g. pharmacological, surgical) aimed to ameliorate clinical signs of spasticity and/or rigidity. In the present study, we characterize a newly developed limb flexion resistance meter which permits a semi-automated, computer-controlled measurement of peripheral muscle resistance (PMR) in the lower extremities during a forced flexion of the ankle in the awake rat. Ischemic paraplegia was induced in Sprague-Dawley rats by transient aortic occlusion (10 min) in combination with systemic hypotension (40 mm Hg). After ischemia the presence of spasticity component was determined by the presence of an exaggerated EMG activity recorded from gastrocnemius muscle after nociceptive or proprioceptive afferent activation and by velocity-dependent increase in muscle resistance. Rigidity was induced by high dose (30 mg/kg, i.p.) of morphine. Animals with defined ischemic spasticity or morphine-induced rigidity were then placed into a plastic restrainer and a hind paw attached by a tape to a metal plate driven by a computer-controlled stepping motor equipped with a resistance transducer. The resistance of the ankle to rotation was measured under several testing paradigms: (i) variable degree of ankle flexion (40 degrees, 50 degrees, and 60 degrees), (ii) variable speed/rate of ankle flexion (2, 3, and 4 sec), (iii) the effect of inhalation anesthesia, (iv) the effect of intrathecal baclofen, (v) the effect of dorsal L2-L5 rhizotomy, or (vi) systemic naloxone treatment. In animals with ischemic paraplegia an increased EMG response after peripheral nociceptive or proprioceptive activation was measured. In control animals average muscle resistance was 78 mN and was significantly increased in animals with ischemic spasticity (981-7900 mN). In ischemic-spastic animals a significant increase in measured muscle resistance was seen after increased velocity (4 > 3 > 2 sec) and the angle (40 degrees > 50 degrees > 60 degrees) of the ankle rotation. In spastic animals, deep halothane anesthesia, intrathecal baclofen or dorsal rhizotomy decreased muscle resistance to 39-80% of pretreatment values. Systemic treatment with morphine induced muscle rigidity and corresponding increase in muscle resistance. Morphine-induced increase in muscle resistance was independent on the velocity of the ankle rotation and was reversed by naloxone. These data show that by using this system it is possible to objectively measure the degree of peripheral muscle resistance. The use of this system may represent a simple and effective experimental tool in screening new pharmacological compounds and/or surgical manipulations targeted to modulate spasticity and/or rigidity after a variety of neurological disorders such as spinal cord traumatic or ischemic injury, multiple sclerosis, cerebral palsy, or Parkinson's disease.

Anesthetics, Inhalation↗
PubMed2026

Insights into the fate and dynamics of antibiotic resistance in multidrug-resistant Bacillus cereus during in vitro simulated gastrointestinal digestion.

Bacillus cereus, an important pathogen responsible for causing foodborne diseases worldwide, releases pore-forming enterotoxins, which target host epithelial cells, leading to osmotic lysis and ultimately manifesting as diarrheal syndrome. Moreover, some B. cereus strains carry antimicrobial resistance genes that confer multidrug resistance against a spectrum of antibiotics. Characterizing the survival traits of multidrug-resistant (MDR) B. cereus strains in the intestinal microenvironment is essential for developing targeted strategies to effectively manage diarrheal foodborne diseases caused by this pathogen. This study used whole-genome sequencing (WGS) to evaluate the pre- and post-digestion toxigenic potential, antimicrobial resistance profiles, and genetic diversity of MDR B. cereus strains isolated from food samples in Guangdong Province, China. The four B. cereus isolates investigated in this study exhibited a genetic diversity, as determined by multilocus sequence typing analysis of WGS data. All four isolates produced the diarrheal toxins Hbl, Nhe, and CytK to varying levels, indicative of their potential to cause outbreaks of foodborne diseases. Each of the four isolates exhibited resistance to more than three classes of antibiotics, fulfilling the criterion for multidrug resistance. At an initial concentration of 9 log colony-forming units (CFU)/mL, the intestinal concentration of these four isolates crossed the threshold required to induce widespread diarrhea in the general population. Under rice slurry protection, all tested isolates maintained intestinal concentration beyond the threshold when the initial concentration was increased to ≥8 log CFU/mL. Moreover, the upregulations of genes associated with acid tolerance, bile tolerance and stress response were observed in the surviving MDR B. cereus isolates. Digestion markedly altered the antibiotic resistance profiles of the MDR B. cereus isolates. In the absence of a food matrix, the MDR isolates lost their resistance to imipenem, meropenem, amoxicillin-clavulanic acid, and trimethoprim-sulfamethoxazole post-digestion and was influenced by the initial concentration of the strains. In the presence of food matrix rice slurry, the effects of digestion on the antibiotic resistance of MDR B. cereus isolates can be mitigated, enabling them to maintain their antibiotic resistance to the greatest extent. Most remarkably, after digestion, the isolates Bce055 and Bce166 exhibited newly emergent resistance to cefotetan and trimethoprim-sulfamethoxazole, respectively. Our findings clarify the fate of MDR B. cereus isolates in the gastrointestinal tract and inform the development of prevention and control strategies for foodborne diseases caused by this pathogen.

Drug Resistance, Multiple, Bacterial↗
PubMed2001

Reduced cellular transport and activation of fluoropyrimidine nucleosides and resistance in human lymphocytic cell lines selected for arabinosylcytosine resistance.

