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Mechanism of acquired resistance to methotrexate in P388 murine leukemia cells and in their doxorubicin-resistant subline.

The mechanisms of acquired resistance to MTX were studied in P388 murine leukemia cell lines that were sensitive or resistant to ADR. The rate of MTX accumulation in ADR-sensitive cells that have acquired resistance to MTX was found to be lower than that measured in cells that were sensitive to both drugs. Furthermore, in contrast to drug-sensitive cells, in the ADR-sensitive MTX-resistant cells, most of the intracellular MTX (86.2%) was bound and MTX polyglutamation was not detected. The initial rate of MTX accumulation in cells that were resistant to both drugs was comparable to that measured in cells that were sensitive to both drugs or that were resistant only to ADR. However, in the cells that were resistant to both drugs, the rate of MTX accumulation was maintained at its initial level for a period that was considerably longer than that found in the other cell lines. After 3 h of exposure to MTX, the accumulation of MTX in cells that were resistant to both drugs was fourfold higher than that measured in cells that were sensitive to both drugs. Furthermore, while 65 to 70% of the intracellular MTX was free, in cells sensitive to both drugs, or resistant only to ADR, the corresponding value in cells that were resistant to both drugs was less than 1.5%, and a much lower proportion of the MTX was polyglutamated. The sensitivity to TMQ of ADR-sensitive, MTX-resistant cells was similar to that found in cells that were sensitive to ADR and MTX. However, ADR-resistant cells, sensitive or resistant to MTX, were markedly resistant to TMQ. The sensitivity of ADR-resistant MTX-sensitive cells to TMQ was restored by the presence of 10 microM verapamil. Such an effect was not observed in cells resistant to both drugs. It is suggested that P388 cells that have previously acquired resistance to ADR, when now selected by MTX, retain the MTX-transport system (in contrast to ADR-sensitive, MTX-resistant cells) and become resistant to MTX by increasing the activity of DHFR. The results obtained in ADR-resistant cells also suggested that resistance to TMQ was part of the multidrug resistance phenomenon.

Animals↗

PubMed1995

The most frequently occurring aminoglycoside resistance mechanisms--combined results of surveys in eight regions of the world. The Aminoglycoside Resistance Study Groups.

Aminoglycoside-resistant isolates from different patients were collected in 149 hospitals in eight regions of the world. Aminoglycoside resistance mechanisms were determined in 11,079 of these isolates by the correlation of resistance phenotypes to 12 aminoglycosides and DNA hybridisation with up to 19 resistance genes. A very large diversity of different resistance mechanisms was found. For example, in Escherichia-Morganella-Proteus-Salmonella-Shigella, at total of 53 different mechanisms was found among the 2080 isolates studied. Therefore, the most common resistance mechanisms in the seven different pathogen groups were summarised. The seven pathogen groups were chosen so that each one had a unique mixture of resistance mechanisms. Among Enterobacteriaceae, the Citrobacter-Enterobacter-Klebsiella, Providencia and Serratia groups had a particularly high incidence of combinations of resistance mechanisms especially when compared with data from eight early surveys. These mechanisms often tended to be combinations of previously common gentamicin-modifying enzymes with AAC(6')-I, an enzyme which can acetylate tobramycin, netilmicin and amikacin but which does not usually cause resistance to isepamicin. Resistance rates among the four Enterobacteriaceae groups reflected the incidence of these combinations; that is, amikacin resistance was 43.1%, 21.7%, 4.2% and 37.6% while that to isepamicin was 9.9%, 9.7% 2.7% and 7.6%, respectively. A very large diversity of mechanisms was found in Pseudomonas. However, three mechanism - permeability, ACC(6')-II and ANT(2")-I - were very common, both alone as single mechanisms and in combination with each other or other mechanisms. Because of the high incidence of permeability resistance in Pseudomonas, resistance to all aminoglycosides was quite high and the difference between amikacin (41.7%) and isepamicin (36.8%) was smaller. The greatest diversity of resistance mechanisms (67 in 1189 isolates) was found in Acinetobacter. The most common mechanisms - APH(3')-VI and AAC(3)-? - were generally very rare in other genera but found frequently in Acinetobacter in combinations with a wide variety of other mechanisms. The most frequent resistance mechanisms in Acinetobacter varied by geographic region much more than did mechanisms in other genera. The resistance rates to all of the clinically useful aminoglycosides were generally higher in Acinetobacter than in any other pathogen group. In contrast to the other pathogen groups, only seven resistance mechanisms were found in the 898 resistant Staphylococcus. These were composed of the three known single mechanisms and four combinations of these three mechanisms. Because the principal resistance mechanism, (APH(2") + ACC(6'), confers high-level resistance to gentamicin and tobramycin and a lower level of resistance to amikacin, isepamicin and netilmicin, the observed resistance rate to netilmicin (15.0%) was the lowest for any of the aminoglycosides.

Acetyltransferases↗

PubMed2004

Increasing prevalence of vancomycin-resistant enterococci, and cefoxitin-, imipenem- and fluoroquinolone-resistant gram-negative bacilli: a KONSAR study in 2002.

