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PubMed1996

Clindamycin resistance among erythromycin-resistant Streptococcus pneumoniae.

The increasing proportion of Streptococcus pneumoniae isolates with reduced susceptibility to penicillin has created an urgent need for therapeutic alternatives to some beta-lactam agents. Clindamycin is an antimicrobial agent with excellent bioavailability after oral administration which has been considered for the therapy of community-acquired pneumococcal otitis media. Using the Etest methodology, we have studied the in vitro susceptibility of 59 erythromycin-resistant strains of S. pneumoniae to clindamycin, penicillin, trimethoprim-sulfamethoxazole, and rifampin. The study also addressed the impact of the susceptibility test medium [Mueller-Hinton (MH) vs IsoSensitest (Iso), both 5% blood supplement] on the results. A total of 20 isolates (37%) displayed constitutive clindamycin resistance on Iso blood agar, compared with only 11 (22%) on MH blood agar. The remaining nine strains found to be clindamycin susceptible on MH manifested resistance only with erythromycin induction. Resistance to penicillin, rifampin, and trimethoprim-sulfamethoxazole in erythromycin-resistant isolates was 83%, 2%, and 85%-89% (medium dependent), respectively. These results indicate that the choice of susceptibility test medium affects the expression (constitutive or inducible) of macrolide-lincosamide-streptogramin (MLS) resistance in S. pneumoniae. In addition, the common assumption that erythromycin resistance in S. pneumoniae implies clindamycin resistance may need to be reconsidered and routine susceptibility tests (including induction if MH medium is used) should be considered for MLS-class drugs.

Clindamycin↗
PubMed1997

Phenotypic characterization of Leishmania mexicana pentamidine-resistant promastigotes. Modulation of the resistance during in-vitro developmental life cycle.

Two clones of Leishmania mexicana resistant to 5 microM (LmR5CL2) and 20 microM (LmR20CL1) pentamidine, derived from a parental wild-type clone (LmWTCL3) were selected in vitro using a continuous drug pressure protocol. Both resistant clones expressed a cross-resistance to diminazene aceturate. No differences in their in-vitro infectivity for mouse peritoneal macrophages between wild-type and pentamidine-resistant promastigotes were observed. During these experiments, promastigotes of LmR20CL1 derived from intramacrophagic amastigote forms reverted to the pentamidine-sensitive phenotype, unlike the lower resistant ones. In the same way, when a complete developmental sequence of L. mexicana was achieved in axenic cultures, LmR20CL1 promastigotes derived from axenically growing amastigotes expressed an IC50 value close to the wild-type one, whereas resulting LmR5CL2 promastigotes remained pentamidine resistant. This modulation of the chemoresistance during the developmental life cycle could be significant in the transmission of drug-resistant strains by Phlebotominae as well as in basic research to follow drug resistance during the in-vitro and in-vivo life cycle of Leishmania.

Animals↗
PubMed2001

Is resistant hypertension really resistant?

