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PubMed1995

Media: lumen ratio in human small resistance arteries is related to forearm minimal vascular resistance.

BACKGROUND: For the evaluation in humans of structural alterations in resistance arteries, most studies have used an indirect index, the measurement of minimal vascular resistance (mean blood pressure divided by maximal postischaemic blood flow) in suitable vascular beds. A sensitive and specific micromyographic technique was recently made available for the study of human small resistance arteries. Whether a correlation really exists between results obtained with the two techniques has not yet been investigated. OBJECTIVE: To evaluate both forearm minimal vascular resistance and media:lumen ratio of omental or subcutaneous small arteries in normotensive subjects and hypertensive patients. DESIGN AND METHODS: Thirty-four individuals were included in the study (age range 35-74 years; 24 hypertensive, 10 normotensive). Twenty-five had elective abdominal surgery and nine hypertensive patients had a gluteal biopsy. Omental and subcutaneous small arteries were dissected and mounted on a wire micromyograph (Mulvany's technique), and media:lumen ratio and media thickness were measured. The dose-response curve to noradrenaline was constructed at cumulative concentrations from 3 x 10(-9) to 3 x 10(-5) mol/l. Venous occlusion plethysmography was used to measure blood flow in the forearm, and minimal vascular resistance was calculated from mean blood pressure and postischaemic maximal blood flow (13 min ischaemia plus exercise). RESULTS: A statistically significant correlation was found between media:lumen ratio and minimal vascular resistance (r = 0.74, P < 0.001) as well as between media:lumen ratio and systolic (r = 0.44, P < 0.01) and diastolic (r = 0.38, P < 0.05) blood pressures. Similar correlations were observed between media thickness and systolic and diastolic blood pressures. Small arteries from hypertensive patients had a significantly increased reactivity to noradrenaline (by analysis of variance) compared with those from normotensive subjects, in terms of wall tension but not of active media stress. CONCLUSIONS: The present study demonstrated that the media:lumen ratio of small resistance vessels is significantly related to forearm minimal vascular resistance, suggesting that direct and indirect evaluations of vascular morphology will give similar results.

Adult↗
PubMed1994

Elevated DNA polymerase alpha, DNA polymerase beta, and DNA topoisomerase II in a melphalan-resistant rhabdomyosarcoma xenograft that is cross-resistant to nitrosoureas and topotecan.

Previous investigations have revealed that the human TE-671 MR human rhabdomyosarcoma xenograft selected in vivo for melphalan resistance (M. C. Rosenberg, et al., Cancer Res., 49: 6917-6922, 1989) is cross-resistant to a wide variety of alkylating agents and to bleomycin, but is collaterally sensitive to etoposide. Although glutathione levels were noted to be elevated in TE-671 MR compared to the melphalan-sensitive parental TE-671 xenograft, treatment with buthionine sulfoximine to deplete glutathione levels did not fully restore melphalan sensitivity in the TE-671 MR xenograft. The present studies were undertaken to search for additional mechanisms of resistance in the TE-671 MR xenograft. Drug sensitivity testing performed at the dose of agents that was lethal to 10% of the animals revealed that the TE-671 MR xenograft maintained resistance to the bifunctional cross-linking agent 1,3-bis(2-chloroethyl)-1-nitrosourea and was cross-resistant to the topoisomerase I poison topotecan. Treatment with buthionine sulfoximine did not sensitize the TE-671 MR xenograft to 1,3-bis(2-chloroethyl)-1-nitrosourea. Further, even though O6-alkylguanine-DNA alkyltransferase levels were high in both the TE-671 and TE-671 MR xenografts, depletion of O6-alkylguanine-DNA alkyltransferase activity by treatment with O6-benzylguanine substantially sensitized the TE-671 xenografts but not the TE-671 MR xenografts, suggesting an additional mechanism of resistance. Measurement of additional enzyme activities that might be involved in DNA repair revealed significant elevations in DNA polymerase alpha (46 +/- 8 (SD) units/mg protein in TE-671, 69 +/- 6 units/mg protein in TE-671 MR, P < 0.05) and DNA polymerase beta (0.43 +/- 0.01 units/mg protein in TE-671, 0.78 +/- 0.12 units/mg protein in TE-671 MR, P < 0.05) but not DNA polymerase delta or total DNA ligase. Examination of topoisomerases by activity assays and Western blotting revealed a 2-fold increase in topoisomerase II and a 2-fold decrease in topoisomerase I in the TE-671 MR xenograft compared to the parental xenograft, apparently explaining the collateral sensitivity to etoposide and cross-resistance to topotecan. These results suggest that TE-671 MR xenografts contain multiple changes in activities of DNA repair-related proteins and other nuclear proteins that could contribute to alkylating agent resistance.