Continued antimicrobial resistance surveillance can provide valuable information for the empirical selection of antimicrobial agents for patient treatment, and for resistance control. In this 6th annual study for 2002, the susceptibility data at 39 Korean Nationwide Surveillance of Antimicrobial Resistance (KONSAR) hospitals were analyzed. Resistance rates of S. aureus were 67% to oxacillin, and 58% to clindamycin. The ampicillin and vancomycin resistance rates of E. faecium were 89% and 16%, respectively. To penicillin, 71% of S. pneumoniae were nonsusceptible. Resistance rates of E. coli were 11% to cefotaxime, 8% to cefoxitin, and 34% to fluoroquinolone, and those of K. pneumoniae were 22% to ceftazidime, and 16% to cefoxitin. Lowest resistance rates to cephalosporins shown by E. cloacae and S. marcescens were to cefepime, 7% and 17%, respectively. This is the first KONSAR surveillance, which detected imipenem-resistant E. coli and K. pneumoniae. To imipenem, 22% of P. aeruginosa and 9% of Acinetobacter spp. were resistant. Trends of resistances showed a slight reduction in MRSA and in penicillin- nonsusceptible S. pneumoniae, but an increase in ampicillin-resistant E. faecium. Ampicillin-resistant E. coli and H. influenzae remained prevalent. Compared to the previous study, amikacin- and fluoroquinolone- resistant Acinetobacter spp. increased to 60% and 62%, respectively. Ceftazidime- resistant K. pneumoniae decreased slightly, and imipenem- resistant P. aeruginosa and Acinetobacter spp., and vancomycin-resistant E. faecium increased. In conclusion, vancomycin-resistant E. faecium, cefoxitin-resistant E. coli and K. pneumoniae, and imipenem-resistant P. aeruginosa and Acinetobacter spp. increased gradually, and imipenem- resistant E. coli and K. pneumoniae appeared for the first time. Continued surveillance is required to prevent further spread of these serious resistances.

Anti-Bacterial Agents↗

PubMed2000

Antibiotic resistance patterns of aerobic coryneforms and furazolidone-resistant Gram-positive cocci from the skin surface of the human axilla and fourth toe cleft.

Samples of skin surface bacteria from 28 healthy subjects plated directly on to selective and non-selective media revealed that the proportion of aerobic coryneforms and furazolidone-resistant Gram-positive cocci (FURECs) resistant to erythromycin was significantly greater in the fourth toe cleft than in the axilla (P < 0.05). There were more erythromycin-resistant bacteria than tetracycline-resistant bacteria at both sites (P = 0.001 for the toe cleft; P < 0.01 for the axilla). In total, 160 distinct isolates were obtained, of which 42 were FURECs and 118 were aerobic coryneforms. Of these, 153 (96%) were resistant to erythromycin and 66 (41%) to tetracycline. All except seven of the tetracycline-resistant strains were also resistant to erythromycin. The resistant isolates belonged to a variety of species. CDC group ANF corynebacteria were most numerous and composed 31% of all isolates. The majority (76%) of FURECs were identified as Micrococcus luteus. MIC determinations on selected strains revealed that tetracycline-resistant FURECs were sensitive to doxycycline and minocycline, as were most tetracycline-resistant coryneforms. Nine coryneform isolates were cross-resistant to all three tetracyclines. Only a minority of erythromycin-resistant FURECs (21%) demonstrated a macrolide-lincosamide-streptogramin type B (MLS)-resistant phenotype with inducible or constitutive cross-resistance to clindamycin and the type B streptogramin, pristinamycin IA. Twenty-nine erythromycin-resistant FURECs had a novel phenotype distinct from MLS and macrolide-streptogramin type B resistance. In contrast, most coryneforms (79%) were MLS resistant. Among the remainder, two unusual erythromycin resistance phenotypes were apparent, both of which differed from the unusual phenotype in FURECs. This study has revealed that the non-staphylococcal aerobic flora of skin contains a considerable reservoir of tetracycline and erythromycin resistance determinants. The three unusual macrolide resistance phenotypes may be associated with novel resistance mechanisms.

Actinomycetales↗

PubMed1993

Cross-resistance to diverse drugs is associated with primary cisplatin resistance in ovarian cancer cell lines.

We have previously obtained, by exposure to near continuous increasing concentrations of cisplatin, a panel of human ovarian cancer cell lines that exhibit a wide range of primary resistance to the drug (9- to > 400-fold). These cells had strikingly increased (4- to 50-fold) levels of glutathione (GSH) as compared with the drug-sensitive cells of origin (A. K. Godwin et al., Proc. Natl. Acad. Sci. USA, 89: 3070-3074, 1992). Utilizing this panel of resistant cell lines, we evaluated cross-resistance to classical alkylating agents, natural product drugs, and irradiation. We observed that cross-resistance to carboplatin paralleled that of cisplatin, culminating in approximately 250-fold resistance. Similarly, melphalan cross-resistance continued to increase to > 400-fold and again paralleled the primary cisplatin resistance. Cell lines with low to very high levels of resistance to cisplatin are 8- to 850-fold resistant to the epipodophyllotoxin derivative etoposide. Cross-resistance is also observed for other natural product drugs, including Adriamycin (approximately 80-fold), mitoxantrone (approximately 440-fold), and taxol (approximately 40-fold). Cross-resistance to irradiation is, however, modest (< 2-fold). The cells with the greatest primary resistance to cisplatin most commonly had the highest cross-resistance to the other drugs examined. The cross-resistance to the natural product category drugs was found not to be mediated by the products of either the multidrug resistance 1 (MDR1) or multidrug resistance-associated protein (MRP) genes based on lack of coordinate increased expression or amplification of these genes as assessed by Northern and Southern blot analyses. Furthermore, verapamil failed to markedly increase drug sensitivity. Although there was no indication that these natural product drug efflux pumps were operative, we observed decreased doxorubicin accumulation in these cell lines cross-resistant to natural products. In addition, alternations in DNA topoisomerase II mRNA levels, which have been observed in a variety of human tumor cell lines selected in vitro for resistance to etoposide or teniposide, were not detected. Only intracellular levels of GSH correlated with cross-resistance to these diverse anticancer agents and partial loss of resistance was associated with a marked decrease in glutathione levels. In the absence of alternative mechanisms, we speculate that the very broad clinically relevant cross-resistance seen in this model system may, at least in part, be the direct result of GSH-mediated drug inactivation or may be due to a combination of GSH conjugation to drug and conjugate efflux mediated by the putative ATP-dependent glutathione S-conjugate export pump.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2025