BACKGROUND: Managing resistant hypertension is difficult and mostly involves expensive testing seeking an underlying secondary cause. This study was undertaken to determine 1) the extent of the white-coat phenomenon in patients with resistant hypertension, and 2) whether 24-h ambulatory blood pressure (BP) monitoring (ABPM) or having BP recorded by a nurse instead of the referring doctor could clarify how many apparently resistant hypertensives actually have controlled BP. METHODS: This study involved 611 patients with BP > or = 140/90 mm Hg who were referred for 24-h ABPM by their specialist or general practitioner, including 277 patients who were taking no antihypertensives (group 1), 216 taking one or two antihypertensive drugs (group 2), and 118 taking at least three antihypertensives in combination (group 3). Each had BP recorded by one of two nurses before 24-h ABPM. Controlled BP was defined as awake ambulatory BP <135/85 mm Hg and the white-coat effect was the difference between the BP recorded by the referring doctor or nurse and the average awake ambulatory BP. RESULTS: Those with resistant hypertension (group 3) were older (61 years (12) v group 1: 46 years (14) and group 2: 56 (14) years; P < .001), but were of similar weight, height, and arm circumference to the other groups. Referral systolic, but not diastolic BP was higher in resistant hypertensives (mean 171/95 v 154/95 mm Hg and 164/94 mm Hg, respectively, P < .001 for systolic BP only). Twenty-eight percent of resistant hypertensives and 32% of those taking no antihypertensive drugs had normal awake ambulatory BP and the white-coat effect attributable to the referring doctor was always greater than that due to the nurse (range 16 to 26/12 to 14 mm Hg v 9 to 17/4 mm Hg, P < .001). Nurse recorded BP was highly sensitive (97%) in identifying awake hypertension but lacked specificity (57%) to replace ABPM. CONCLUSION: Our results show that approximately one in four patients with apparent resistant hypertension referred for ABPM have controlled BP and one-third of patients referred for initial evaluation of office or clinic hypertension have normal BP using ABPM, ie, white-coat hypertension. Twenty-four-hour ABPM appears an appropriate initial step before further investigating or treating patients with apparently resistant hypertension.

Adult↗
PubMed2001

Antibiotic resistance rates and macrolide resistance phenotypes of viridans group streptococci from the oropharynx of healthy Greek children.

A total of 200 isolates of viridans group streptococci isolated from the oropharynx of healthy Greek children were studied. Vancomycin, rifampicin, fluoroquinolones and dalfopristin/quinupristin were active against all tested isolates. High level resistance to gentamicin was not seen. Intermediate and high-level penicillin resistance was present in 28.5 and 14.5% isolates, respectively, with 41.3% of the latter group, being also resistant to cefotaxime. Resistance rates to other antimicrobials were as follows - erythromycin 38.5%, clarithromycin 33.5%, clindamycin 7.5% and tetracycline 23%. Penicillin resistance occurred more frequently in Streptococcus mitis isolates, while macrolide resistance was more frequent in S. oralis. MLSB resistance phenotype M was dominant (74%) among erythromycin resistant isolates, with phenotypes IR and CR being represented by 6 and 20% of isolates, respectively.

Adolescent↗
PubMed1997

Cellular and molecular mechanisms of resistance to antifolate drugs: new analogues and approaches to overcome the resistance.

A number of antifolate drugs, which inhibit the key enzymes in the 'thymidylate cycle', dihydrofolate reductase (DHFR) and thymidylate synthase (TS), have been developed as part of the search for analogues with superior antitumor efficacy to a 'classical' antifolate, methotrexate (MTX), and those which are active against the MTX-resistant tumor cells. Recent development of newer classes of antifolate drugs is based on the extensive understanding of the relationship between chemical structures and biological properties and of analogue interactions with target enzymes, transport proteins and folate metabolizing enzyme, folylpolyglutamate synthetase (FPGS). Tumor cells may develop resistance to an antifolate drug by virtue of, (1) amplified activity in its target enzyme, (2) impaired function of drug transport protein, e.g. reduced folate carrier (RFC), (3) induction of mutated target enzyme with low affinity for antifolate(s), and (4) defective polyglutamation of drug(s) in the cells. Recent studies have elucidated in part the molecular events involved in the resistance to antifolates. These include amplification and/or mutation of the gene encoding a target enzyme, reduced or altered gene expression of the RFC, and mutated expression of the FPGS gene. To overcome or circumvent the resistance mechanisms, new antifolates with diverse structures and different biological properties have been designed and developed for clinical use. Trimetrexate (TMQ), a lipophilic DHFR inhibitor which is not a substrate for RFC and FPGS, could overcome the MTX-resistance through impaired RFC and diminished polyglutamation, and partially through amplified DHFR. Selective inhibitors of TS with a folate structure such as raltitrexed could circumvent the resistance by virtue of DHFR overproduction, and this class of compounds which have higher substrate activities for FPGS than MTX may be of value for the treatment of myeloid leukemias in addition to lymphocytic malignancies resistant to conventional chemotherapy. Several strategies to overcome antifolate resistance by using gene therapy are currently under investigation.