Arabinofuranosylcytosine (araC) resistant H9-araC0.05 and H9-araC0.5 sublines were obtained following in vitro exposure of H9 cells to 0. 05 and 0.5 microM araC, respectively. These cell lines were 83.3- and 266.7-fold, 21- and 80-fold, and 2.4- and 4.0-fold more resistant to 5-fluorouridine (FUR), 5-fluoro-2'-deoxyuridine (FdUR), and 5-fluorouracil (FU), respectively. Compared with H9 cells, the cellular accumulation of FUR was 2.2 and 0.2%, FdUR 15.6 and 0.9%, and FU 56.9 and 66.5% in H9-araC0.05 and H9-araC0.5 cells, respectively. An araC resistant HL60 cell line (promyelocytic cell line) was 5.0- and 1.7-fold resistant to FUR and FdUR, respectively, but displayed no resistance to FU. The lower FUR and FdUR nucleotide levels in the resistant cells were a result of reduced cellular transport and uridine kinase (UR kinase) and thymidine kinase (TK) activities. Compared with the parental cell line, the p-nitrobenzyl thioinosine (an inhibitor of nucleoside transport) binding sites also were lower in the araC resistant cells. There was no difference in the expression of multidrug-resistant protein and thymidylate synthase mRNA in the parental and the resistant cell lines. Data presented here suggest that araC exposure of H9 cells, in addition to araC resistance, induced/selected cells that were resistant to FUR and FdUR. These cells had altered cellular drug transport and lower TK and UR kinase activities. Further studies to understand molecular mechanisms of this phenomenon are warranted.

Antimetabolites, Antineoplastic↗
PubMed2002

[Antibiotic resistance in blood isolates of Staphylococcus aureus in 31 Spanish hospitals participating in the European Antimicrobial Resistance Surveillance System (2000)].

BACKGROUND: In 1998, the European Union funded the European Antimicrobial Resistance Surveillance System. We present here Staphylococcus aureus data in 2000 in Spain. MATERIAL AND METHOD: 31 hospitals were involved, covering almost 25% Spanish total population. All nosocomial blood isolates of S. aureus were included. Each laboratory carried out microbiological studies with its own usual methods. Quality control was carried out by UK National External Quality (NEQAS). A questionnaire including hospital, patient and specimen data was filled out for each isolate. Results were registered in a single database and analyzed and validated with Whonet. 5 software. RESULTS: Invasive S. aureus was isolated in 903 patients. Overall incidence was 1.45/1000 admitted patients. Resistance was 28.1% (95% CI, 25.2-31.1) to oxacillin (O), 26.6% to ciprofloxacin (C), 23.8% to erythromycin (E) and 16.6% to gentamicin (G). Multiresistance was noticed in 80% oxacillin-resistant strains. More frequent multiresistance profiles were OECG (11.3% of all isolates) and OEC (6.3%). Oxacillin resistance was higher in ICU units (44.5%) than in other medical departments (27.4%) (p < 0.001). Hospitals with 500 beds or more showed 36.4% prevalence of O resistance, while in hospitals having less than 500 beds it was 18.8% (p < 0.001). A decreased susceptibility to vancomycin was not detected. CONCLUSIONS: In Spain, invasive S. aureus shows a high prevalence of resistance to oxacillin, ciprofloxacin, erythromycin and gentamicin. Most oxacillin-resistant strains were resistant to three or more antibiotics. Nearly 50% oxacillin-resistant isolates were susceptible to gentamicin. Oxacillin resistance and resistance to multiple antibiotics was more frequent in ICU units and in hospitals with 500 beds or more.

Adolescent↗
PubMed2000

Effect of the breast-cancer resistance protein on atypical multidrug resistance.

Simultaneous resistance of malignant cells to several antineoplastic agents that are structurally and functionally unrelated is known as multidrug resistance. It is one of the main causes of chemotherapy failure. Besides the classic multidrug-resistant phenotype, mediated by increased activity of the ATP-binding cassette (ABC) transporter P-glycoprotein, there are other multidrug-resistant tumours, with resistance caused by different mechanisms. This is called atypical multidrug resistance. Pronounced overexpression of a novel ABC transporter has been observed in various human cancer cell lines with atypical multidrug resistance (which were established by in vitro exposure to mitoxantrone, topotecan, doxorubicin, or bisantrene). This novel transporter was originally named breast-cancer resistance protein (BCRP). BCRP is a 655-aminoacid protein of about 72 kDa. It can be thought of as an ABC 'half-transporter', and it forms dimers to produce an active transport complex. Transfection experiments with BCRP cDNA showed that the phenotype of atypical multidrug resistance could be transferred to formerly drug-sensitive cancer cells. Although the role of BCRP in drug resistance of clinical cancers is still unclear, preliminary data obtained by mRNA and protein expression analyses support the assumption that it has a role in clinical multidrug resistance.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2001

Impact of HIV type 1 drug resistance mutations and phenotypic resistance profile on virologic response to salvage therapy.

This study examines the association between presence of drug resistance mutations and phenotypic resistance at baseline to virologic response to salvage therapy in a community setting. The study population consisted of 58 antiretroviral drug-experienced patients with HIV-1 infection who had recently switched therapy because of virologic failure. Drug resistance mutations in the reverse transcriptase- and protease-coding regions and phenotypic susceptibility to 13 antiretroviral drugs were assessed at baseline. Plasma HIV-1 RNA levels were assessed at baseline and at subsequent clinic visits. Results showed that three variables were significant in predicting virologic response: HIV-1 levels at baseline, number of protease mutations, and phenotypic sensitivity score for the regimen at baseline. For four drugs there was a significant association between the presence of specific drug resistance mutations and >10-fold phenotypic resistance to that drug. With phenotypic resistance defined as >4-fold resistance, the association between specific drug resistance mutations and phenotypic resistance was significant for seven drugs. Overall, these data show that phenotypic susceptibility and absence of drug resistance mutations, particularly protease mutations, are significant predictors of virologic response. For several drugs, specific combinations of drug resistance mutations are associated with decreased phenotypic susceptibility and might provide useful clinical guidelines in selecting therapeutic options.

Adult↗