Molecular characterization of colistin resistance in carbapenem-resistant Klebsiella pneumoniae from a tertiary hospital in China.

Colistin resistance in carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant global health challenge, as colistin remains the last-resort antibiotic for treating multidrug-resistant K. pneumoniae infections. This study aimed to investigate the prevalence and molecular mechanisms underlying colistin resistance in CRKP (Colr-CRKP) isolates in Henan, China, from 2021 to 2024. The minimum inhibitory concentrations of colistin for 134 K. pneumoniae isolates were determined using the broth microdilution method. Whole-genome sequencing was performed using the Illumina platform to identify carbapenemase genes and sequence types (STs). Colistin resistance mechanisms were investigated, including mutations in two-component systems (pmrA/pmrB, phoP/phoQ), inactivation of the mgrB gene, and the presence of plasmid-mediated mcr genes. Most isolates were collected from intensive care units (99/134, 73.9%), with 48.5% (59/134) of patients having no documented colistin exposure history. Notably, ST11 was the predominant sequence type among Colr-CRKP isolates (113/134, 84.3%), all of which carried blaKPC-2 as the sole carbapenemase determinant. In contrast, seven non-carbapenemase-producing isolates exhibited phenotypic resistance to carbapenems. Genomic analysis revealed inactivation or loss of the mgrB gene in 53.7% (72/134) of isolates, predominantly due to insertion mutations (54/72). Although 32.8% (44/134) of isolates carried mutations in two-component systems, these alterations did not exhibit pathway-specific clustering. Intriguingly, plasmid-mediated mcr genes were detected in only 1.5% (2/134) of cases (mcr-8.2 and mcr-1.1), while 22.4% (30/134) of colistin-resistant strains lacked identifiable resistance determinants based on current detection methods. Our findings indicate that disruption of the mgrB gene is the primary mechanism of colistin resistance in ST11 CRKP clones. The emergence of resistance in 48.5% of patients without prior colistin exposure, combined with low mcr gene prevalence (1.5%) and unexplained resistance in 22.4% of isolates, suggests complex selective pressures beyond direct antimicrobial use. These findings underscore the urgent need for strengthened antimicrobial stewardship and the development of alternative therapeutic strategies to combat this high-risk pathogen.IMPORTANCEThe global rise of colistin-resistant Klebsiella pneumoniae, particularly in carbapenem-resistant Klebsiella pneumoniae (CRKP) strains, has severely restricted treatment options for multidrug-resistant infections. Our study provides the first comprehensive molecular characterization of colistin resistance in CRKP in a large tertiary hospital in central China. We identified mgrB disruption as the predominant resistance mechanism, while plasmid-mediated mcr genes were rare. Notably, nearly half of the resistant isolates occurred in patients without prior colistin exposure, suggesting alternative selective pressures driving resistance. These findings highlight the complex dynamics of colistin resistance in CRKP and underscore the need for enhanced genomic surveillance and stewardship interventions to limit further dissemination.

Colistin↗

PubMed1994

Cross resistance relevance of the chemical structure of different anthracyclines in multidrug resistant cells.

Positively charged doxorubicin (DOX) and non-positively charged anthracyclines, aclarubicin (ACR) and morpholino-carminomycin (KRN 8602), have been investigated with respect to pharmacological parameters, cytotoxicity, DNA damage and repair in DOX-sensitive and -resistant murine and human cells. Friend leukemia cells (FLC) resistant to high concentrations of doxorubicin (DOX-RFLC3) or daunorubicin (DNR-RFLC3) (1771 and 1543 fold resistance respectively) express less than 10 fold resistance to aclarubicin (ACR). In these cells, the intracellular accumulation of ACR is similar in sensitive and resistant cells. Resistance to ACR was not observed in either DOX-RFLC1 or DNR1 with a lower level of resistance (27 fold). Increased expression of a 170,000-dalton surface antigen (gp-170) was found to be correlated with the level of resistance. However, when the selective agent in ACR, despite the low level of resistance (2.8 fold) both high expression of gp 170 and resistance to DOX (77 fold) or DNR (62 fold) are observed. It is assumed therefore that induction of multidrug resistance phenotype can be achieved by compounds which do not display cross resistance with DOX or DNR. Reduced levels or absence of cross-resistance can be related to the electrical charge of the compound. This assumption is supported by further studies on DOX-sensitive or -resistant human K562 cells exposed to another non-positively charged anthracycline, KRN 8602. In the continuous presence of drug, K562/DOX were less resistant to KRN 8602 (2.9 fold) than to DOX (31 fold). After short time exposure followed by growth in drug-free medium, absence of cross-resistance to KRN 8602 has been observed in K562/DOX. Furthermore, accumulation experiments showed that high intracellular drug concentrations were rapidly achieved (within 15 min) in both DOX-sensitive and -resistant cells. In cells exposed to DOX, DNA single-strand break (DNA-SSBs) frequencies were related to time and drug concentration while those produced by KRN 8602 or ACR were maximal after short time incubation. DNA-SSBs produced by these anthracyclines are not repaired when cells are incubated in drug free medium. In DOX resistant cells, DNA-SSBs produced by DOX were repaired whereas those produced by ACR or KRN 8602 were not. It is suggested, therefore, that absence of cross resistance to various anthracyclines is related to differences in the chemical electrical charge, which may influence drug accumulation and DNA repair in resistant cells.