Antimetabolites, Antineoplastic↗
PubMed2000

Modulation of drug resistance by alpha-tubulin in paclitaxel-resistant human lung cancer cell lines.

Beta(beta)-tubulin isotype variation has recently been implicated in the modulation of resistance to paclitaxel in human lung cancer cells and in primary human ovarian tumour samples. Whether alpha-tubulin is involved in drug resistance has not been reported. We have generated a paclitaxel-resistant cell line (H460/T800) from the sensitive human lung carcinoma parental cell line NCI-H460. The resistant cells are more than 1000-fold resistant to taxol and overexpress P-glycoprotein. Interestingly, H460/T800 cells also overexpress alpha- and beta-tubulin as detected by Western blot analysis. From Northern blot analysis, the mechanism of tubulin overexpression appears to be post-transcriptional. To understand whether alpha-tubulin plays a role in drug resistance, we transfected antisense human kalpha1 cDNA construct into the H460/T800 paclitaxel-resistant cells. The antisense clones displayed a reduced alpha-tubulin expression, and the cells were 45-51% more sensitive to paclitaxel and other known antimitotic drugs, compared with vector transfected controls. Complementary experiments of transfecting the sense kalpha1 cDNA into H460 cells conferred a 1.8- to 3.3-fold increase in the IC(50) of several antimitotic agents. Our study suggests that alpha-tubulin is one of the factors that contributes to drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Role of the kdr and super-kdr sodium channel mutations in pyrethroid resistance: correlation of allelic frequency to resistance level in wild and laboratory populations of horn flies (Haematobia irritans).

The kdr and super-kdr point mutations found in the insect sodium channel gene are postulated to confer knockdown resistance (kdr) to pyrethroids. Using an allele-specific PCR assay to detect these mutations in individual horn flies, Haematobia irritans (L.), we determined the allelic frequency of the kdr and super-kdr mutations in several wild and laboratory populations. Wild populations with very similar allelic frequencies had resistance levels that ranged widely from 3- to 18-fold relative to a susceptible population. Conversely, the kdr allele frequency in a lab population with 17-fold resistance was nearly double that found in a heavily pressured wild population with 18-fold resistance. We conclude that, although the kdr mutation confers significant levels of pyrethroid resistance, a substantial component of resistance in insecticidally pressured populations is conferred by mechanisms that are PBO-suppressible. High super-kdr allele frequencies were detected in two resistant lab populations, but in wild populations with equivalent resistance the super-kdr allele frequency was very low. Interestingly, in over 1200 individuals assayed, the super-kdr mutation was never detected in the absence of the kdr mutation.

Alleles↗
PubMed2004

Genetic analysis and cross-resistance spectrum of a laboratory-selected chlorfenapyr resistant strain of two-spotted spider mite (Acari: Tetranychidae).

A laboratory susceptible strain of Tetranychus urticae was selected with chlorfenapyr resulting in a resistant strain. After 12 cycles of exposure, the resistance ratio (RR) calculated from the LC50s of susceptible and selected strain was 580. The resistant strain was screened with 16 currently used acaricides for cross-resistance. Cross-resistance was detected with amitraz (RR = 19.1), bifenthrin (RR = 1.3), bromopropylate (RR = 7.5), clofentezine (RR = 29.6) and dimethoate (RR = 17.6). No cross-resistance was detected with the new molecules acequinocyl, bifenazate and spirodiclofen. Mortality caused by chlorfenapyr in the F1 progeny from reciprocal crosses between both strains indicated that the mode of inheritance was incomplete recessive. Mortality in F2 progeny indicated that the resistance was under the control of more than one gene. Synergist experiments with S,S,S-tributylphosphorotrithioate (DEF), piperonylbutoxide (PBO) and diethylmaleate (DEM), which are inhibitors of esterases, monooxygenases and glutathion-S-transferases respectively, suggested a major role of esterases in the resistance to chlorfenapyr.

