[Biochemical aspects of microbial drug resistance].
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Drug Resistance, Microbial↗
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[Problems of the development of microbial drug resistance].
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Animals↗
beta-Lactam resistance in gram-negative bacteria: global trends and clinical impact.
Microbial drug resistance is an inescapable consequence of the utilization of antimicrobial agents in a given environment. Nowhere is the importance of resistance more evident than among agents of the beta-lactam family. Trends toward increased resistance can be seen among fastidious gram-negative bacteria like Haemophilus influenzae, where ampicillin resistance varies from 1% to 64% globally. For Escherichia coli, ampicillin resistance has risen to > or = 50% in high-risk populations, and resistance to third-generation cephalosporins is now being seen in certain areas. Inducible beta-lactamases have been responsible for increasing multiple beta-lactam resistance among certain Enterobacteriaceae and Pseudomonas aeruginosa, and this has been associated with increased use of newer cephalosporins. Xanthomonas maltophilia with its two inducible beta-lactamases is becoming an increasingly important nosocomial pathogen, especially in areas of heavy imipenem utilization. Only through the recognition of factors associated with increasing resistance and the mechanisms responsible can strategies be designed for minimizing beta-lactam resistance.
Ampicillin Resistance↗
The post-antibiotic effect of teicoplanin: monotherapy and combination studies.
The post-antibiotic effect (PAE) of teicoplanin was measured alone and in combination with other antibiotics against Staphylococcus aureus. A total of five strains were used: the Oxford S. aureus and two clinical isolates each of methicillin sensitive and methicillin resistant strains. Fusidic acid had no or a small post-antibiotic influence (range 0-1.25 h) whereas a relatively higher PAE was seen for all other drugs against all strains: teicoplanin 2.4-4.1 h: gentamicin 3.1-5.2 h, rifampicin 3.0-3.95 h, and ciprofloxacin 1.6-3.4 h. Combination of teicoplanin with fusidic acid resulted in shorter PAEs than teicoplanin alone. In contrast, PAEs for all other combinations with teicoplanin were longer than PAE of teicoplanin, gentamicin, rifampicin or ciprofloxacin alone. Addition of teicoplanin during the post-antibiotic phase of the other antibiotics and vice versa showed that the only combination which was consistently bactericidal was that of teicoplanin with gentamicin. We conclude that these in-vitro results suggest that the combination of teicoplanin with gentamicin is likely to be the most effective of those tested and should be further evaluated in clinical trials.
Anti-Bacterial Agents↗
The design of new drugs that resist microbial inactivation.
Several possible strategems for overcoming the development of bacterial resistance are discussed. The design of new drugs that resist microbial inactivation is reviewed, with particular emphasis on the aminoglycoside and beta-lactam antibiotics. Examples of alteration of the inactivation site, decreased enzyme affinity, steric hindrance of enzymic inactivation, and semiempirical systematic modification of the parent antibiotic are presented. The role of the 7-alpha-methoxy group in cefoxitin and the cephamycins in conferring stability in the presence of beta-lactamase is best rationalized by its steric bulk. The effects of other 7-alpha-substituents are also discussed.
Aminoglycosides↗
Beyond borders: plasmids drive a shared antibiotic resistome in European urban water systems.
BACKGROUND: Urban wastewater systems (UWSs) act as reservoirs and conduits for the dissemination of antibiotic resistance genes (ARGs), with plasmids playing a central role in their spread. Despite their significance, the diversity and persistence of plasmids in UWSs remain underexplored. RESULTS: This study applies a multi-omics approach, including metagenomic and direct plasmidome sequencing, high-throughput qPCR array, and whole genome sequencing of plasmid isolates, to comprehensively profile the microbial plasmidome and resistome on 78 samples across UWSs in Denmark, Spain, and the UK. We successfully uncovered an extensive plasmid and ARG diversity that could not be fully captured by a single method, especially identified 78,574 plasmids, including 20,925 plasmids previously unreported. We also observed that plasmids carried a disproportionate share of clinically relevant ARGs, particularly beta-lactamase resistance genes; most importantly, they were preferentially located on transmissible plasmids. Furtherly, plasmids harbor ARG can enhance their persistence in wastewater ecosystems, especially harboring multiple types of ARGs. Moreover, Bacteroides emerged as a unique persistent ARG reservoir not only for harboring and disseminating diverse resistance genes especially in residential-relevant areas, but also emerged as a major driver of antimicrobial resistance dynamics across different wastewater treatment processes. CONCLUSIONS: Overall, this work provides the first attempt at a holistic description of the UWSs' resistome, its structure, dynamics, and mobility and significantly expands the current knowledge. Video Abstract.