Aclarubicin↗

PubMed1995

Nitrogen mustard drug resistant B-cell chronic lymphocytic leukemia as an in vivo model for crosslinking agent resistance.

Acquired resistance is a limiting factor in chemotherapy. We have employed nitrogen mustard resistant B-cell chronic lymphocytic leukemia (B-CLL) as a clinically relevant model to study this phenomenon. Resistance in B-CLL is associated with enhanced repair of nitrogen mustard crosslinks. In order to identify the repair pathway responsible for nitrogen mustard resistance, lymphocytes were screened for cross-resistance to a variety of DNA damaging agents. The MTT assay was used to measure the resistance of B-CLL lymphocytes to various DNA damaging agents, including nitrogen mustards, UV light, methyl methanesulfonate, and mitomycin C. We have shown that B lymphocytes from patients with nitrogen mustard resistant chronic lymphocytic leukemia reflect their clinical status. This assay allows us to classify lymphocytes as nitrogen mustard sensitive or resistant, based on in vitro observations. The resistant population was 5.6 and 4.1 fold more resistant to the nitrogen mustard analogs, chlorambucil and melphalan, respectively. Resistant lymphocytes displayed no increased resistance to either methyl methanesulfonate or UV light, indicating that neither classical base nor nucleotide excision repair is rate-limiting in resistance. Resistant lymphocytes were 6.0 and 2.2 fold more resistant to mitomycin C and cis-diamminedichloroplatinum (II), respectively, suggesting enhanced crosslink repair. Neither glutathione nor glutathione S-transferase levels correlated with resistance. The development of nitrogen mustard drug resistance in B-CLL appears to be associated with cross-resistance to other bifunctional alkylating agents which produce interstrand crosslinks. Our results indicate that resistance to nitrogen mustards in chronic lymphocytic leukemia is associated with enhanced repair of DNA crosslinks which may involve a recombination dependent system. This model should prove very useful in the elucidation of the molecular mechanisms of crosslink repair.

B-Lymphocytes↗

PubMed1997

In vitro life cycle of pentamidine-resistant amastigotes: stability of the chemoresistant phenotypes is dependent on the level of resistance induced.

Using a continuous drug pressure protocol, we induced pentamidine resistance in an active and dividing population of amastigote forms of Leishmania mexicana. We selected in vitro two clones with different levels of resistance to pentamidine, with clone LmPENT5 being resistant to 5 microM pentamidine, while clone LmPENT20 was resistant to 20 microM pentamidine. Resistance indexes (50% inhibitory concentration [IC50] after drug presure/IC50 before drug pressure) of 2 (LmPENT5) and 6 (LmPENT20) were determined after drug selection. Both resistant clones expressed significant cross-resistance to diminazene aceturate and primaquine. Pentamidine resistance was not reversed by verapamil, a calcium channel blocker known to reverse multidrug resistance (A. J. Bitonti, et al., Science 242:1301-1303, 1988; A. R. C. Safa et al., J. Biol. Chem. 262:7884-7888, 1987). No difference in the in vitro infectivity for resident mouse macrophages was observed between the wild-type clone (clone LmWT) and pentamidine-resistant clones. During in vitro infectivity experiments, when the life cycle was performed starting from the intramacrophagic amastigote stage, the drug resistance of the resulting LmPENT20 amastigotes was preserved even if the intermediate promastigote stage could not be considered resistant to 20 microM pentamidine. In the same way, when a complete developmental sequence of L. mexicana was achieved axenically by manipulation of appropriate culture conditions, the resulting axenically grown LmPENT20 amastigotes remained pentamidine resistant, whereas LmPENT5 amastigotes lost their ability to resist pentamidine, with IC50s and index of resistance values close to those for the LmWT clone. These results strongly indicate that the level of pentamidine tolerated by resistant amastigotes after the life cycle was dependent on the induced level of resistance. This fact could be significant in the in vivo transmission of drug-resistant parasites by Phlebotominae. Particular attention should be given to the finding that the emergence of parasite resistance is a potential risk of the use of inadequate doses as therapy in humans.

Animals↗

PubMed1999

Erythromycin resistance genes in group A streptococci in Finland. The Finnish Study Group for Antimicrobial Resistance.