Alkyl and Aryl Transferases↗
PubMed1997

The relationship between erythromycin consumption and resistance in Finland. Finnish Study Group for Antimicrobial Resistance.

Because the discovery of new antimicrobial agents cannot be expected in the near future, we will have to manage with the antimicrobials currently available at least for the next decade or two. Therefore, attempts to prevent development of antimicrobial resistance are of major importance. The relationship of local antimicrobial consumption and antimicrobial resistance has been shown in many hospital studies but not in the community, even though this is where most antibiotics are used. At the beginning of 1990s, erythromycin resistance in group A streptococci increased rapidly in Finland. The geographical variations found led to a nationwide study of the possible relation between local erythromycin consumption and variations in erythromycin resistance in the community. Erythromycin resistance was found to be significantly (P = 0.006) linked to local consumption of erythromycin. In further experiments, we found that a new erythromycin resistance phenotype belonging to the T4 serotype was spread over the whole country; 83% of the erythromycin-resistant isolates were of this new phenotype in 1994. In 1991, recommendations were given to reduce use of erythromycin in Finland. Following these recommendations, macrolide consumption decreased by 40% from 1991-1994. Studies are now in progress to evaluate the effect of this reduction on erythromycin resistance of group A streptococci.

Anti-Bacterial Agents↗
PubMed1996

[Establishment of human ovarian cancer cisplatin resistant cell line COC1/DDP and its mechanism of resistance].

OBJECTIVE: To establish cisplatin (DDP)-resistant subline of human ovarian cancer and investigate the mechanism responsible for resistance to DDP. METHODS: A DDP-resistant human ovarian adenocarcinoma cell subline (COC1/DDP) was developed by contineous stepwise selection in increasing concentration of DDP from the parent cell line COC1 in vitro. The multiple changes of biological properties in COC1/DDP cell line were determined. RESULTS: COC1/DDP cells were of 6.5-fold resistance to DDP and displayed significant cross-resistant with carplatin and mitomycin C, but still remained sensitive to 5-fluorouracil and adriamycin. As compared to the parent cells, in COC1/DDP cells: the doubling time was reduced by 12.9%. Cellular content of DDP was diminished by more one half and the DNA-interstrand cross-links (ISC) was lower than that of the sensitive cells. Evidence of P-glycoprotein overexpression was not shown in COC1 and COC1/DDP cell lines by means of immunohistochemical method. CONCLUSIONS: The primary factor causing COC1/DDP resistance to DDP is the reduction of intracellular platinum accumulation and DNA ISC formation. The resistance is not considered to be associated with the multidrug resistant and P-glycoprotein.

Adenocarcinoma↗
PubMed1997

[Resistance to protein biosynthesis inhibitors in Staphylococci: resistance genes and their spread--a review].

The rapid spread of antibiotic resistances in a wide variety of bacteria is mainly due to the location of antibiotic resistance genes on mobile genetic elements such as plasmids and transposons. Principal ways of transfer of plasmid- and transposon-encoded resistance genes are presented using examples of the predominant genes mediating resistances to protein biosynthesis inhibitors such as tetracyclines, aminoglycosides, macrolide-lincosamide-streptogramin B antibiotics, and chloramphenicol in staphylococci. Transfer between different staphylococcal cells is substantially based on transduction, transformation, conjugation and mobilization while transfer of resistance genes within the same bacterial cell often includes interplasmidic recombination events and chromosomal integration of resistance plasmids or transposons. The abilities of the transferred resistance plasmids or transposons to integrate or to be integrated into DNA molecules, plasmids or chromosomal DNA, of the new host cell are of major importance to circumvent strain-, species- or genusspecific barriers such as restriction/modification systems, plasmid incompatibilities or deficiencies of plasmid replication which may limit efficient resistance gene transfer.