Plasmids↗
Occurrence of antibiotic-resistant E. coli and antibiotic resistance genes from culturable bacteria in drinking water sources along the Upper Mahaweli River, Sri Lanka.
Antibiotic-resistant Escherichia coli (AR-E. coli) and antibiotic resistance genes (ARGs) in aquatic environments pose a serious threat to public health. However, their presence in river water in South Asian countries is not well established. The present study investigated AR-E. coli and ARGs from culturable bacteria in drinking water sources from 14 drinking water treatment plants situated along the Upper Mahaweli River, a tropical central hill-country river system in Sri Lanka. A total of 167 E. coli isolates were tested against ten antibiotics using the Kirby-Bauer method, and genomic DNA from culturable bacteria in 45 water samples were screened for 11 ARGs using PCR. Overall, 60.48% E. coli isolates exhibited resistance to at least one antibiotic and multidrug resistance was detected in 27.54%. Highest resistance was for amoxicillin (47.31%), tetracycline (26.95%), and co-trimoxazole (24.55%) and four antibiotics showed seasonal variation. ARGs, dominated by blaTEM (80.0%), tetA (66.67%), and tetM and qnrS (62.22%) were detected in 42.42% PCR assays (n = 210). Multiple antibiotic resistance index varied from 0.00 to 0.80, with 44.91% exceeding the 0.2 threshold value, and the antibiotic resistance index varied from 0.00 to 0.32, with eight above the threshold (≥ 0.2). Hierarchical cluster analysis grouped majority of drinking water sources into the intermediate category while few were categorized under low (Kotagala and Thalawakelle-Galkanda) and high (Haragama, Paradeka, and Nawalapitiya), reflecting the variability of anthropogenic interference. Results highlight the risk associated with AR-E. coli and ARGs from culturable bacteria in one of Sri Lanka's key drinking water sources. Proactive interventions ensuring long-term safety of drinking water sources are urgently needed to safeguard public health.
Sri Lanka↗
Perfluorooctane sulfonate drives the synergistic dissemination of antimicrobial resistance and pathogenicity during sludge anaerobic digestion.
Per- and polyfluoroalkyl substances, one of the most prevalent and persistent emerging contaminants in sludge, may drive the dissemination of antimicrobial resistance and pathogenicity during sludge treatment. However, the mechanisms underlying perfluorooctane sulfonate (PFOS)-mediated propagation of antibiotic resistance genes (ARGs) and virulence factors (VFs) remain poorly understood. This study investigated the effects of PFOS (1 and 10 μg/g-dw) on ARGs dynamics and virulence risks. Quantitative PCR and metagenomic analysis revealed that PFOS stress led to the widespread enrichment of ARGs, the total abundance of mobile genetic elements (MGEs) and VFs also increased by 33.22-37.62% and 6.71-8.41%, respectively. Metagenomic binning results demonstrated that most metagenome-assembled genomes carrying ARGs or VFs simultaneously harbored MGEs. Mechanistically, excessive reactive oxygen species production and enhanced substrate-level phosphorylation for ATP generation may contribute to the increased horizontal transfer potential of ARGs under PFOS stress, which further facilitated the convergence of antimicrobial resistance and virulence traits within pathogens. Furthermore, PFOS may have hindered the negative regulation of the RhlI/RhlR quorum sensing system on the Type III secretion system, stimulating the secretion of VFs. This study elucidates the mechanisms by which PFOS promotes the dissemination of ARGs and pathogenicity during anaerobic digestion, highlighting the potentially overlooked environmental health risks of PFOS during sludge disposal.
