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PubMed1999

A novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents.

Following transduction with a retrovirus (SF1MIH) expressing both the multidrug resistance 1 (MDR1) and O6-alkylguanine-DNA-alkyltransferase (ATase) proteins, human erythroleukaemic progenitor (K562) cells were isolated which were resistant to killing by the MDR1 substrate, colchicine. In colony-forming survival assays, K562-SF1MIH cells exhibited resistance to colchicine and doxorubicin, as well as to the O6-alkylating agents N-Methyl-N-nitrosourea (MNU) and temozolomide. Furthermore, the resistance to doxorubicin was abolished by preincubation with the MDR1 inhibitor verapamil while resistance to MNU was ablated by the specific ATase inactivator, O6-benzylguanine (O6-beG) confirming that resistance to doxorubicin and MNU was conferred by MDR1 and ATase, respectively. When K562-SF1MIH were exposed to combinations of colchicine and MNU or doxorubicin and temozolomide, simultaneous resistance to these agents was observed. Thus, transduction of K562 with SF1MIH conferred dual resistance to these cells. These data offer the prospect of designing vectors that will confer resistance to entire regimens of chemotherapy rather than just to individual components of such drug cocktails, thereby substantially increasing the efficacy of therapy. Furthermore, the use of such dual expression constructs is likely to be highly informative for the design of effective in vivo selection protocols, an issue likely to make a major impact in a clinical context in gene therapy in the near future.

Antineoplastic Agents↗
PubMed2004

Distribution across the USA of macrolide resistance and macrolide resistance mechanisms among Streptococcus pneumoniae isolates collected from patients with respiratory tract infections: PROTEKT US 2001-2002.

BACKGROUND: Resistance to the macrolides has increased rapidly among isolates of Streptococcus pneumoniae from community-acquired respiratory tract infections (CARTIs). METHODS: A total of 10 012 S. pneumoniae isolates were submitted from 46 US states and the territory of Puerto Rico in the PROTEKT US Year 2 (2001-2002) surveillance study. Antimicrobial susceptibilities were determined according to NCCLS guidelines and genes encoding common macrolide resistance mechanisms were sought by PCR. RESULTS: Overall, 27.9% (n=2793) of S. pneumoniae isolates were macrolide (erythromycin) resistant; the highest prevalence was recorded in Louisiana (48.2%). Of the 2738 genotyped macrolide-resistant S. pneumoniae, 68.7% possessed mef(A) (state range: Delaware 40.0%-Georgia 84.8%), 16.8% of isolates harboured erm(B) (Georgia 6.1%-Idaho and Rhode Island both 36.4%) and 12.2% possessed erm(B) + mef(A) (Arkansas and Rhode Island 0%-South Dakota 32.9%). Five isolates possessed an erm(A) subclass erm(TR) gene (from California, Illinois, Missouri, Pennsylvania and Virginia), while the mechanisms for 56 isolates were not definable by the methods used in this study. Susceptibility to telithromycin was high, irrespective of macrolide resistance mechanism, with > or =96.4% of the macrolide-resistant isolates susceptible. CONCLUSIONS: The prevalence of macrolide resistance and the resistance mechanisms among S. pneumoniae isolates are highly variable among the US states. Telithromycin may represent an effective treatment option for CARTIs caused by macrolide-resistant pneumococci.

Anti-Bacterial Agents↗
PubMed1999

Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development.

OBJECTIVES: To assess the in-vitro drug susceptibility of a panel of five well-characterized drug-resistant HIV variants to recently developed anti-HIV compounds including seven reverse transcriptase (RT) inhibitors and seven protease inhibitors. METHODS: Drug-resistant viral strains were selected on the basis of the prevalence of these mutants in patient samples from local area HIV clinics. The isolates included one multinucleoside-resistant virus containing the Q151M mutation, and four clinical isolates containing multiple RT and protease resistance mutations. The activity of the experimental compounds against these isolates was determined using drug susceptibility assays and measuring the viral antigen p24 end-point. RESULTS: These clinically relevant highly drug-resistant viruses were resistant to many of the new compounds in clinical development. In most cases the resistance mutations of the clinical isolate were different from those selected in vitro for the particular experimental compound. CONCLUSIONS: It is critical to expand the preclinical development of new drugs to include the assessment of their activity against currently circulating highly drug-resistant clinical strains, in order to develop appropriate salvage therapies for patients harboring resistant strains.