Anti-Bacterial Agents↗
PubMed1998

[Antibiotic resistance among strains of Helicobacter pylori in Gothenburg. Bacteria resistant to metronidazole].

AIM: Primary resistance of H pylori strains to antimicrobials has direct therapeutical implications. For this reason we studied the prevalence of primary resistance of H pylori of Sweden, in a regional setting. MATERIAL AND METHODS: A total of 244 patients referred to our endoscopy unit have been evaluated prospectively for the occurrence of H pylori. Helicobacter pylori infection was established by a positive rapid urease test on an antral biopsy. If positive the biopsy specimen was transferred to a transportmedium for culture on a Skirrow medium. Antimicrobial resistance was evaluated by the E-test. RESULTS: In 109 patients H pylori infection was seen and in all of them the culture was positive. No resistance was seen for amoxycillin and tetracycline. The resistance against metronidazole was 40.3% and and against clarithromycin it was 2.8%. For metronidazole there was a significantly higher resistance seen in women compared to men (53.3% vs 31.2%; p < 0.001). CONCLUSIONS: Primary resistance to metronidazole was higher than expected and over average in Europe. The resistance for clarithromycin is still rare. Further monitoring is mandatory to detect changes in the community.

Antitrichomonal Agents↗
PubMed1998

Prednisolone resistance in childhood acute lymphoblastic leukemia: vitro-vivo correlations and cross-resistance to other drugs.

As an important determinant of response to chemotherapy, accurate measurement of cellular drug resistance may provide clinically relevant information. Our objectives in this study were to determine the relationship between in vitro resistance to prednisolone (PRD) measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and (1) short-term clinical response to systemic PRD monotherapy, (2) long-term clinical outcome after combination chemotherapy within all patients and within the subgroups of clinical good and poor responders to PRD, and (3) in vitro resistance to 12 other drugs in 166 children with newly diagnosed acute lymphoblastic leukemia (ALL). The 12 clinical poor PRD responders had ALL cells that were median 88-fold more in vitro resistant to PRD than 131 good responders (P = .013). Within all patients, increased in vitro resistance to PRD predicted a significantly worse long-term clinical outcome, at analyses with and without stratification for clinical PRD response, and at multivariate analysis (P </= .001). Within both the clinical good and poor responder subgroups, increased in vitro resistance to PRD was associated with a worse outcome, which was significant within the group of clinical good responders (P < .001). LC50 values, ie, lethal concentrations to 50% of ALL cells, for PRD and each other drug correlated significantly with those of all other 12 drugs, with an average correlation coefficient of 0.44 (standard deviation 0.05). The highest correlations were found between structurally related drugs. In conclusion, in vitro resistance to PRD was significantly related to the short-term and long-term clinical response to chemotherapy, the latter also within the subgroup of clinical good responders to PRD. There was a more general in vitro cross-resistance between anticancer drugs in childhood ALL, although drug-specific activities were recognized.

Adolescent↗
PubMed1998

Prevention of brefeldin A-induced resistance to teniposide by the proteasome inhibitor MG-132: involvement of NF-kappaB activation in drug resistance.