Animals↗
PubMed1988

Cross resistance pattern towards anticancer drugs of a human carcinoma multidrug-resistant cell line.

Puromycin-resistant (PurR) mutants/variants of a human carcinoma cell line (HeLa), which show greatly reduced cellular uptake of 3H-puromycin and 3H-daunomycin have been isolated after one- and two-step selections in presence of the drug. The cross-resistance pattern of these mutant cell lines towards numerous anticancer drugs and other inhibitors has been examined. Both the first- and the second-step mutants exhibited increased resistance to a number of antimitotic drugs (viz. vinblastine, vincristine, colchicine, taxol and maytansine), several protein synthesis inhibitors (viz. chalcomycin, bruceantin, harringtonine, homoharringtonine), a large number of DNA interactive compounds (viz. aclacinomycin A, actinomycin D, adriamycin, m-AMSA, chromomycin A3, coralyne sulphoacetate, daunomycin, ellipticine, mithramycin, mitoxantrone, 5-methoxysterigmatocystin, rubidazone, variamycin, VM26 and VP16-213) and a number of other drugs acting via other mechanisms (viz. Baker's antifol, nitidine chloride and rhodamine 123). Whereas the first-step mutants showed stable resistance to these drugs, the second-step lines partially reverted upon growth in non-selective medium. Further, treatment of these mutant lines with non-cytotoxic doses of the calcium channel blocker verapamil reverted or abolished their resistance to the above drugs in a dose-dependent manner. In contrast to the above compounds, the PurR mutants showed no significant cross-resistance to a large number of other drugs which included asaley, AT-125, 5-azacytidine, azaserine, cyclocytidine, cis-platin, cytosine arabinoside, chlorambucil, chlorpromazine, alpha-difluoromethyl ornithine, 5-fluorouracil, ftorafur, gallium nitrate, hydroxyurea, ICRF-159, ICRF-187, imipramine, methotraxate, 6-methylmercaptopurine riboside, mycophenolic acid, melphalan, mitomycin C, methyl GAG, nafoxidine, reumycin, 6-selenoguanosine, 6-thioguanine, tiazofurin, tamoxifen, thalicarpine, tiapamil and verapamil). These cross-resistance data should prove useful in developing suitable drug combinations to which cellular resistance would not develop readily.

Animals↗
PubMed1991

Multidrug resistance-associated antigens on drug-sensitive and -resistant human tumour cell lines.

In this paper the biochemical properties of the antigens detected by six murine monoclonal antibodies (MAbs) are described. These MAbs react selectively with the multidrug-resistant small cell lung cancer (SCLC) cell line, H69AR, compared to its sensitive parent cell line, H69 (Mirski & Cole, 1989). Because H69AR cells do not overexpress P-glycoprotein, the antigens detected by these MAbs may be markers for non-P-glycoprotein-mediated mechanisms of resistance. We found that the 36 kDa protein precipitated by MAb 3.186 is phosphorylated and has a pI of approximately 6.7. The 55 kDa protein precipitated by MAb 3.50 is also phosphorylated and has a pI of approximately 5.7. Several observations suggest that MAbs 3.80, 3.177 and 3.187 recognise the same 47 kDa molecule and hence only MAb 3.187 was characterised further. This MAb precipitates an acidic protein which runs as a streak on isoelectric focusing gels. The 25 and 22.5 kDa cell surface proteins precipitated by MAb 2.54 both have a pI of approximately 7.6. Treatment of immunoprecipitates with glycosidase F indicated that none of the proteins detected by MAbs 2.54, 3.187, 3.50 and 3.186 have large N-linked carbohydrates. The peptide nature of the epitopes detected by MAbs 2.54 and 3.186 was unequivocally demonstrated by precipitation from in vitro translation products of H69AR RNA. The antigens detected by MAbs 3.50 and 3.187 were not detectable in immunoprecipitates of translation products but the epitopes are probably peptides because they were destroyed by boiling in sodium dodecyl sulphate. When the reaction of the MAbs with a panel of 15 paired drug-sensitive and -resistant cell lines was examined in a cell enzyme-linked immunosorbent assay, only a few resistance associated reactions were observed. Most of the reactions were either negative or not resistance-associated. When tested with three SCLC cell lines, MAb 3.187 reacted in a manner consistent with the relative resistance of the cell lines. Antigens that had similar electrophoretic mobility to those from H69AR cells were precipitated from extracts of five human cell lines of various tumour types. These data indicate that the cross-reactivities of the MAbs are due to antigens shared among the cell lines and not just the expression of common epitopes on different proteins. Resistance-associated proteins with the biochemical properties of the antigens described in this paper have not been reported previously and they remain potential markers for the as yet to be determined mechanisms of drug resistance in SCLC and other human malignancies.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance.