Alkanesulfonic Acids↗
Environmental antibiotic contamination and AMR: Integrating pathways, impacts, and artificial intelligence-driven mitigation.
The widespread contamination of the environment with antibiotic residues is a significant factor contributing to the global crisis of antimicrobial resistance (AMR). Antibiotics from various sources, such as effluents from municipal and hospital wastewater treatment plants, agricultural runoffs, discharges from pharmaceutical manufacturing and improper disposal of expired or unused medicines, create selective pressures in the spread of antibiotic resistance genes. These environmental reservoirs act as hotspots for horizontal gene transfer, facilitating the emergence of multidrug-resistant pathogens. Conventional detection methods including culture-based assays, chromatographic quantification, and molecular diagnostics, provide essential insights but are limited by low throughput, reduced sensitivity to new Antibiotic Resistance Genes, and challenges in real-time monitoring across complex environments. Recent advances, such as whole-genome sequencing, metagenomics, and biosensor-based detection, help to address these gaps by enabling more comprehensive surveillance of the resistome. Artificial intelligence further enhances these approaches by improving data interpretation and pattern recognition, thus complementing traditional and molecular methods rather than replacing them. This review examines the pathways of environmental antibiotic contamination, ecological and health impacts of AMR, and limitations of conventional detection methods. It aims to clarify how these pathways contribute to the AMR crisis, assess the effectiveness of existing surveillance techniques, and identify gaps in current research.
Anti-Bacterial Agents↗
Effects of the microbial environment on drug resistance.
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Culture Media↗
Microbial development of drug resistance: mechanisms and clinical significance.
Bacteria have demonstrated a disconcerting ability to develop resistance to antimicrobial agents nearly as quickly as new compounds become available. During the past two decades the molecular bases of several types of resistance have been elucidated. Mechanisms of resistance include the transference of genetic material either through conjugation (involving direct contact between microorganisms), or indirectly through transduction (involving bacteriophages). In addition to this "infectious" drug resistance, genetic mutations which permit the utilization of new metabolic pathways, and the production of enzymes which can inactivate the antimicrobic have been described. One particularly complex problem has been the ability of many Enterobacteriaceae to develop resistance to multiple antimicrobials simultaneously. The possible effect of such an occurrence is illustrated by the recent epidemic of multiply resistant Salmonella typhi in Mexico. Because the typhoid bacilli shared an identical resistance pattern to an epidemic Shigella dysenteriae type 1 the in vivo interspecies transmission of resistance has been postulated. Understanding the various mechanisms of resistance development should allow more rational use of antimicrobial agents.
Anti-Bacterial Agents↗
[Studies on the microbial resistance to the drug combination sulfamethoxazole trimethroprim with special reference to enterococci].
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Anti-Bacterial Agents↗
[Evaluation of in vitro antimicrobial activity of cefazolin alone and in combination with cefmetazole or flomoxef using agar dilution method and disk diffusion method].