Brefeldin A, an agent that disrupts protein transport from the endoplasmic reticulum to the Golgi, induces the expression of GRP78 and the activation of nuclear factor (NF)-kappaB in cells. Treatment of cells with brefeldin A causes the development of resistance to topoisomerase II-directed agents, such as etoposide and doxorubicin. In this study, we show that treatment of EMT6 mouse mammary tumor cells with brefeldin A strongly induces GRP78 mRNA (8.5-fold) and resistance to teniposide (VM26). Treatment with okadaic acid causes a minor increase in GRP78 mRNA (2.1-fold) yet still induces resistance to VM26 as effectively as brefeldin A. In contrast, cells treated with castanospermine show a moderate increase in GRP78 mRNA (3.9-fold) but no resistance to VM26. These data imply that GRP78 induction does not mediate the development of drug resistance. An alternative mechanism of drug resistance may involve activation of the transcription factor, NF-kappaB, and we show that both brefeldin A and okadaic acid activate NF-kappaB in EMT6 cells. Furthermore, we demonstrate that treatment with the proteasome inhibitor MG-132 blocks the activation of NF-kappaB and prevents the development of resistance to VM26 induced by brefeldin A. Collectively, these results suggest that the resistance to VM26 in EMT6 cells treated with brefeldin A is mediated by the activation of NF-kappaB rather than the induction of GRP78. Our results also suggest that inhibition of NF-kappaB activation in tumor cells may increase the efficacy of topoisomerase II-directed agents in chemotherapy.

Animals↗
PubMed1998

Lack of cross-resistance with gemcitabine and cytarabine in cladribine-resistant HL60 cells with elevated 5'-nucleotidase activity.

Cross-resistance patterns between chemotherapeutic agents have implications for the treatment of hematologic and other diseases. Previous in vitro models have shown cross-resistance between the purine analog 2-chlorodeoxyadenosine (cladribine) and the pyrimidine analogs 2',2'-difluorodeoxycytidine (gemcitabine) and 1-beta-D-arabinofuranosylcytosine (cytosine arabinoside, cytarabine) with reduced deoxycytidine kinase (dCK) activity as the underlying determinant of resistance. In this study, we continuously exposed the human promyelocytic leukemia cell line HL60 to as much as 1024 nM cladribine. After limiting dilution, the cladribine concentrations that caused 50% growth inhibition (IC50) of the two clones R13 and R23 were 33.3- and 18.7-fold, respectively, higher than the IC50 of the parental HL60 cells (8.7+/-1.3 nM). These cladribine-resistant clones, however, showed no cross-resistance to gemcitabine and only 3.3- and 2.7-fold resistance to cytarabine, respectively. Characterization of both clones revealed stably elevated levels of purine-specific "high-Michaelis constant (Km)" 5'-nucleotidase (5'-NT) messenger RNA expression and specific activity, whereas pyrimidine-specific "low-Km" 5'-NT activity was undetectable, and dCK activity was only marginally decreased in R13. Thus, the ratio of dCK (specific for cladribine) to high-Km 5'-NT activity in R13 and R23 was reduced to 65.3% and 63.7%, respectively. These results show that changes of high-Km 5'-NT activity can induce cladribine resistance, without cross-resistance to gemcitabine.

5'-Nucleotidase↗
PubMed1998

[Multidrug-resistant tuberculosis. 5. Human immunodeficiency virus infection and multidrug-resistant tuberculosis].

Outbreaks of multidrug-resistant tuberculosis (MDR-TB) among human immunodeficiency virus (HIV)-infected persons reported in the United States were very serious and the risks were increased by the delay of diagnosis, rapid progression from infection to active disease, inadequate therapy and poor tuberculosis (TB) control. Prevalence of drug-resistant TB among HIV-infected patients in Japan was studied. The results of drug susceptibility were collected through the nationwide working group for a survey of HIV-infected TB. Data of susceptibility for 39 cases were obtained. The isolates of two cases were resistant to isoniazid and rifampicin (including clinical failure of response), although no outbreak of MDR-TB was found in Japan. Case study of a patient who developed MDR-TB revealed that drug resistance might be selected by insufficient anti-TB therapy. The rate of resistance to any of the anti-TB drugs in HIV-infected patients seemed to be high, although strictly evaluation was difficult due to no standardization for drug susceptibility testing. Of 9 cases with resistance to any of the anti-TB drugs, 8 had extrapulmonary TB including 5 cases of disseminated TB. In contrast thirteen of 30 cases without drug resistance had extrapulmonary TB. Since it has been reported that HIV infection is related to increased rates of drug resistance of TB bacilli, treatment with four-drug regimen should be started and sufficient courses of therapy are needed in HIV-infected TB patients.