In this report, we investigate several examples of hypoxia-induced drug resistance and compare them with P-glycoprotein associated multidrug resistance (MDR). EMT6/Ro cells exposed to drugs in air immediately after hypoxic treatment developed resistance to adriamycin, 5-fluorouracil, and actinomycin D. However, these cells did not develop resistance to colchicine, vincristine or cisplatin. When the cells were returned to a normal oxygen environment, they lost resistance. There was no correlation between the content of adriamycin and the development of adriamycin resistance induced by hypoxia. There was no difference between the efflux of adriamycin from aerobic cells and that from hypoxia-treated cells. The mRNA for P-glycoprotein was not detected in the hypoxia-treated cells. These results suggest that hypoxia-induced drug resistance is different from P-glycoprotein associated multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Spontaneous development of drug resistance: mismatch repair and p53 defects in resistance to cisplatin in human tumor cells.

The contributions of defective mismatch repair and mutated p53 to cisplatin resistance of human tumor cells were analysed. Mismatch repair defects were not associated with a predictable degree of resistance among several tumor cell lines. Repair defective variants of the A2780 ovarian carcinoma cell line which were isolated by selection for a methylation tolerant phenotype and did not express the hMLH1 mismatch repair protein, were highly resistant to cisplatin. Their cisplatin resistance was not a simple consequence of the mismatch repair defect. They were members of a drug-naive subpopulation of A2780 in which a silent hMLH1 gene accompanies a mutated p53. Two complementary approaches indicated that each defect contributes to cisplatin resistance independently and to a different extent. Firstly, separate introduction of a p53 defect into A2780 cells significantly increased their cisplatin resistance; defective hMLH1 provided less extensive protection. Secondly, azadeoxycytidine reactivation of the silent hMLH1 gene or expression of a transfected hMLH1 cDNA sensitized the doubly hMLH1/p53 deficient cells only slightly to cisplatin. Both approaches indicate that defective p53 status is a major determinant of cisplatin resistance and defective mismatch repair is a minor, and independent, contributor. The data have implications for the development of intrinsic cisplatin resistance.

Adaptor Proteins, Signal Transducing↗
PubMed1990

A biological price of antibiotic resistance: major changes in the peptidoglycan structure of penicillin-resistant pneumococci.