Streptococcus pyogenes isolates (group A streptococcus) of different erythromycin resistance phenotypes were collected from all over Finland in 1994 and 1995 and studied; they were evaluated for their susceptibilities to 14 antimicrobial agents (396 isolates) and the presence of different erythromycin resistance genes (45 isolates). The erythromycin-resistant isolates with the macrolide-resistant but lincosamide- and streptogramin B-susceptible phenotype (M phenotype) were further studied for their plasmid contents and the transferability of resistance genes. Resistance to antimicrobial agents other than macrolides, clindamycin, tetracycline, and chloramphenicol was not found. When compared to our previous study performed in 1990, the rate of resistance to tetracycline increased from 10 to 93% among isolates with the inducible resistance (IR) phenotype of macrolide, lincosamide, and streptogramin B (MLSB) resistance. Tetracycline resistance was also found among 75% of the MLSB-resistant isolates with the constitutive resistance (CR) phenotype. Resistance to chloramphenicol was found for the first time in S. pyogenes in Finland; 3% of the isolates with the IR phenotype were resistant. All the chloramphenicol-resistant isolates were also resistant to tetracycline. Detection of erythromycin resistance genes by PCR indicated that, with the exception of one isolate with the CR phenotype, all M-phenotype isolates had the macrolide efflux (mefA) gene and all the MLSB-resistant isolates had the erythromycin resistance methylase (ermTR) gene; the isolate with the CR phenotype contained the ermB gene. No plasmid DNA could be isolated from the M-phenotype isolates, but the mefA gene was transferred by conjugation.

Anti-Bacterial Agents↗

PubMed1985

Effect of the source of Mueller-Hinton agar and resistance frequency on the detection of methicillin-resistant Staphylococcus aureus.

Inconsistencies in the results of disk diffusion tests of oxacillin against Staphylococcus aureus that occurred when using commercially prepared Mueller-Hinton agar from different sources led us to evaluate the ability of media from different sources to detect resistance to oxacillin, methicillin, and nafcillin in S. aureus. Mueller-Hinton agar from five manufacturers was prepared in our laboratory and used for standard disk diffusion and agar dilution tests. Ten oxacillin-resistant S. aureus isolates, of which three were definitive-resistant and seven were occult-resistant, were examined. All definitive-resistant strains were resistant to all three antimicrobial agents on four out of five agars. The occult-resistant strains were consistently detected as resistant on only one of the agars. With only slight differences, oxacillin, methicillin, and nafcillin resistance was more readily detected by disk diffusion and agar dilution when initially incubated at 30 degrees C, and extended incubation improved the detection. The frequency of resistance within a population of occult-resistant cells was low compared with the frequency within a population of definitively resistant cells. The heterogeneity of colony morphology and apparent growth rates within a population of occult-resistant cells contributed to the problem of detecting some resistant isolates. Definitive-resistant isolates were characterized by a very high and stable frequency of resistance. Occult-resistant strains were characterized by a lower frequency of resistance, although the true frequency of resistance may be difficult to ascertain because of heterogeneity in growth rates.

Agar↗

PubMed2003

[Characteristics and treatment outcomes of INH-resistant or RFP-resistant tuberculosis].