Antimicrobial activities of cefazolin (CEZ) against 251 strains of various clinical isolates obtained during 1989 and 1990 were determined using the Mueller-Hinton agar dilution method at an inoculum level 10(6) CFU/ml. The reliability of the disk susceptility test was also studied using Mueller-Hinton agar and various disks at inoculum levels of 10(3-4) CFU/cm2 in estimating approximate values of MICs. In addition, antimicrobial activities of CEZ and cefmetazole (CMZ) or flomoxef (FMOX) in combination were investigated against methicillin-sensitive and -resistant Staphylococcus aureus (MSSA and MRSA) using the checkerboard agar dilution MIC method and the disk diffusion test either with the disks contained CEZ, CMZ, and FMOX alone, or CEZ, and CMZ or FMOX in combination. In this study, the MICs of CEZ against S. aureus were distributed with the 3 peak values at 0.39 microgram/ml, 3.13 micrograms/ml and > 100 micrograms/ml. MICs against MSSA were 0.39 microgram/ml to 0.78 microgram/ml, whereas those against MRSA were greater than 0.78 microgram/ml. MICs against majority of strains of Enterococcus faecalis were 25 micrograms/ml. Over 90% of strains of Escherichia coli and Klebsiella pneumoniae were inhibited at the level of 3.13 micrograms/ml. About 60% of isolates of indole negative Proteus spp. were inhibited at the levels of less than 3.13 micrograms/ml and 100% at 6.25 micrograms/ml, but MICs against indole positive Proteus spp., Serratia spp. and Pseudomonas aeruginosa were over 100 micrograms/ml. The antimicrobial activities of CEZ against these clinical isolates were not significantly different compared to those reported about 15-20 years ago, except for S. aureus. Highly resistant strains of S. aureus to CEZ were more prevalent in this study. The inhibitory zones obtained with the disk test were compared with MICs. The results of CEZ disk susceptibility test with 30 micrograms disk (Showa) or 10 micrograms disk (prepared in this laboratory) were well correlated with MICs (r = -0.837 and -0.814, respectively), showing the reliavility of the disk method in estimating approximate values of MICs. In the 4 category classification system currently used in Japan, break points in MIC values proposed are () MIC < or = 3 micrograms/ml, (++) > 3-15 micrograms/ml, (+) > 15-60 micrograms/ml, (-) > 60 micrograms/ml. The results obtained with 30 micrograms disks showed false positive in 7.7% and false negative in 6.8% of the samples. The disk results with E. faecalis showed a higher ratio of false positive results.(ABSTRACT TRUNCATED AT 400 WORDS)
Bacteria↗
Species identification and antibiotic resistance patterns of the enterococci.
One hundred and forty isolates were identified using the GPI Card (Vitek Systems) and a conventional biochemical scheme. Agar dilution susceptibility testing was performed and isolates were screened for beta-lactamase production. The GPI Card was accurate in identifying Enterococcus faecalis, but discrepant results were obtained for seven (29.1%) of the 24 non-Enterococcus faecalis isolates. Ampicillin resistance was present in 2.9% of isolates and there were no beta-lactamase producers. There was no vancomycin resistance but 12.1% of isolates showed high-level resistance to gentamicin.
Ampicillin Resistance↗
[Combined effects of arbekacin with other antibiotics against methicillin-resistant Staphylococcus aureus. III. Combined effects of arbekacin with cefotiam or cefuzonam].
Antibacterial effects of combination use of arbekacin (ABK) with cefotiam (CTM) or cefuzonam (CZON) were evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and the following results were obtained. 1. Antibacterial effects of combinations of ABK with CTM and with CZON were equally potent against MRSA at clinically expected 1 MIC of ABK in blood. However, at a sub MIC of ABK the different effects were observed between the 2 combinations. The antibacterial effect of the former was strong and that of the latter was a little weak. 2. In either combination the potency of the antibacterial activity was less dependent on the concentration of CTM or CZON, but was strongly dependent on ABK concentrations. These results suggest that antibacterial effects of the combinations were highly dependent on antibacterial potency and concentration of ABK as previously reported for combinations of ABK with other drugs. 3. The combination use of ABK with CTM appears to be useful in cases of infection by MRSA alone while the combination use of ABK with CZON appears to be useful in cases of double infection with MRSA and Gram-negative bacterium.
Aminoglycosides↗
[Combined effects of arbekacin with other antibiotics against methicillin-resistant Staphylococcus aureus. IV. Combined effects of arbekacin with cefmetazole or flomoxef].
Antibacterial effects of combination use of arbekacin (ABK) with cefmetazole (CMZ) or flomoxef (FMOX) were evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and the following results were obtained. 1. Antibacterial effects of combinations of ABK with CMZ and with FMOX were equally potent against MRSA at clinically expected 1 MIC of ABK in blood. However, at a sub MIC of ABK different effects were observed between the 2 combinations. The former combination was slightly less effective than the latter. 2. In either combination the potency of the antibacterial activity was less dependent on the concentration of CMZ or FMOX, but was strongly dependent on ABK concentrations. These results suggest that antibacterial effects of the combinations were highly dependent on antibacterial potency and concentration of ABK as previously reported for combinations of ABK with other drugs. 3. It appears that the antibacterial activity of the combination of the sub MIC of ABK with a beta-lactam is an important point in considering the effectiveness of a combination therapy.