Drug Resistance, Microbial↗
PubMed2004

N-acetylcysteine enhances multidrug resistance-associated protein 1 mediated doxorubicin resistance.

BACKGROUND: Resistance of cancer cells against anticancer agents is caused partly by multidrug resistance-associated protein 1 (MRP1). The exact mechanism of MRP1-involved multidrug resistance has not yet been clarified, although glutathione (GSH) is likely to have a role for the resistance to occur. N-acetylcysteine (NAC) is a pro-glutathione drug. DL-buthionine (S,R)-sulfoximine (BSO) inhibits GSH synthesis. The aim of our study was to investigate the effect of NAC and BSO on MRP1-mediated doxorubicin resistance in human embryonic kidney (HEK293) and its MRP1-transfected 293MRP cells. MATERIALS AND METHODS: Human embryonic kidney cells were transfected with a plasmid encoding the whole MRP1 gene. Both cells were incubated with doxorubicin in the presence or absence of NAC and/or BSO. The viability of both cells was determined under different incubation conditions. Glutathione, glutathione S-transferase (GST) and glutathione peroxidase (GPx) levels were measured in the cell extracts obtained from both cells incubated with different drugs. RESULTS: N-acetylcysteine increased the resistance of both cells against doxorubicin. DL-buthionine (S,R)-sulfoximine decreased NAC-enhanced MRP1-mediated doxorubicin resistance, indicating that induction of MRP1-mediated doxorubicin resistance depends on GSH synthesis. Doxorubicin decreased the cellular GSH concentration and increased GPx activity. Glutathione S-transferase activity was decreased by NAC. CONCLUSION: Our results demonstrate that NAC enhances MRP1-mediated doxorubicin resistance and this effect depends on GSH synthesis. DL-buthionine (S,R)-sulfoximine seems a promising chemotherapy improving agent in MRP1 overexpressing tumour cells.

Acetylcysteine↗
PubMedDate not supplied

Application of molecular genetic methods in macrolide, lincosamide and streptogramin resistance diagnostics and in detection of drug-resistant Mycobacterium tuberculosis.

Antimicrobial susceptibility testing has traditionally been based on measurements of minimal inhibitory concentrations of antimicrobials. Molecular genetic studies on antimicrobial resistance have produced a great deal of genetic information which can be used for diagnosis of antimicrobial resistance determinants. Bacteria can acquire resistance to macrolides, lincosamides and streptogramin antibiotics by modification of the target site of the drugs, by active efflux of the drugs, and by inactivation of the drugs. The genetic backgrounds of these resistance mechanisms are well known and several molecular methods for detection of resistance determinants have been developed. Outbreaks of multidrug-resistant tuberculosis have focused international attention on the emergence of Mycobacterium tuberculosis strains that are resistant to antimycobacterial agents. Knowledge of the antimycobacterial resistance genetics and progress in molecular methods has made it possible to develop rapid molecular methods for susceptibility testing. This review presents the genetic background of drug resistance and introduces some methods for genotypic susceptibility testing.

ATP-Binding Cassette Transporters↗
PubMed2001

[Functional characterization of a multiple-antibiotic resistant plasmid from clinical isolates of methicillin-resistant Staphylococcus aureus].

During surveillance done as part of the investigation of nosocominal infections due to methicillin-resistant Staphylococcus aureus (MRSA), we have been aware of the close relationship between the presence of certain plasmids and the characteristic patterns of antibiotic resistance. The hypothesis that a mechanism for the rapid and widespread dissemination of resistance to multiple aminoglycosides in clinical isolates of MRSA at our university hospital was the result of transfer of a single plasmid among these strains was examined. About 45% of the total isolates of MRSA (91/200 isolates) carried a 35.5 kb plasmid (designated pCL4) and these isolates always showed resistance to gentamicin, tobramycin, kanamycin, amikacin, astromicin, and arbekacin. Mating experiments between a susceptible strain and resistant MRSA isolates carrying pCL4 showed high frequency transfer of the plasmid. The aminoglycoside resistance patterns of all the transconjugants obtained corresponded well with those of parental strains. However, the plasmid could not necessarily be detected in the transconjugants, whereas the transformants obtained by means of electroporation usually possessed the plasmid. The plasmid-encoded aminoglycoside-resistance determinant, which has been identified as the gene aacA/aphD that encodes the bifunctional enzyme AAC (6')/APH(2"), either in the transconjugants and transformants could be transposed to their chromosomes in the absence of whole-plasmid integration resulting from a recombination event. Southern hybridization analysis using an aacA/aphD specific probe demonstrated that there are multiple sites of the insertions indistinguishable among the chromosomes of plasmid-free transconjugants and transformants. These results indicate that rapid dissemination of multiple-aminoglycoside-resistance in nosocominal strains of MRSA resulted from transfer of a conjugative plasmid and has been facilitated by translocations of the resistance gene to the chromosome.