BACKGROUND: As an effective regimen for isoniazid-resistant but rifampicin-susceptible tuberculosis (INHr-TB), the use of a 6-month three or four-drug treatment regimen including refampicin (or rifampin) and pyrazinamide has been recommended by many experts of the world. On the other hand, treatment regimen for rifampicin-resistant but isoniazide-susceptible tuberculosis (RFPr-TB) has not been well established because of the small number of such patients. In Japan the standard regimen has not been established even for INHr-TB, and the treatment has been done by each physician on the empirical bases. OBJECTIVES: To determine the adequate therapy of INH-resistant TB or RFP-resistant TB. DESIGN: Retrospective cohort study. SUBJECTIVES: Hundred and eleven INHr-TB patients (4.9%) and 5 RFPr-TB patients (0.2%) out of 2252 new smear-positive tuberculosis patients who were admitted to our hospital from 1994 to 1998. RESULTS: Patients with previous tuberculosis history was found in 35 of 111 INHr-TB (31.5%) patients, of which 13 (37.1%) were re-treated within 3 years. On the other hand 146 patients (21.1%) of all new culture-positive tuberculosis patients (N = 690) treated in our hospital from 1997 to 1999 had the previous tuberculosis history of which only 8 patients (5.5%) were retreated within 3 years while 115 patients relapsed more than 10 years after the onset of previous tuberculosis history. The frequency of recurrence within 3 years after the onset of previous tuberculosis history was, significantly higher (p < 0.0001) in cases of INHr-TB (13/111 [11.7%]) than in cases of newly registered ones (8/690 [1.2%]), and the fact indicates that the incidence of tuberculosis recurrence was higher in INHr-TB patients than in pan-sensitive TB patients when the previous treatment was discontinued or insufficiently implemented. The resistance pattern of the INHr-strains were as follows. INH alone 40 (36.0%), SM-resistant 47 (42.3%), TH resistant 19 (17.1%), EB-resistant 18 (16.2%), KM-resistant 6 (5.4%), and others 3 (2.7%). Therefore the mean number (+/- SD) of resistant drugs excluding INH was 1.4 +/- 0.7. Eighteen out of 71 (25.4%) strains with low grade INH-resistance (0.1 microgram/ml complete resistance) had also TH-resistance, while only one out of 40 (2.5%) strains with high grade INH-resistance (1 microgram/ml resistance) was resistant to TH (p = 0.005). Of 111 INHr-TB patients, 9 patients (8.1%) discontinued treatment by themselves, 17 patients (15.3%) admitted to another hospital, and 17 patients (15.3%) died. The patients who died (age [M +/- SD] 66.4 +/- 14.0 yrs) were older than those who were alive (48.7 +/- 17.8, p < 0.001), and were too seriously ill to accept sufficient chemotherapy, and therefore their deaths were not considered to be related to INH resistance. The treatment outcomes of the remaining 68 patients who were followed in our hospital were summarized as follows. 1) Treatment failure occurred in 3 patients, of whom 2 patients could not be treated with full dose rifampicin in the initial phase of treatment because of side effects to liver or accompanying idiopathic thrombocytepenic purpura (ITP). Two out of these 3 patients developed multi-drug resistant tuberculosis (MDR-TB). Success rate of treatment was 65/68 (95.6%). 2) Alterations of regimens after knowing INHr-TB were done in 41 of 65 patients (63.0%) with treatment success in all cases. The susceptible drugs used were 65 (100%) for RFP, 62 (95.4%) for EB, 23 (35.4%) for PZA, 26 (40.0%) for SM, 32 (49.2%) for new quinolone (NQ). 3) The sputum culture conversion rates two months after starting chemotherapy with (N = 16) and without (N = 52) PZA were 13/16 (81.3%) and 31/52 (59.6%), respectively. 4) After the completion of treatment, relapse occurred in 4 patients during follow-up period (1-39 months). The recurrence occurred in 3 out of 20 patients (15%) treated with INH and two susceptible drugs, none out of 13 with three susceptible drugs (0%), 1 out of 20 with INH and three susceptible drugs (5%), and none out of 11 with more than 4 susceptible drugs (0%), and the fact indicates that there was no significant advantage to add INH of usual dose to the regimens. 5) The durations of treatment were not less than 9 months except one case. When 3 or more susceptible drugs were used, the recurrence rate in the group of treatment duration 9-12 months was 0/12 and that in the group of treatment duration more than 12 months was 1/33. Even in the groups without PZA in the initial 2 months of treatment, the recurrence rate in the group of treatment duration 9-12 month was 0/8, and that in the group of treatment duration more than 12 months was 0/22. The fact indicates that 12 months therapy was sufficient irrespective of the use of PZA. 6) One of 5 RFPr-TB patients discontinued treatment by himself. Remaining 4 patients were treated by 4.5 +/- 0.5 susceptible drugs including INH for more than 20 months (21.7 +/- 2.8 months) after sputum culture conversion with the successful result of treatment and no relapses during the followup period for 3-60 months. CONCLUSION: For INHr-TB, even when PZA can't be used because of adverse effects or resistance, 3 or 4 susceptible drugs regimens including RFP for 12 months were effective. For RFPr-TB, the treatment with 4 or more susceptible drugs for 20 months after sputum culture conversion might be adequate.

Adult↗

PubMed2006

Phenotypic resistance of resistant strains of HIV type-1 subtype B in China.

BACKGROUND: This study was aim to explore the characteristics of phenotypic resistance of resistant strains of HIV type-1 (HIV-1) subtype B and to compare the concordance between the phenotypic resistance and genotypic resistance. METHODS: The genotypic resistance assay for the HIV-1 clinical isolates was performed. One isolate without resistance mutation was chosen as a drug-sensitive reference strain and seven subtype B isolates with resistance mutations were phenotypically tested. Fifty percent inhibitory concentrations (IC50) between resistant and sensitive viruses were compared. The resistance extent was determined by the folds of the increased IC50. The concordance between the phenotypic resistance and genotypic resistance was also analyzed. RESULTS: IC50 of resistant isolates were 0.0006 - 0.1300 micromol/L for zidovudine (AZT), 0.0016 - 0.0390 micromol/L for lamivudine (3TC), 0.0104 - 0.4234 micromol/L for nevirapine (NVP), and 0.0163 - 0.1142 micromol/L for indinavir (IDV), respectively. Genotypic and phenotypic resistance assays indicated that the resistant strains were intermediately and highly resistant to nucleotide analog reverse transcriptase inhibitors and non-nucleotide analog reverse transcriptase inhibitors. The phenotypic assay was consistent with the genotypic assay. For measuring the potential resistance, the genotypic assay was more sensitive than the phenotypic. In evaluating the resistance to protease inhibitors, these two assays were discrepant. CONCLUSIONS: Both the phenotypic and genotypic assays indicate that the resistant viruses exist in HIV-infected patients in China who have received treatment. Phenotypic and genotypic assays have high concordance, and the genotypic assay could replace the phenotypic assay to predict the HIV-1 resistance.

Anti-Retroviral Agents↗

PubMed1990

Characterization of auromomycin-resistant hamster cell mutants that display a multidrug resistance phenotype.