Aminoglycosides↗
[Effects of sulbactam on the activity of cefoperazone against various clinical isolates].
Sulbactam/Cefoperazone (SBT/CPZ) have been used in clinical infusion at ratios of 1:1 and 1:2 in Japan and U.S.A., respectively. After an administration of these drugs as a 1:1 parenteral formulation, the ratio of levels of CPZ and SBT in blood was 1:1/4 to 1:1/5 for 1 to 2 hours, whereas the ratio of free, unbound drug levels was 1:1.4 to 1:1.5. In urine these drugs were excreted at a ratio between 1:1 and 1:4 during 6 hours after the infusion. Antimicrobial interaction studies using various combinations of CPZ and SBT were performed to obtain information with respect to the effect of SBT on the antimicrobial activity of CPZ in vivo and the most appropriate ratio of these drugs for the in vitro test system. Antimicrobial activities were determined using the agar dilution method and the disk diffusion susceptibility test. SBT increased the activity of CPZ against various clinical isolates tested except Enterococcus faecalis. CPZ-SBT at a fixed ratio of 1:1/5 significantly increased the antimicrobial activity of CPZ, resulting in decreases in MIC values and increases in disk inhibitory zone diameters. These drugs at ratios 1:1 to 1:3 maximized the synergistic enhancement of the activity. Therefore, a fixed ratio between 1:1/5 and 1:1 would be appropriate for the in vitro antimicrobial test system using either the agar dilution method or the disk susceptibility test. Based on pharmacokinetic data for CPZ and SBT, results of the present study on antimicrobial activity would support that the parenteral formulation of CPZ-SBT at the fixed ratios of 1:1 and 2:1 for the intravenous infusion used in Japan and U.S.A., respectively, are appropriate. The effect of SBT on the activity of CPZ was more marked against clinical isolates with greater production abilities of beta-lactamase than against those with less production abilities. SBT/CPZ, however, exerted a synergistic effect against methicillin-resistant Staphylococcus aureus without beta-lactamase production. The MIC80 of SBT/CPZ (1:1) against various clinical isolates with 10(6) CFU/ml inoculum size were as follows: S. aureus 12.5 micrograms/ml, Staphylococcus epidermis 3.13 micrograms/ml, and E. faecalis 50 micrograms/ml. Those of Gram-negative bacilli were: Escherichia coli 0.20 microgram/ml, Klebsiella pneumoniae 0.20 micrograms/ml, Proteus mirabilis 0.78 microgram/ml, Proteus vulgaris 0.78 microgram/ml, Pseudomonas aeruginosa 12.5 micrograms/ml, Serratia marcescens 25 micrograms/ml, Enterobacter spp. 3.13 micrograms/ml, Citrobacter spp. 12.5 micrograms/ml and Acinetobacter spp. 0.78 microgram/ml.
Bacteria↗
[The occurrence of antibiotic resistant coliforms in the waste water of a water treatment plant].
Colony counts and total coliforms of the investigated biological treatment plant were decreased by more than 90% on average. In activated sludge processes the colony counts increased, whereas total coliforms did not show significant differences between raw sewage and activated sludge processes. With regard to the antibiotics tetracycline, chloramphenicol, kanamycin and gentamicin raw sewage samples contained on average 10(3) antibiotic resistant coliforms/ml. From agar plates supplemented with antibiotics a total of 896 strains were characterized. Single resistant E. coli strains (29.3%) were isolated most frequently from agar plates supplemented with tetracycline. However, coliforms isolated from agar plates which were supplemented with chloramphenicol, kanamycin and gentamicin showed a prevalent resistance to 5 and 6 antibiotics tested. The variety of resistance patterns of gentamicin-resistant coliforms was determined by few plasmids encoding gentamicin resistance only.
Chloramphenicol Resistance↗