AIDS-Related Opportunistic Infections↗
PubMed2004

Penicillin and macrolide resistance in pneumococcal pneumonia: does in vitro resistance affect clinical outcomes?

In vitro resistance to antimicrobial agents is escalating among pathogens responsible for the most serious respiratory tract infections. Some reports have suggested that this has direct clinical implications. Because of penicillin and macrolide resistance in Streptococcus pneumoniae, current guidelines for the initial treatment of respiratory tract infections advocate less reliance on the use of either of these classes of drugs in single-agent therapy. Recent studies that have assessed the impact of beta -lactam and macrolide resistance on clinical outcomes in community-acquired pneumonia fail to provide incontrovertible evidence for a direct link between in vitro resistance and treatment failure. However, there are anecdotal reports of breakthrough bacteremia due to macrolide-resistant pneumococci among patients receiving macrolide therapy, unlike the situation for beta -lactams and penicillin-resistant pneumococci. Continued efforts, including in vitro surveillance, appropriate antibiotic use campaigns, and immunization programs, will be important in limiting the spread of drug-resistant S. pneumoniae.

Community-Acquired Infections↗
PubMed2004

Clinical outcomes of pneumococcal pneumonia caused by antibiotic-resistant strains in asian countries: a study by the Asian Network for Surveillance of Resistant Pathogens.

To evaluate the clinical outcomes of pneumococcal pneumonia caused by antibiotic-resistant strains in Asian countries, we performed a prospective observational study of 233 cases of adult pneumococcal pneumonia in 9 Asian countries from January 2000 to June 2001. Among 233 isolates, 128 (55%) were not susceptible to penicillin (25.3% were intermediately susceptible, and 29.6% were resistant). Clinical severity of pneumococcal pneumonia was not significantly different between antibiotic-resistant and antibiotic-susceptible groups. Mortality rates among patients with pneumococcal pneumonia caused by penicillin-, cephalosporin-, or macrolide-resistant strains were not higher than those with antibiotic-susceptible pneumococcal pneumonia. Bacteremia and mechanical ventilation were significant risk factors for death, but any kind of antibiotic resistance was not associated with increased mortality due to pneumococcal pneumonia. Outcome of pneumococcal pneumonia was not significantly affected by drug resistance, and current antimicrobial regimens are mostly effective in the treatment of pneumococcal pneumonia, despite the widespread emergence of in vitro resistance.

Adolescent↗
PubMed1993

Invasive pneumococcal disease in central Oklahoma: emergence of high-level penicillin resistance and multiple antibiotic resistance. Pneumococcus Study Group.

Relatively penicillin-resistant pneumococci have caused 10% of invasive pneumococcal disease in central Oklahoma during the last decade, but almost no high-level penicillin or other antibiotic resistance has been described. This study evaluated antibiotic susceptibility and serotype distribution in invasive pneumococcal disease in the Oklahoma City metropolitan area (1990 population 848,000). A total of 144 cases of invasive infection was collected in 1 year (17 with meningitis, 120 with other bacteremic infections, and 7 with other invasive infections), for a rate of 16.9/100,000 (95% confidence interval [CI], 14.0-19.5). For the population aged > or = 60, invasive pneumococcal disease rates were higher among nursing home residents (352/100,000) than among nonresidents (25.6/100,000; relative risk, 13.7; 95% CI, 7.7-24.7). Antibiotic-resistant organisms caused 19.4% of the cases: relative penicillin resistance, 7.6%; high-level penicillin resistance, 1.4% (2 cases), and 11% resistance to erythromycin, trimethoprim-sulfamethoxazole, or both, with 5% sharing both resistances plus a MIC of penicillin of 0.06 microgram/mL.

Adolescent↗
PubMed2001

Development of vancomycin and lysostaphin resistance in a methicillin-resistant Staphylococcus aureus isolate.