We have selected and characterized Chinese hamster ovary (CHO) cells resistant to auromomycin (AUR), an antitumor antibiotic composed of a protein moiety and a nonpeptide chromophore. AUR is cytotoxic as a consequence of DNA strand-scission activity associated with the chromophore. Initial single-step selections for clones resistant to AUR detected a subpopulation of phenotypically resistant colonies, but nearly all such clones failed to display heritable resistance. One isolate that did show somewhat increased resistance was selected further and yielded a clone designated AURR-R1 that exhibits stable 10-fold increased resistance to AUR. The R1 line is also resistant to the AUR chromophore and cross-resistant to the closely related agent neocarzinostatin (NCS) and to the NCS chromophore. For AUR-treated whole cells, resistance to AUR cytotoxicity was inversely correlated with DNA damage as measured by filter elution; by contrast, isolated nuclei from sensitive and resistant cells displayed similar levels of AUR-induced DNA damage. The R1 cell line was found to be cross-resistant to colchicine, Adriamycin, Daunomycin, and vinblastine. The resistance phenotype is expressed with incomplete dominance in cell hybrids and appears similar to the "classic" multidrug resistance of CHO cells selected with other agents. Indeed, we found the multidrug-resistant CHO line CCHR-C5 to be about 5-fold cross-resistant to AUR and to NCS. We ascertained that AUR-resistant (AURR) isolates express elevated levels of the molecular weight 170,000 P-glycoprotein often associated with multidrug resistance and also contain amplified DNA sequences that contain the gene for P-glycoprotein. When multiple-step enrichment selections were carried out as an alternative approach for isolating AURR mutants, each of nine clonal isolates showed phenotypes resembling the AURR-R1 line. Thus, our findings imply that increased cellular resistance to AUR may frequently be associated with P-glycoprotein-mediated multidrug resistance.

Animals↗

PubMed1984

Acquisition of multiple drug resistance by CCRF-CEM cells selected for different degrees of resistance to vincristine.

We studied the acquisition of multiple drug resistance to several "natural product" drugs by cultured human leukemic lymphoblasts selected for increasing resistance to vincristine (VCR). Three apparent types of cross-resistance patterns could be distinguished: specific, pleiotropic, and mixed. Cross-resistance to vindesine developed in parallel with VCR resistance, appearing at the lowest levels of VCR resistance (approximately fivefold). Vinblastine resistance did not become noticeable until VCR resistance was higher (approximately equal to 50-100-fold). Cross-resistance resistance to three other tubulin-binding agents developed in a different pattern, however. While cross-resistance to maytansine was seen in cells of intermediate (approximately equal to 50-fold) resistance to VCR, colchicine cross-resistance occurred only in cells that were highly resistant to VCR (approximately equal to 500-fold). Even at the highest level of VCR resistance (approximately equal to 600-fold), complete sensitivity to podophyllotoxin was retained. Conversely, cross-resistance to the epipodophyllotoxins , teniposide and etoposide, semisynthetic derivatives of podophyllotoxin, was seen in cells that were greater than 50-fold resistant to VCR. The same pattern obtained for the anthracyclines, doxorubicin and daunorubicin. We conclude that resistance to low concentrations of VCR does not uniformly confer cross-resistance to other classes of natural product drugs.

Animals↗

PubMed2025

Molecular characterization of drug-resistance genes and dynamics of multidrug-resistant Salmonella spp. in waterfowl: a pre- and post-antibiotic ban surveillance in Guangdong, China from 2013 to 2023.

BACKGROUND: Multidrug-Resistant Organism (MDRO) refers to bacteria that are Resistant to three or more types of antibiotics in clinical use. The global health threat posed by multidrug-resistant (MDR) bacterial pathogens and their cross-species transmission necessitates rigorous Surveillance. This urgency is amplified in China where antibiotic growth promoters were widely used in animal husbandry until the 2020 implementation of Announcement No. 194 launched by Ministry of Agriculture and Rural Affairs (Announcement 194), banning non-therapeutic antibiotics in feed. This study conducted a decade long investigation on the correlation between antimicrobial resistance (AMR) phenotypes and genetic determinants in 314 Salmonella isolates collected from waterfowl across Guangdong Province, China, utilizing disk diffusion (Kirby-Bauer method) and PCR-based detection of antibiotic resistance genes (ARGs). The study period covered the antibiotic policy transition in China, specifically encompassing the pre-ban (2013-2019) and post-ban (2020-2023) phases of the nationwide prohibition on growth-promoting antimicrobials in animal feed. METHODS: Antimicrobial Susceptibility profiles against 16 agents were determined via Kirby-Bauer testing, while PCR amplification targeted 20 ARGs. Statistical analyses evaluated phenotype-genotype correlations using Pearson`s chi-square test. RESULTS: Surveillance revealed escalating resistance rates annually. Highest resistance prevalence was observed against β-lactams and amphenicols (92.25%), whereas amikacin exhibited the lowest resistance rate (9.55%). MDR prevalence reached 87.23%, with the AMP-CAZ-GEN-FFC-TET resistance profile predominating (51.6% of isolates). Genetic analysis identified 3 to 16 ARGs per isolate was harboring, with blaTEM demonstrating the highest detection frequency (90.76%). Significant phenotype-genotype correlations (p < 0.05) were observed for 13 genes: blaCTX-M, blaTEM, blaOXA, aacC2, aph(3')-I, aac(3)-IV, aadA1, qnrS, qnrA, clmA, floR, sulII, tetA. Notably, significant declines in resistance to aminoglycosides (e.g., gentamicin from 71.7 to 3.5%) and florfenicol (from 81.1 to 9.6%) were observed after China's 2019 antibiotic ban policy (p < 0.001), underscoring the impact of targeted antimicrobial stewardship in avian husbandry. CONCLUSIONS: Analysis of 314 waterfowl Salmonella strains revealed severe multidrug resistance (MDR) and diverse resistance genes (DRGs), with 13 DRGs linked to resistance. China's antibiotic ban reduced targeted resistance, but MDR persists alarmingly via acquired DRGs and adaptation. Continued enforcement may lower aminoglycoside/phenicol resistance, but β-lactam resistance will likely endure, worsened by transcontinental blaCTX-M spread. Critically, plasmid co-selection threatens to amplify MDR, demanding genomic surveillance. Mitigation requires boosting policy compliance, developing non-antibiotic therapies, mapping mutations, establishing cross-species barriers, and prioritizing One Health interventions to block resistance spread.