Cross Infection↗
PubMed2004

[Epidemiological study of Arbekacin-resistant, methicillin resistant Staphylococcus aureus in Saitama Medical School Hospital].

Arbekacin-resistant, methicillin-resistant Staphylococcus aureus was frequently isolated in Saitama Medical School Hospital during 1996 and 1998. The minimum inhibitory concentration for ABK was 8 micrograms/ml in 14 strains, 16 micrograms/ml in 6 strains, and 32 micrograms/ml in 2 strains. The maximum isolation rate of these resistant strains in one month was 8%. Use of ABK in the hospital did not increase during the same period. The infection control team (ICT) of the hospital recognized the increase of resistant strains and started intervention for the hospital staff. The ICT instructed the staff of each ward to follow standard precautions for the prevention of nosocomial infections and the risk of ABK-resistant MRSA was explained repeatedly. Thereafter, the isolation rate decreased to 3%. An epidemiological study was done using 22 strains of ABK-resistant MRSA that were isolated in this period. The strains originated from different patients and from 10 different wards, which were designated as wards A to J. Eight strains were isolated from surgical ward A, followed by the other wards (ward B: 3, C: 2, D: 2, E: 2, F: 1, G: 1, H: 1, I: 1, J: 1). The specimens from which ABK-resistant MRSA were isolated were as follows,: sputum: 4, wound: 4, decubitus ulcer: 4, urine: 2, pus: 2, blood :1, central venous catheter: 1, drainage tube: 1, tracheal aspirate: 1, skin: 1, stool: 1. Several investigations were done using these strains. Sensitivity tests for ABK, VCM, MINO, LVFX, FOM, IPM were performed by the standard method of the Japan Society for Chemotherapy. Coagulase types were determined. Production of toxic shock syndrome toxin-1 (TSST-1), enterotoxin, and beta-lactamase was assayed. Pulse-field gel electrophoresis (PFGE) using Sma I was also done and differences were compared. Seven of the 8 strains from ward A showed the same drug sensitivity profile and biological phenotype. Two of the 3 strains from ward B and 2 strains from ward C were also identical by these methods. Six of the 8 strains from ward A were also identical by PFGE. These 6 isolates showed the same drug sensitivity pattern, same coagulase type, and same production of TSST-1 and enterotoxin. Two other strains from ward B, one strain from ward F, and one from ward I also showed the same PFGE pattern, drug sensitivity profile, and toxin profile as the 6 strains from ward A. Our data show that the same strains were transmitted around the hospital during the study period, although serious nosocomial infections due to ABK-resistant MRSA were avoided. Thus, intervention by the ICT in each ward was effective. ABK-resistant MRSA should be recognized as an important hospital pathogen and should be surveyed consistently.

Aminoglycosides↗
PubMed1988

Genetic analysis of gentamicin resistance in methicillin- and gentamicin-resistant strains of Staphylococcus aureus isolated in Dublin hospitals.

Methicillin- and gentamicin-resistant strains of Staphylococcus aureus isolated in Dublin hospitals have been classified into groups I, II, and III based on resistance to antimicrobial agents and plasmid profiles. Each group expresses a characteristic level of resistance to gentamicin, tobramycin, and sisomicin. Enzyme assays showed that resistant strains expressed 2"-aminoglycoside phosphotransferase-6'-aminoglycoside transferase activity by a determinant which is known to be chromosomally located. The gentamicin resistance (Gmr) determinants were transferred from group I, II, or III strains by transduction into a laboratory strain where each expressed the same low level of resistance. This finding suggests that high-level resistance in some clinical strains is due to a second, unlinked resistance mechanism. No evidence was obtained by hybridization experiments that clinical isolates or spontaneous mutants expressing high-level Gmr carried more than one copy of the Gmr determinant, thus eliminating the possibility that a gene dosage effect was responsible for high-level resistance. Hybridization experiments with transductants and wild strains suggested that the Gmr determinant was located at homologous sites in wild strains from different groups, although restriction site differences were observed in flanking sequences. Electron microscope analysis of a cloned Gmr determinant and genetic evidence suggested that a Dublin clinical isolate harbored a transposon very similar to Tn4001.

