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A monthly survey of resistance gene frequencies was conducted in a larval population of Culex pipiens breeding in an hypogeous site ("molestus" form) between July 1989 and September 1991, after interrupting mosquito control. Several significant variations in resistance gene frequency were observed. Some variations are explained by fitness differences between resistant and susceptible insects, others by an immigration of insects from the surrounding epigeous populations ("pipiens" form), which are highly resistant.
From 1980 to 1991, 925 non epidemic hospital isolates of S. aureus were selected and phage typed. MIC of 20 antibiotics and 4 antiseptics were determined by agar dilution method. The proportion of isolates susceptible to all antibiotics remains constant; however the trend to the resistance is strong during the study period (oxacillin 10-->20%, erythromycin 17-->28%, pefloxacin 4-->19%...). Strains resistant to oxacillin become more and more multiple resistant; some of recent isolates are resistant to 7 antibiotic families. There are very few products active against these strains i.e, glycopeptides (100%), pristinamycin (96%), fusidic acid (94%). This finding implies the need for continuous surveillance at the local and national level.
OBJECTIVE: To assess the changes in antibiotic resistances in Staphylococcus aureus, both methicillin-susceptible and methicillin-resistant strains, in Australia. DESIGN: Retrospective review of data collected annually. SETTING: Twenty metropolitan teaching hospitals in the six States of Australia and the Australian Capital Territory from 1988 to 1994. OUTCOME MEASURES: Changes in prevalence and resistance rates of methicillin-resistant S. aureus (MRSA) and methicillin-susceptible strains, based on antibiotic susceptibility testing of clinical isolates of S. aureus. RESULTS: Prevalence of MRSA has remained constant on the eastern seaboard of Australia. A distinctive strain of MRSA emerged in Western Australia which had different antimicrobial susceptibilities. Resistances emerged in MRSA strains from eastern Australia, principally to ciprofloxacin and rifampicin, while resistance to fusidic acid remained stable and resistance to chloramphenicol significantly declined. Resistances in methicillin-susceptible strains remained fairly stable, except for a decline in resistance levels for tetracycline. High levels of resistance were seen to penicillin, moderate levels to erythromycin and low levels to trimethoprim and fusidic acid in methicillin-susceptible strains. CONCLUSIONS: The continued high prevalence of and increasing resistance in MRSA in some Australian hospitals have meant that some strains are now untreatable with oral antibiotics.
Methicillin-resistant Staphylococcus aureus (MRSA) has two mechanisms of resistance to beta-lactam antibiotics; one is mediated by mecA gene expression, and the other by penicillinase production. It has been generally accepted in the clinical field that beta-lactam antibiotics are not the drugs of choice for MRSA infection. In this report, however, ampicillin and penicillin G were shown to have relatively good activity against MRSA if combined with a beta-lactamase inhibitor, sulbactam. These beta-lactam antibiotics were found to have relatively high binding affinities to PBP2', the mecA-encoded MRSA-specific penicillin-binding protein. The possible therapeutic application of sulbactam/ampicillin against MRSA infection in combination with arbekacin, an aminoglycoside antibiotic newly developed and introduced into clinical use in Japan, is discussed.
The Swedish Reference Group for Antibiotics appointed a subcommittee on methodology (SRGA-M) in 1987 to investigate ways of defining interpretive breakpoints for antimicrobial susceptibility testing. The minimum inhibitory concentration (MIC) breakpoints for susceptibility categories are mainly based on pharmacological properties of the antibiotic, and they are, with few exceptions, valid for all species. However, for several species the MIC breakpoints have failed to distinguish strains with reduced susceptibility from normal susceptible strains. Disk diffusion is the routine method for susceptibility testing in Sweden. Studies of distribution of MICs and zone diameters for clinically important bacterial species have resulted in an emphasis on resistance rather than on susceptibility. The SRGA-M chose to place the zone diameter breakpoints close to the native (often susceptible) population of each species or group of related species. Such species-related zone diameter breakpoints used for susceptibility categories no longer correspond to the pharmacological MIC breakpoints, but divide each species into the fully susceptible (native) population and into those isolates/populations that have acquired a resistance mechanism, resulting in high- or low-grade resistance. By this method the risk of reports of false susceptibility is minimized and early detection of the emergence of antibiotic resistance is ensured.