China↗

PubMed1989

Multidrug resistance in a human leukemic cell line selected for resistance to trimetrexate.

Trimetrexate (TMQ) is a lipophilic antifolate shown to have antitumor activity in humans. TMQ-resistant sublines of the MOLT-3 human acute lymphoblastic leukemia cell line were developed and were designated as MOLT-3/TMQ200, MOLT-3/TMQ800, and MOLT-3/TMQ2500 based on degrees of resistance to TMQ. The TMQ resistance was accompanied by 5- to 7-fold increases in dihydrofolate reductase activity and markedly reduced cellular TMQ accumulation. Methotrexate accumulation was not impaired in TMQ-resistant cells. TMQ retention (efflux) was unchanged in these TMQ-resistant cells. Verapamil enhanced the TMQ accumulation in the resistant cells to the level seen in the parent cells but had no effects on the TMQ retention. These sublines were cross-resistant not only to methotrexate but also to vincristine, doxorubicin, daunorubicin, and mitoxantrone. There was no cross-resistance to bleomycin or cisplatin. Resistance to vincristine, doxorubicin, daunorubicin, and mitoxantrone was reversed by verapamil. TMQ resistance was only minimally reversed by verapamil and methotrexate resistance not affected at all. Both cellular accumulation and retention of vincristine and daunorubicin in the TMQ-resistant cells were markedly decreased. Verapamil enhanced both accumulation and retention of the drug. Plasma membrane fractions of the TMQ-resistant cells analyzed by urea-sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by staining with Coomassie Blue revealed the presence of a distinct band with a molecular weight of 170,000. Immunoblot analysis with 125I-labeled monoclonal antibody raised against P-glycoprotein of multidrug-resistant Chinese hamster ovary cells (C219) cross-reacted with the Mr 170,000 protein of the TMQ-resistant cells. These results show that the TMQ-resistant cells displayed not only decreased TMQ uptake and increased dihydrofolate reductase but also characteristics associated with a classical multidrug-resistant phenotype. Multidrug resistance includes lipophilic antifolate.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1989

In vitro multidrug resistance of P388 murine leukemia selected for resistance to diaziquone.

P388 leukemia sublines were isolated from leukemia-cell-bearing CD2F1 mice that had been treated in vivo with increasing amounts of diaziquone (AZQ). The sublines isolated for in vitro studies were AZQ19 and AZQ30 which corresponded to the 19th and 30th in vivo passages, respectively. The AZQ19 subline displayed a very low degree of resistance to AZQ (1.5-fold), whereas the AZQ30 subline was sensitive. Both sublines, however, had much higher degrees of resistance to Adriamycin than to AZQ (24-fold for AZQ30 cells and 10-fold for AZQ19 cells). Both cell lines were also more resistant to actinomycin D, colchicine, and vincristine than to AZQ. The AZQ19 line was resistant to the alkylator thio-TEPA to the same degree that it was to AZQ, but the AZQ30 line was sensitive to thio-TEPA. On the other hand, AZQ30 cells were resistant to hydrogen peroxide with a very low degree of resistance (1.27-fold, P less than 0.05), whereas the AZQ19 line was sensitive. Drug accumulation experiments indicated that AZQ-resistant cells differed from the parental line in that they did not accumulate Adriamycin or vinblastine. In the case of AZQ, however, resistant and parental lines accumulated the same amounts of exchangeable AZQ. Using the immunoblotting technique, no P-glycoprotein was found in resistant cells. The resistant lines consumed oxygen at greater rates than the parental line. Oxygen consumption (Mean +/- SD) in sensitive cells was 2.0 +/- 0.4% O2 consumed/min, whereas in resistant cells it was nearly 3.1 +/- 0.6% O2 consumed/min. The increase in oxygen consumption with drug resistance was statistically significant (P less than 0.01). The kinetics of production of hydroxyl free radicals and of AZQ free radicals were faster in the resistant lines reflecting, in essence, their increased oxygen consumption. It appears that the two sublines analyzed here show resistance mechanisms that may have been elicited by the two distinct chemical constituents of AZQ. Therefore, in the AZQ19-resistant line, the alkylating aspect of AZQ was emphasized, whereas in the AZQ30 line, the quinone and, thus, free radical aspect was emphasized. This is consistent with AZQ30 cells being sensitive to the alkylator thio-TEPA and resistant to hydrogen peroxide, and the AZQ19 line being resistant to thio-TEPA and sensitive to hydrogen peroxide. In addition, the AZQ30 cell line was relatively more resistant than the AZQ19 line to Adriamycin.

ATP Binding Cassette Transporter, Subfamily B, Mem↗