Anti-Bacterial Agents↗
PubMed1999

Construction and characterization of mutants of the TEM-1 beta-lactamase containing amino acid substitutions associated with both extended-spectrum resistance and resistance to beta-lactamase inhibitors.

Extended-spectrum TEM beta-lactamases (ESBLs) do not usually confer resistance to beta-lactamase inhibitors such as clavulanate or tazobactam. To investigate the compatibility of the two phenotypes we used site-directed mutagenesis of the bla(TEM-1) gene to introduce into the TEM-1 beta-lactamase amino acid substitutions that confer the ESBL phenotype: TEM-12 (Arg164-->Ser), TEM-26 (Arg164-->Ser plus Glu104-->Lys), TEM-19 (Gly238-->Ser), and TEM-15 (Gly238-->Ser plus Glu104-->Lys). These were combined with three sets of substitutions that confer inhibitor resistance: TEM-31 (Arg244-->Cys), TEM-33 (Met69-->Leu), and TEM-35 (Met69-->Leu and Asn276-->Asp). Introduction of the Arg244-->Cys substitution gave rise to inhibitor-resistant hybrid enzymes that either lost ESBL activity (TEM-12, TEM-15, and TEM-19) or had reduced activity (TEM-26) against ceftazidime. In contrast, the introduction of Met69-->Leu or Met69-->Leu plus Asn276-->Asp substitutions did not significantly affect the abilities of the enzymes to confer resistance to ceftazidime, although increased susceptibility to cefotaxime was observed with Escherichia coli strains that expressed the TEM-19 and TEM-26 beta-lactamases. With the exception of the TEM-12 beta-lactamase, introduction of the Met69-->Leu substitution did not give rise to enzymes with increased resistance to clavulanate compared to that of the TEM-1 beta-lactamase. However, introduction of the double substitution Met69-->Leu plus Asn276-->Asp in the ESBLs did give rise to low-level (TEM-19, TEM-15, and TEM-26) or moderate-level (TEM-12) clavulanate resistance. None of the hybrid enzymes were as resistant to clavulanate as the corresponding inhibitor-resistant TEM beta-lactamase mutant, suggesting that active-site configuration in the ESBLs limits the degree of clavulanate resistance conferred.

Amino Acid Substitution↗
PubMed2004

Penicillin-binding protein 2 is essential for expression of high-level vancomycin resistance and cell wall synthesis in vancomycin-resistant Staphylococcus aureus carrying the enterococcal vanA gene complex.

A combination of biochemical and genetic experiments were performed in order to better understand the mechanism of expression of high-level vancomycin resistance in Staphylococcus aureus. The transcription of pbp2 of the highly vancomycin- and oxacillin-resistant strain COLVA200 and its mutant derivative with inactivated mecA were put under the control of an inducible promoter, and the dependence of oxacillin and vancomycin resistance and cell wall composition on the concentration of the isopropyl-beta-D-thiogalactopyranoside inducer was determined. The results indicate that mecA--the genetic determinant of oxacillin resistance--while essential for oxacillin resistance, is not involved with the expression of vancomycin resistance. Penicillin binding protein 2A, the protein product of mecA, appears to be unable to utilize the depsipeptide cell wall precursor produced in the vancomycin-resistant cells for transpeptidation. The key penicillin binding protein essential for vancomycin resistance and for the synthesis of the abnormally structured cell walls characteristic of vancomycin-resistant S. aureus (A. Severin, K. Tabei, F. Tenover, M. Chung, N. Clarke, and A. Tomasz, J. Biol. Chem. 279:3398-3407, 2004) is penicillin binding protein 2.

Bacterial Proteins↗
PubMed1964

EPISOME-MEDIATED TRANSFER OF DRUG RESISTANCE IN ENTEROBACTERIACEAE. 8. SIX-DRUG-RESISTANCE R FACTOR.