The resistance change to different insecticides in Culex quinquesfasciatus strain select at the laboratory with doses of pyrethroid lambdacyhalothrin that would cause a larva mortality of 90% were studied. It was attained an increase of the resistance to this insecticide of 144.5 times compared with the original level, and it was obtained a resistant strain (287x). There was an increase of the levels of resistance to methyl-pyrimifos (2.4 times), propoxur (6 times), DDT (5.2 times), clorpirifos (22 time), cypermethrin (67.5 times), and deltamethrin (20.2 times). The frequencies of the genes that codify for the elevated esterases enzymes and for the modified acetylcholinesterase reached their maximum value. Significant changes were observed in the phenotypes for esterases in the electrophoresis in polyacrylamide gels. It was detected synergism of DEF and PB with lambdacyhalothrin. Therefore, the elevated esterases and the esterases of multiple function may contribute to resistance.
In order to determine the resistance patterns and evolution trends of four common Enterobacteriaceae (Escherichia coli, Proteus spp., Klebsiella spp. and Enterobacter spp.), aminoglycoside resistance phenotypes of 8917 non-repetitive strains, isolated over an 8-year period, were analysed. Phenotypes were defined by examining the susceptibility of the strains to a panel of aminoglycosides, using disk diffusion method. A large diversity of different resistance phenotypes was encountered. A significant progressive increase in the proportions of wild-type E. coli strains was noted. Among resistant strains of Enterobacter spp. and Klebsiella spp., the incidence of phenotype KTANt (kanamycin, tobramycin, amikacin and netilmicin), indicative of AAC(6')-I production, was very high (66.7 and 46.5%, respectively). Phenotypes indicative for gentamicin-modifying enzymes as well as broad-spectrum combinations (combinations of gentamicin-modifying enzymes with AAC(6')-I) were infrequent.
Important human pathogens resistant to antibiotics result from the human use of antibiotics. Does this imply that reducing their usage or removing antibiotics from medicine and agriculture will restore the effectiveness of these drugs? The authors argue that resistance evolution and susceptibility evolution are not, in a sense, just different sides of the same coin. Resistance genes acquire new functions and the initial costs of resistance can evolve into advantages. Decreasing drug use might not replace a fundamental change in drug design to avoid the evolution of resistant, and encourage the evolution of susceptible, microorganisms.
Two field-collected Culex quinquefasciatus colonies were subjected to selection pressure by three strains of Bacillus sphaericus, C3-41, 2362, and IAB59, under laboratory conditions. After 13 and 18 generations of exposure to high concentrations of C3-41 and IAB59, a field-collected low-level-resistant colony developed >144,000- and 46.3-fold resistance to strains C3-41 and IAB59, respectively. A field-collected susceptible colony was selected with 2362 and IAB59 for 46 and 12 generations and attained >162,000- and 5.7-fold resistance to the two agents, respectively. The pattern of resistance evolution in mosquitoes depended on continuous selection pressure, and the stronger the selection pressure, the more quickly resistance developed. The resistant colonies obtained after selection with B. sphaericus C3-41 and 2362 showed very high levels of cross-resistance to B. sphaericus 2362 and C3-41, respectively, but they displayed only low-level cross-resistance to IAB59. On the other hand, the IAB59-selected colonies had high cross-resistance to both strains C3-41 and 2362. Additionally, the slower evolution of resistance against strain IAB59 may be explained by the presence of another larvicidal factor. This is in agreement with the nontoxicity of the cloned and purified binary toxin (Bin1) of IAB59 for 2362-resistant larvae. We also verified that all the B. sphaericus-selected colonies showed no cross-resistance to Bacillus thuringiensis subsp. israelensis, suggesting that it would be a promising alternative in managing resistance to B. sphaericus in C. quinquefasciatus larvae.