Glycopeptide resistance in Staphylococcus aureus is poorly understood. The diversity of change documented in cell walls of clinical glycopeptide-intermediate S. aureus (GISA) isolates is evidence that a single genetic or biochemical change cannot account for resistance in all isolates described to date. Therefore, identification of new GISA clinical isolates provides an opportunity to gain insight into the range of adaptive strategies employed by staphylococci to survive in the presence of glycopeptides. In April 1999, a GISA isolate was obtained from the blood of a 63-year-old dialysis patient in Illinois. This isolate was one of six clonally identical MRSA isolates (A-F) serially obtained from the blood of this patient who was receiving vancomycin therapy. All isolates were resistant to oxacillin (MIC > 256 mg/L). The initial isolate had an MIC of vancomycin of 1 mg/L. However, the presence of a subpopulation that could grow in the presence of 5 mg/L of vancomycin indicated that this isolate was predisposed to the acquisition of the GISA phenotype (MIC of vancomycin 10-12 mg/L), which occurred 13 days later, associated with an increased MIC of the endopeptidase lysostaphin and slightly increased cell wall thickness. The first and last isolates in the series, A and F, resisted killing when incubated in vancomycin 2 mg/L, resisted autolysis when incubated in Triton X-100 and had a decreased expression of a c. 116 kDa autolytic band, properties that were different from glycopeptide-susceptible control isolates. Lysostaphin resistance was not accompanied by alterations in the peptidoglycan pentaglycine cross-bridge or a decrease in oxacillin MIC. These data, when taken together with the demonstration of increased cross-linking in isolate F compared with isolate A, demonstrate that vancomycin resistance in these isolates probably occurred by a mechanism different from that of other GISA isolates described to date.

Anti-Bacterial Agents↗
PubMed2002

Resistance to beta-lactamase inhibitor protein does not parallel resistance to clavulanic acid in TEM beta-lactamase mutants.

In order to compare patterns of resistance to inhibition by clavulanic acid with patterns of resistance to inhibition by a beta-lactamase inhibitor protein (BLIP), R164S, R244S, and R164S/R244S mutant forms of TEM beta-lactamase were prepared by site-directed mutagenesis. When kinetic parameters were determined for these mutant and wild-type forms of TEM, the single mutants showed properties that were similar to those in the literature but the double mutant showed properties that were very different. The R164S/R244S double mutant form of TEM retained its resistance to inhibition by clavulanic acid (characteristic of the R244S mutation) but lost all its ability to hydrolyze ceftazidime (characteristic of the R164S mutation). While these characteristics are contrary to those previously reported for an R164S/R244S double mutant, this discrepancy resulted from the use of a defective mutant in the earlier study. Both the single and double mutant forms of TEM remained highly sensitive when tested for inhibition by BLIP, showing only slightly increased resistance compared to that of the wild type; this pattern of resistance is quite different from the pattern of clavulanic acid resistance. The slight increases in resistance to inhibition by BLIP seen in the mutants may have been related to the fact that all of the mutations effected changes in the net charge on the TEM protein that could impede interactions with BLIP.

Ampicillin Resistance↗
PubMed2004

Trends in antimicrobial resistance in 1,968 invasive Streptococcus pneumoniae strains isolated in Spanish hospitals (2001 to 2003): decreasing penicillin resistance in children's isolates.

To address the public health problem of antibiotic resistance, the European Union (EU) founded the European Antimicrobial Resistance Surveillance System. A network of 40 hospitals that serve approximately 30% of the Spanish population (about 12 million) participated. Each laboratory reported data on antimicrobial susceptibility testing using standard laboratory procedures that were evaluated by an external quality control program. The antibiotic consumption data were obtained from the National Health System. We compared the antibiotic susceptibility of Spanish isolates of invasive Streptococcus pneumoniae (2001 to 2003) with antibiotic consumption. Invasive S. pneumoniae was isolated from 1,968 patients, 20% of whom were children at or below the age of 14 years. Of non-penicillin-susceptible strains (35.6%; 95% confidence interval, 34 to 37.2), 26.4% were considered intermediate and 9.2% were considered resistant. Between 2001 and 2003, penicillin resistance decreased from 39.5 to 33% overall and from 60.4 to 41.2% in children at or below the age of 14 years (P = 0.002). Resistance to erythromycin was at 26.6%, and coresistance with penicillin was at 19.1%. Of total isolates, the ciprofloxacin MIC was >2 mug/ml for 2.1%, with numbers increasing from 0.4% (2001) to 3.9% (2003). Total antibiotic use decreased from 21.66 to 19.71 defined daily doses/1,000 inhabitants/day between 1998 and 2002. While consumption of broad-spectrum penicillins, cephalosporins, and erythromycin declined, use of amoxicillin-clavulanate and quinolones increased by 17.5 and 27%, respectively. The frequency of antibiotic resistance in invasive S. pneumoniae in Spain was among the highest in the EU. However, a significant decrease in penicillin resistance was observed in children. This decrease coincided with the introduction of a heptavalent conjugate pneumoccocal vaccine (June 2001) and with a global reduction in antibiotic consumption levels.