Watanabe, Tsutomu (Keio University School of Medicine, Tokyo, Japan), Chizuko Ogata, and Sachiko Sato. Episome-mediated transfer of drug resistance in Enterobacteriaceae. VIII. Six-drug-resistance R factor. J. Bacteriol. 88:922-928. 1964.-The multiple-drug-resistant Escherichia coli strain isolated by Lebek in 1963 was found to transfer resistance to sulfonamide, streptomycin, chloramphenicol, tetracycline, kanamycin, and neomycin together by conjugation, as well as by transduction with phage P1kc, suggesting that these drug-resistance markers are carried by a single R factor (R(6)). The results of transductional and spontaneous segregations of the drug-resistance markers of R(6) have shown that R(6) has independent genetic determinants for sulfonamide, streptomycin, chloramphenicol, tetracycline, and kanamycin-neomycin resistance. Resistance to kanamycin and neomycin is probably controlled by a single gene, because no segregation was observed between these two. The resistance transfer factor of R(6) was found to be of the fi(+) type.

Anti-Bacterial Agents↗
PubMed2002

Possible connection between a widely disseminated conjugative gentamicin resistance (pMG1-like) plasmid and the emergence of vancomycin resistance in Enterococcus faecium.

A total of 640 vancomycin-resistant Enterococcus faecium (VRE) isolates, which were obtained between 1994 and 1999 from the Medical School Hospital of the University of Michigan, Ann Arbor, were used in this study. Of the 640 strains, 611 and 29 were VanA and VanB VRE, respectively, based on PCR analysis. Four hundred ninety-two (77%) of the strains exhibited resistance to concentrations of gentamicin from 64 micro g/ml (MIC) to more than 1,024 micro g/ml (MIC). The gentamicin resistance of each of 261 (53%) of the 492 gentamicin-resistant strains was transferred to E. faecium at a frequency of about 10(-5) to 10(-6) per donor cell in broth mating. More than 90% of vancomycin resistances of the 261 strains cotransferred with the gentamicin resistances to E. faecium strains by filter mating. The conjugative gentamicin resistance plasmids were identified and were classified into five types (A through E) with respect to their EcoRI restriction profiles. The transfer frequencies of each type of plasmid between E. faecium strains or Enterococcus faecalis strains were around 10(-3) to 10(-5) per donor cell or around 10(-6) to 10(-7) per donor cell, respectively, in broth mating. Type A and type B were the most frequently isolated, at an isolation frequency of about 40% per VRE isolate harboring the gentamicin resistance conjugative plasmid. The plasmids did not show any homology in Southern hybridization with the pheromone-responsive plasmids and broad-host-range plasmids pAMbeta1 and pIP501. The EcoRI or NdeI restriction fragments of each type of plasmids hybridized to the conjugative gentamicin resistance plasmid pMG1 (65.1 kb), which was originally isolated from an E. faecium clinical isolate, and transfer efficiently in broth mating.

Anti-Bacterial Agents↗
PubMed2025

Genomic detection of Panton-Valentine Leucocidins encoding genes, virulence factors and distribution of antiseptic resistance determinants among Methicillin-resistant S. aureus isolates from patients attending regional referral hospitals in Tanzania.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a formidable public scourge causing worldwide mild to severe life-threatening infections. The ability of this strain to swiftly spread, evolve, and acquire resistance genes and virulence factors such as pvl genes has further rendered this strain difficult to treat. Of concern, is a recently recognized ability to resist antiseptic/disinfectant agents used as an essential part of treatment and infection control practices. This study aimed at detecting the presence of pvl genes and determining the distribution of antiseptic resistance genes in Methicillin-resistant Staphylococcus aureus isolates through whole genome sequencing technology. MATERIALS AND METHODS: A descriptive cross-sectional study was conducted across six regional referral hospitals-Dodoma, Songea, Kitete-Kigoma, Morogoro, and Tabora on the mainland, and Mnazi Mmoja from Zanzibar islands counterparts using the archived isolates of Staphylococcus aureus bacteria. The isolates were collected from Inpatients and Outpatients who attended these hospitals from January 2020 to Dec 2021. Bacterial analysis was carried out using classical microbiological techniques and whole genome sequencing (WGS) using the Illumina Nextseq 550 sequencer platform. Several bioinformatic tools were used, KmerFinder 3.2 was used for species identification, MLST 2.0 tool was used for Multilocus Sequence Typing and SCCmecFinder 1.2 was used for SCCmec typing. Virulence genes were detected using virulenceFinder 2.0, while resistance genes were detected by ResFinder 4.1, and phylogenetic relatedness was determined by CSI Phylogeny 1.4 tools. RESULTS: Out of the 80 MRSA isolates analyzed, 11 (14%) were found to harbor LukS-PV and LukF-PV, pvl-encoding genes in their genome; therefore pvl-positive MRSA. The majority (82%) of the MRSA isolates bearing pvl genes were also found to exhibit the antiseptic/disinfectant genes in their genome. Moreover, all (80) sequenced MRSA isolates were found to harbor SCCmec type IV subtype 2B&5. The isolates exhibited 4 different sequence types, ST8, ST88, ST789 and ST121. Notably, the predominant sequence type among the isolates was ST8 72 (90%). CONCLUSION: The notably high rate of antiseptic resistance particularly in the Methicillin-resistant S. aureus strains poses a significant challenge to infection control measures. The fact that some of these virulent strains harbor the LukS-PV and LukF-PV, the pvl encoding genes, highlight the importance of developing effective interventions to combat the spreading of these pathogenic bacterial strains. Certainly, strengthening antimicrobial resistance surveillance and stewardship will ultimately reduce the selection pressure, improve the patient's treatment outcome and public health in Tanzania.