We used computer simulation modeling to clarify the relationship between generation time and the rate of evolution of pesticide resistance. We examined the influence of generation time under various assumptions about genetics, population dynamics and selection pressures. The simplest model demonstrated that the time required for resistance to evolve can be independent of generation time. However, interactions of generation time with genetic, biological and operational factors resulted in positive, negative, and U-shaped relationships between the number of generations per year and the time required for resistance to evolve. These results preclude any generalizations concerning the influence of generation time on resistance evolution. Some ability to predict the influence of generation time may still exist on a case-by-case basis if the context of the resistance episode can be specified.
BACKGROUND: To analyse the evolution of resistance patterns in patients undergoing treatment interruption (TI) and re-initiating highly active anti-retroviral therapy (HAART). METHODS: HIV-RT and -PR gene-sequences were analysed in 14 patients (>5 failing prior drugs) before and during TI and under a new HAART. Genotypes were interpreted using two bioinformatics systems. Additionally, virus load (VL) and CD4(+)-T-cell counts were measured. RESULTS: Six patients (42%) achieved sustained undetectable VL up to one year after TI (responders), while 8 (57%) maintained VL of more than 2,000 copies/mL (non-responders). Different patterns of resistance-mutations evolution were detected. During TI loss of all mutations was observed in three patients, a reduction of mutations was detected in seven patients, and no alteration was seen in four patients. In the responders, 87.5% of protease inhibitor (PI)-resistance mutations waned during TI and remained undetectable under the new treatment. In contrast, in the non-responder group most PI-resistance mutations continued noticeable under the new therapy. Loss of primary PI-resistance mutations and the presence of one fully active PI in the new regimen significantly correlated with success of subsequent treatment (p=0.028). In two patients new reverse transcriptase associated mutations were detected during TI, G190A (NNRTI mutation) and K70R (NRTI mutation). Appearance of K70R could be explained by a reverse direction of a previously described pathway of thymidin analogues mutation resistance development, while G190A could be due to prolonged subinhibitory drug levels after cessation of NNRTIs. CONCLUSION: In the evolution of HAART-resistance, different patterns were observed in responders and non-responders during but not before TI. Absence of PI-resistance associated mutations during and after TI and administration of a predicted fully active PI for the new therapy correlated with success. Newly detected mutations during TI may indicate reversibility of previously described mutational pathways.
Rapid adaptation to novel environments is often shaped not only by newly acquired mutations but also by historical genetic backgrounds established through prior evolutionary events. However, the extent to which such historical contingency contributes to the rapid evolution of insecticide resistance remains poorly understood. Here, we investigated the emergence of resistance to flonicamid, a recently deployed insecticide, in the green peach aphid, Myzus persicae. We show that constitutive overexpression of the P450 enzymes CYP6CY3 and CYP6CY4, already widespread in populations of M. persicae before flonicamid deployment, confers a previously cryptic tolerance phenotype to flonicamid. However, biochemical and transgenic analyses demonstrated that these metabolic adaptations provide only weak protection against flonicamid. Following flonicamid deployment, however, a novel target-site mutation, NaamV251I, in the recently identified molecular target of 4-trifluoromethylnicotinamide (TFNA-AM), emerged in M. persicae on a genetic background of CYP6CY3 or CYP6CY4 overexpression. Structural modeling, enzymatic assays, and CRISPR-Cas9 genome editing demonstrated that this mutation reduces target sensitivity and independently confers moderate resistance. Strikingly, combining the nicotinamidase (Naam) mutation with pre-existing CYP6CY3 or CYP6CY4 overexpression produced substantially elevated resistance phenotypes that far exceeded the effects of either mechanism alone. Our results demonstrate that the pre-existing metabolic background did not itself evolve further following flonicamid deployment but fundamentally altered the phenotypic consequences of a subsequently acquired target-site mutation. These findings provide direct evidence that historical adaptive variation can potentiate rapid resistance evolution to newly introduced insecticides and reveal how interactions between past and contemporary adaptations shape evolutionary responses to novel environmental challenges.