Adolescent↗
PubMed2000

[Drug-resistant bacteria of current topics and their resistance mechanisms--PRSP and BLNAR].

The prevalence of resistant isolates for beta-lactam antibiotics have been rapidly increasing in Streptococcus pneumoniae and Haemophilus influenzae. These strains having resistant elements are called penicillin-resistant S. pneumoniae(PRSP) and beta-lactamase-negative ampicillin-resistant H. influenzae(BLNAR). The mechanism of resistance was identified as the reduction of penicillin-binding proteins(PBPs) affinities as the target of beta-lactams. In PRSP, pbp1a, pbp2x, and pbp2b encoding PBP1A, -2X, and -2B enzymes, respectively, were altered. In contrast, mutations in the ftsI gene encoding PBP3A were only clarified in BLNAR. Characteristics of the resistance caused by PBPs alterations are a low-level resistance that decrease bactericidal action.

Ampicillin Resistance↗
PubMed2000

Zonisamide for drug-resistant partial epilepsy.

BACKGROUND: The majority of epileptic patients have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding a new antiepileptic drug, zonisamide, when used as an add-on treatment for drug-resistant partial epilepsy. OBJECTIVES: To evaluate the efficacy and tolerability of zonisamide when used as an add-on treatment for patients with drug -resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trial register, the Cochrane Controlled Trials Register (Cochrane Library Issue 4, 1999). In addition, we contacted Dianippon and Elan Pharma (makers and licensees of zonisamide) and experts in the field to seek any ongoing studies or unpublished studies. SELECTION CRITERIA: Randomized placebo controlled add-on trials of zonisamide in patients with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted relevant data. The following outcomes were assessed: (a) 50% or greater reduction in total seizure frequency; (b) treatment withdrawal (any reason); (c) adverse events. Primary analyses were intention to treat. Sensitivity best and worst case analyses were also undertaken. Summary odds ratios (ORs) were estimated for each outcome. MAIN RESULTS: Three trials were included with 499 patients randomized. EFFICACY: Overall odds ratio (OR, 95% CI) for 50% reduction in seizure frequency compared to placebo was 2.07 (1.36,3.15) for a 400mg/day dose of zonisamide. When the full treatment period of 12 weeks was considered for all three trials including varied rates of titration to 400mg/day the OR compared to placebo was 2.72 (1.74,4. 25). There was insufficient evidence to support a dose response relationship between dose and responder rate. Tolerability: Treatment withdrawal OR compared to placebo was 1.74 (1.03,2.95). Adverse events: ataxia 3.94 (1.23,12.57), somnolence 2.11 (1.11, 3. 98), agitation 3.52 (1.26,9.68), agitation and irritability 2.43(1. 04,5.66) and anorexia 2.98(1.38,6.42) were significantly associated with zonisamide. REVIEWER'S CONCLUSIONS: Zonisamide has efficacy as an add-on treatment in patients with drug-resistant partial epilepsy. Minimum effective and maximum tolerated doses cannot be identified. The trials reviewed were of 12 week duration and results cannot be used to conform longer periods of effectiveness in seizure control. The results cannot be extrapolated to monotherapy or to patients with other seizure types or epilepsy syndromes.

Anticonvulsants↗