Methicillin-Resistant Staphylococcus aureus↗
PubMed1997

[Drug resistance mechanism of doxorubicin-resistant human gastric cancer cells BGC-823/DOX].

To further investigate drug resistance mechanism of BGC-823/DOX, we analysed the amplication, transcription and overexpression of genes associated with drug resistance by Southern blot, RT-PCR, immunohisto clogical assay and the concentration of Doxorubicin in the cells by flow cytometry. The results showed that parent cells of BGC-823 were cell line with intrinsic drug resistance similar to the gastrointestinal tumors. Multidrug resistance was the main mechanism of drug resistance in BGC-823/DOX. There was a significant difference between the doxorubicin-resistant cells line from parent cells with intrinsic drug resistance and from parent cells without intrinsic drug resistance in drug resistance.

ATP-Binding Cassette Transporters↗
PubMed1999

Primary resistance to antituberculosis drugs: a national survey conducted in Côte d'Ivoire in 1995-1996. Ivoirian Study Group on Tuberculosis Resistance.

SETTING: A national survey of resistance to the antituberculosis drugs used in Côte d'Ivoire was conducted in 1995-1996. OBJECTIVE: To determine the rate of primary resistance to antituberculosis drugs. METHODS: Consecutive new tuberculous patients with positive smear were recruited from tuberculosis centres and rural health centres. Drug susceptibility testing was performed according to the proportion method. Positive cultures were tested against streptomycin, isoniazid, rifampicin, and ethambutol. All resistant strains and 10% of all randomly sampled cultures were sent to an external laboratory for quality control. Human immunodeficiency virus (HIV) tests were performed for consenting patients at the tuberculosis centres. RESULTS: Among the 430 samples, 320 were available for analysis. Primary resistance to antituberculosis drugs was observed for 13.4% of the patients (43/320); multidrug resistance (to at least isoniazid and rifampicin) was observed for 5.3% of the patients; 14.2% of HIV-negative and 16.2% of HIV-positive patients were resistant to at least one antituberculosis drug (P = 0.70). CONCLUSION: This study is representative of antituberculosis drug resistance in Côte d'Ivoire. The rate of primary resistance is high and emphasises the need for a sentinel survey of tuberculous resistance. The National Tuberculosis Control Programme needs to make improvements in its management of tuberculosis cases.

Adolescent↗
PubMed2000

[Predominance of multidrug resistant strains with reduced susceptibility to fusidic acid among methicillin-resistant Staphylococcus aureus strains (MRSA) isolated in the Gdánsk region].