The evolution of pesticide resistance provides some of the most striking examples of darwinian evolution occurring over a human life span. Identification of resistance alleles opens an outstanding framework in which to study the evolution of adaptive mutations from the beginning of pesticide application, the evolution of interactions between alleles (dominance) or between loci (epistasis). Here we show that resistance alleles can also be used as markers to dissect population processes at a microevolutionary scale. We have focused on the antagonistic roles of selection and migration involved in the dynamics of local adaptation with reference to allelic frequencies at two resistance loci in the mosquito Culex pipiens. We find that their frequencies follow an annual cycle of large amplitude (25%), and we precisely unravel the seasonal variation of migration and selection underlying this cycle. Our results provide a firm basis on which to devise an insecticide treatment strategy that will better control the evolution of resistance genes and the growth of mosquito populations.
The rapid evolution of drug resistance remains a major obstacle for HIV therapy. The capacity of the virus for recombination is widely believed to facilitate the evolution of drug resistance. Here, we challenge this intuitive view. We develop a population genetic model of HIV replication that incorporates the processes of mutation, cellular superinfection, and recombination. We show that cellular superinfection increases the abundance of low fitness viruses at the expense of the fittest strains due to the mixing of viral proteins during virion assembly. Moreover, we argue that whether recombination facilitates the evolution of drug resistance depends critically on how resistance mutations interact to determine viral fitness. Contrary to the commonly held belief, we find that, under the most plausible biological assumptions, recombination is expected to slow down the rate of evolution of multi-drug-resistant virus during therapy.
To confirm the vertical transmission of multidrug-resistant (MDR) human immunodeficiency virus type 1 (HIV-1) and to assess its impact on further evolution of drug-resistant virus in an infant, proviral DNA amplified from infected peripheral blood mononuclear cell cultures was sequenced to identify reverse transcriptase (RT) and protease (PR) mutations. The infant had proviral DNA with evidence of RT mutations (M41L, L74V, and T215Y) and 3 PR substitutions (K20R, M36I, and V82A). After delivery, the mother's proviral DNA had the same substitutions. Phylogenetic analyses of these HIV-1 RT and PR sequences indicated epidemiological linkage. Plasma drug susceptibility was determined by using a recombinant virus assay. Plasma HIV-1 obtained after the infant's birth demonstrated reduced susceptibility to zidovudine and ritonavir. Thus, vertical transmission of MDR HIV-1 was demonstrated in the setting of detectable maternal plasma viremia. Further accumulation of broad MDR in the infant's virus to 3 antiretroviral classes occurred, despite postnatal therapy.
Special mechanisms of mutation are induced during growth-limiting stress and can generate adaptive mutations that permit growth. These mechanisms may provide improved models for mutagenesis in antibiotic resistance, evolution of pathogens, cancer progression and chemotherapy resistance. Stress-induced reversion of an Escherichia coli episomal lac frameshift allele specifically requires DNA double-strand-break-repair (DSBR) proteins, the SOS DNA-damage response and its error-prone DNA polymerase, DinB. We distinguished two possible roles for the DSBR proteins. Each might act solely upstream of SOS, to create single-strand DNA that induces SOS. This could upregulate DinB and enhance mutation globally. Or any or all of them might function other than or in addition to SOS promotion, for example, directly in error-prone DSBR. We report that in cells with SOS genes derepressed constitutively, RecA, RuvA, RuvB, RuvC, RecF, and TraI remain required for stress-induced mutation, demonstrating that these proteins act other than via SOS induction. RecA and TraI also act by promoting SOS. These and additional results with hyper-mutating recD and recG mutants support roles for these proteins via error-prone DSBR. Such mechanisms could localize stress-induced mutagenesis to small genomic regions, a potentially important strategy for adaptive evolution, both for reducing additional deleterious mutations in rare adaptive mutants and for concerted evolution of genes.