Pneumococcal strains with greatly elevated levels of resistance to penicillin have by now been described with increasing frequency worldwide. The mechanism of antibiotic resistance in these strains involves the molecular remodeling of cell wall synthetic enzymes (penicillin binding proteins). We have now analyzed the peptidoglycan structures of 10 penicillin-susceptible and 10 penicillin-resistant clinical isolates (4 of intermediate and 6 of high level resistance) with a high-resolution HPLC technique. Cell wall peptidoglycan of the susceptible strains contained monomeric and oligomeric forms of primarily (70% or more) linear stem peptides with the sequence of L-Ala-D-iGln-L-Lys-D-Ala (where iGln is isoglutamine). In contrast, the major peptide species (70% or more) of resistant cell walls were abnormal branched-stem peptides carrying Ala-Ser or Ala-Ala dipeptides on the epsilon-amino groups of the stem peptide lysine residues. The structural alteration in the peptidoglycan was not related to serotype, date, or site of isolation but showed strong correlation with penicillin resistance and was cotransformed with high-level penicillin resistance during genetic transformation. We suggest that the remodeling of the active site of penicillin binding proteins in the resistant bacteria, which results in the reduced affinity for penicillin, also changes the substrate preference of these enzymes for the more hydrophobic branched peptides (instead of linear peptides) for cell wall synthesis.

Amino Acid Sequence↗
PubMed1998

Coordinated action of glutathione S-transferases (GSTs) and multidrug resistance protein 1 (MRP1) in antineoplastic drug detoxification. Mechanism of GST A1-1- and MRP1-associated resistance to chlorambucil in MCF7 breast carcinoma cells.

To examine the role of multidrug resistance protein 1 (MRP1) and glutathione S-transferases (GSTs) in cellular resistance to antineoplastic drugs, derivatives of MCF7 breast carcinoma cells were developed that express MRP1 in combination with one of three human cytosolic isozymes of GST. Expression of MRP1 alone confers resistance to several drugs representing the multidrug resistance phenotype, drugs including doxorubicin, vincristine, etoposide, and mitoxantrone. However, co-expression with MRP1 of any of the human GST isozymes A1-1, M1-1, or P1-1 failed to augment MRP1-associated resistance to these drugs. In contrast, combined expression of MRP1 and GST A1-1 conferred approximately 4-fold resistance to the anticancer drug chlorambucil. Expression of MRP1 alone failed to confer resistance to chlorambucil, showing that the observed protection from chlorambucil cytotoxicity was absolutely dependent upon GST A1-1 protein. Moreover, using inhibitors of GST (dicumarol) or MRP1 (sulfinpyrazone), it was shown that in MCF7 cells resistance to chlorambucil requires both intact MRP1-dependent efflux pump activity and, for full protection, GST A1-1 catalytic activity. These results are the first demonstration that GST A1-1 and MRP1 can act in synergy to protect cells from the cytotoxicity of a nitrogen mustard, chlorambucil.

Antineoplastic Agents↗
PubMed2003

Fluoroquinolone-resistant Campylobacter in animal reservoirs: dynamics of development, resistance mechanisms and ecological fitness.

Thermophilic Campylobacter species, including Campylobacter jejuni and Campylobacter coli, are responsible for foodborne campylobacteriosis in humans and are increasingly resistant to fluoroquinolone (FQ) antimicrobials. The therapeutic use of FQ antimicrobial agents in food animal production, particularly in poultry, has become a concern for public health, because the practice may promote the emergence of FQ-resistant Campylobacter that can be transmitted to humans through the food chain. Recent studies have indicated that Campylobacter displays a hypermutable phenotype in response to in vivo treatment with FQ antimicrobials, resulting in the rapid emergence of resistant mutants. Distinct from other Gram-negative bacteria, the acquisition of FQ resistance in Campylobacter does not require stepwise accumulation of gyrA mutations and overexpression of efflux pumps, and is mainly mediated by single-step point mutations in gyrA in the presence of a constitutively expressed multidrug efflux pump, CmeABC. The simplicity of the resistance mechanisms may facilitate the rapid adaptation of Campylobacter to FQ treatment. The FQ-resistant Campylobacter mutants derived from chickens do not show a fitness cost in vivo and are ecologically competitive in the colonization of chickens even in the absence of antimicrobial selection pressure. These findings suggest that FQ-resistant Campylobacter may continue to persist regardless of antimicrobial usage, and highlight the need for extra effort to prevent the occurrence and spread of FQ-resistant Campylobacter in animal reservoirs.