The aim of the present study was to follow the changes in the drug resistance among the methicillin-resistant Staphylococcus aureus strains (MRSA) isolated from clinical samples in various hospitals during 8 years, with particular consideration of Gdansk area. The study was carried out on 225 strains of MRSA from which 95 were isolated in the years 1990-1995 and 130 in the years 1997-1998. The drug susceptibility was determined by the disc-diffusion method. The sensitivity to fusidic acid was determined by both disc-diffusion method and minimal inhibitory concentration (MIC) using agar dilutions. The results obtained show that in 1997-1998 in the hospitals of Gdansk area have been appeared MRSA strains which have not occurred before. These strains were intermediately sensitive or resistant to fusidic acid and simultaneously resistant to doxycycline, gentamicin, erythromycin, clindamycin, ciprofloxacin and rifampin. They represented 66.2% of all MRSA strains isolated in 1997-1998 and were present in majority of the hospitals monitored. Only in this group of staphylococci the strains additionally resistant to mupirocin (6.2%) occurred. Among the MRSA strains with reduced susceptibility to fusidic acid 64.4% were intermediately sensitive (MIC 8-16 mg/L) and 15.4% were resistant to this drug (MIC > 16). In 1997-1998 the percentages of MRSA strains resistant to rifampin, clindamycin and ciprofloxacin increased significantly from 12.6% to 90.8%, from 42.1% to 92.3% and from 18.9% to 92.3% respectively. The percentage of the chloramphenicol resistant strains decreased from 14.7% to 0.8%. Like in 1990-1995, the MRSA strains resistant to vancomycin and teicoplanin were not found out in the same period of time.

Drug Resistance, Multiple↗
PubMedDate not supplied

Development of a double-drug-resistant human leukemia model to cytosine arabinoside and L-asparaginase: evaluation of cross-resistance to other treatment modalities.

We have developed an in vitro model of 38 T-lymphoblastic leukemia lines resistant to cytosine arabinoside (ara-C) and L-asparaginase (ASNase). Of these, 26 cell lines resistant to both drugs, 6 resistant to ara-C, and 6 resistant to ASNase were isolated. In 18 of these cell lines, all randomly selected, resistance to ara-C, ASNase and gamma radiation was documented by the MTT and trypan blue assays, as well as flow cytometry with Annexin V and propidium iodide (PI) staining. In these lines, p53, p21WAF1, and bcl-2 levels were measured by ELISA. Results show that P21WAF1 upregulation following p53 induction did not occur, suggesting that p53 function may be lost. Moreover, the data imply that upregulation of bcl-2 is critical in the development of resistance to ara-C and ASNase in these leukemic lines. In the CEM/0 parent line, p53 maintained its ability to interact with its DNA binding site as documented by the electrophoretic mobility shift assay (EMSA). But in one single- and one double-resistant leukemic cell line examined, p53 was not shown to maintain this ability. We conclude that double-resistant clones to ara-C and ASNase are refractory to both drugs, providing an excellent leukemic model to investigate the multiple-drug resistance.

Annexin A5↗
PubMed2001

[A case of drug-resistant pulmonary tuberculosis treated successfully following disappearance of rifampicin resistance after 17 years' chemotherapy].

A female who first acquired pulmonary tuberculosis in 1962 when she was 25 years old, admitted to the National Hiroshima Hospital in 1982. Her sputum has been smear positive for acid-fast bacilli for 3 years before admission in spite of continuous antituberculous chemotherapy, and were resistant to isoniazid (INH) and rifampicin (RFP). She was treated with a regimen containing ethambutol (EB), prothionamide (TH) and enviomycin (EVM) but continued to be culture positive. Though she was treated with various regimens which include one to three sensitive drugs, her sputum continued to be positive for M. tuberculosis in the following 14 years. During the course, resistance to EB, TH, cycloserine (CS) and streptomycin (SM) emerged. Resistance to RFP temporarily retracted in 1988, but her sputum was bacilli negative only for 2 months after the addition of RFP to previous regimen, and followed by resurgence of RFP resistance. In 1992, data of drug sensitivity tests showed sensitivity to TH, CS and RFP in turn, which were not used for 3 to 5 years. In 1993, she was treated with RFP, TH and EVM successfully and continued to be bacteriologically negative for 7 years so far. Drug resistance to M. tuberculosis is induced by inappropriate chemotherapy as seen in this case. Regimens with less than three drugs without RFP and INH was not only insufficient to get cure but, what was worse, also induced additional resistance to used drugs. The reason of successful chemotherapy in this case was spontaneous disappearance of drug resistance to RFP and TH. This case suggests that the disappearance of drug resistance is possible, when drugs are not used for more than a few years, hence the successful treatment could be expected. However it must be emphasized that the drug resistance is produced by incorrect treatment as seen in this case, and its prevention is of the prime importance.

Antitubercular Agents↗