Animals↗
PubMed1992

Cross-resistance pattern in brain tumour cells resistant to antitumour chloroethylnitrosoureas.

We tested acquired resistance and cross-resistance of brain tumour cells after repeated treatments of antitumour agents including chloroethylnitrosoureas (CENUs) in clinical use for brain tumour chemotherapy. Within ten repeated 2-day incubation periods with either 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) or methyl-6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyr anoside (MCNU), brain tumour cells (9L) developed high degrees of resistance to these drugs, as evidenced by about 3- and 6-fold increases, respectively, at the 10% survival dose (SD10). The resistance has unchanged with time after termination of challenging treatments. Repeated challenges with bleomycin (BLM), cis-diaminedichloroplatinum (II) (CDDP), and methotrexate (MTX) did not develop a significant resistance. ACNU-resistant (9L/ACNU) cells showed complete cross-resistance to MCNU, and MCNU-resistant (9L/MCNU) cells to ACNU. Drug sensitivity to other DNA-damaging agents (BLM, NCS, CDDP, etoposide) than CENUs fluctuated to a lesser extent among 9L parent, 9L/ACNU, and 9L/MCNU cells. These data suggest clinical disadvantage of prolonged adjuvant CENU chemotherapy and advantage of combined CENU chemotherapy with other agents than CENUs in brain tumours.

Animals↗
PubMed1996

The multidrug resistance phenotype confers immunological resistance.

Multidrug resistance (MDR), which is due, in part, to the overexpression of P-glycoprotein, confers resistance to a variety of natural product chemotherapeutic agents such as daunorubicin, vincristine, and colchicine. RV+ cells are a P-glycoprotein overexpressing variant of the HL60 myeloid leukemia cell line. In addition to classic MDR, RV+ cells displayed relative resistance to complement-mediated cytotoxicity with both immunoglobulin G and M antibodies against different cell surface antigens, but not to antibody-dependent cellular cytotoxicity and lymphokine-activated killing. Complement resistance was reversed both by treatment with verapamil and with specific monoclonal antibodies (mAbs) capable of binding to P-glycoprotein and blocking its function. To further confirm that the resistance of RV+ cells was not a consequence of the selection of the cells on vincristine, a second system involving P-glycoprotein infectants was also investigated. K562 cells infected with the MDR1 gene, which were never selected on chemotherapeutic drugs, also displayed relative resistance to complement-mediated cytotoxicity. This MDR1 infection-induced resistance was also reversed by mAbs that bind to P-glycoprotein. Therefore, the MDR phenotype as mediated by P-glycoprotein provides resistance to complement-mediated cytotoxicity. The increased intracellular pH and the decreased membrane potential due to the MDR phenotype may result in abnormal membrane attack complex function. This observation may have implications for the possible mechanisms of action of P-glycoprotein and for a possible physiologic role for P-glycoprotein in protection against complement-mediated autolysis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Nosocomial antibiotic resistance in multiple gram-negative species: experience at one hospital with squeezing the resistance balloon at multiple sites.

Increased use of antibiotics has led to the isolation of multidrug-resistant bacteria, especially in intensive care units and long-term care facilities. Resistance in specific gram-negative bacteria, including Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, is of great concern, because a growing number of reports have documented mechanisms whereby these microorganisms have become resistant to all available antibacterial agents used in therapy. Reduction in the selection of these multidrug-resistant bacteria can be accomplished by a combination of several strategies. These include having an understanding of the genetics of both innate and acquired characteristics of bacteria; knowing resistance potentials for specific antibacterials; monitoring resistance trends in bacteria designated as problematic organisms within a particular institution on a routine basis; modifying antibiotic formularies when and where needed; creating institutional education programs; and enforcing strict infection-control practices. Strategies appropriate for primary prevention of nosocomial resistance may differ from those required for control of existing epidemic or endemic resistance.

Anti-Bacterial Agents↗