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PubMed1997

Rational approach to limiting emergence of antimicrobial drug resistance.

Microbial resistance to the available antimicrobial agents continues to be a major problem with regard to nosocomial and community acquired pathogens. The development of resistance to commonly used antimicrobials is of particular concern when it occurs in pathogenic organisms that cause invasive disease. This has implications on morbidity and mortality of infectious diseases, and will also result in escalated costs of care due to the use of alternative antimicrobials which are often more costly. The increasing frequency of drug resistance has been attributed to combinations of microbial characteristics, selective pressure of antimicrobial use and societal factors that enhance the transmission of drug resistant organisms. The emergence of antibiotic resistant bacteria has generally correlated with the rise and fall of specific antibiotic use in clinical practice. Although the discovery of a new drug temporarily confers therapeutic superiority over bacterial pathogens, the subsequent rapid evolution of resistance limits the duration of the effectiveness of specific agents against pathogens. Surveillance and the development of drug policies that encourage judicious use of antimicrobials will help to minimise the spread of resistant infections. This paper reviews how this dual strategy may be used to control antimicrobial resistance.

Bacterial Infections↗
PubMed2005

Dynamics of multiple infection and within-host competition in genetically diverse malaria infections.

Within-host competition between coinfecting parasite strains shapes the evolution of parasite phenotypes such as virulence and drug resistance. Although this evolution has a strong theoretical basis, within-host competition has rarely been studied experimentally, particularly in medically relevant pathogens with hosts that have pronounced specific and nonspecific immune responses against coinfecting strains. We investigated multiple infection in malaria, using two pairs of genetically distinct clones of the rodent malaria Plasmodium chabaudi in mice. Clones were inoculated into mice simultaneously or 3 or 11 days apart, and population sizes were tracked using immunofluorescence or quantitative polymerase chain reaction. In all experiments, at least one of the two clones suffered strong competitive suppression, probably through both resource- and immune-mediated (apparent) competition. Clones differed in intrinsic competitive ability, but prior residency was also an important determinant of competitive outcome. When clones infected mice first, they did not suffer from competition, but they did when infecting mice at the same time or after their competitor, more so the later they infected their host. Consequently, clones that are competitively inferior in head-to-head competition can be competitively superior if they infect hosts first. These results are discussed in the light of strain-specific immunity, drug resistance, and virulence evolution theory.

Animals↗
PubMed2003

Modelling the spatial configuration of refuges for a sustainable control of pests: a case study of Bt cotton.

The 'high-dose-refuge' (HDR) strategy is widely recommended by the biotechnology industry and regulatory authorities to delay pest adaptation to transgenic crops that produce Bacillus thuringiensis (Bt) toxins. This involves cultivating nontoxic plants (refuges) in close proximity to crops producing a high dose of Bt toxin. The principal cost associated with this strategy is due to yield losses suffered by farmers growing unprotected, refuge plants. Using a population genetic model of selection in a spatially heterogeneous environment, we show the existence of an optimal spatial configuration of refuges that could prevent the evolution of resistance whilst reducing the use of costly refuges. In particular, the sustainable control of pests is achievable with the use of more aggregated distributions of nontransgenic plants and transgenic plants producing lower doses of toxin. The HDR strategy is thus suboptimal within the context of sustainable agricultural development.

Bacillus thuringiensis↗
PubMed2004

Polymyxin B-lipid interactions in Langmuir-Blodgett monolayers of Escherichia coli lipids: a thermodynamic and atomic force microscopy study.

The dramatically increased frequency of antibiotic resistance has led to intensive efforts towards developing new families of antibiotics. Membrane-active antibiotic peptides such as polymyxin B (PxB) hold promise as the next generation of antibiotics, since they rarely spur the evolution of resistance. At low concentrations in the membrane, PxB forms vesicle-vesicle contacts and induces lipid exchange without leakage or fusion, a phenomenon that can explain its specificity towards gram-negative bacteria by contact formation between the two phospholipids interfaces in the periplasmatic space. In this work, the interaction of PxB and the nonantibiotic derivative polymyxin B nonapeptide (PxB-NP) with monolayers of Escherichia coli membrane lipids (ECL) has been studied by thermodynamic and structural methods. PxB inserts itself into ECL monolayers as a conformation that forms intermembrane contacts with vesicles injected underneath, and induces lipid exchange when the monolayer surface pressure is set at 32 mN/m (membrane equivalence pressure) or net transfer vesicle-to-monolayer at lower surface pressures. Thermodynamic analysis of the compression isotherms of mixed monolayers indicates that PxB inserts into the monolayer with an expansion of the mean molecular area, implying that peptide and lipids form nonideal mixtures. At low concentrations, corresponding to the membrane-membrane contact form of PxB, the mixed monolayers present positive excess energy values (deltaGm(Ex)), and atomic force microscopy (AFM) imaging reveals structures of approximately 120-nm diameter that protrude from the lipid surface approximately 0.7 nm. At concentrations of PxB above 4 mol %, thermodynamic analysis gives a very high deltaGm(Ex), corresponding to nonfavorable interactions, and AFM images show round structures of 20-30 nm diameter. PxB-NP behaves in a totally different way, in agreement with its inability to form vesicle-vesicle contacts and its lack of antibiotic effect. These results are discussed in the light of the mechanism of action of PxB on the membrane of gram-negative bacteria.

Anti-Bacterial Agents↗
PubMed1998

Predicting insecticide resistance: mutagenesis, selection and response.

Strategies to manage resistance to a particular insecticide have usually been devised after resistance has evolved. If it were possible to predict likely resistance mechanisms to novel insecticides before they evolved in the field, it might be feasible to have programmes that manage susceptibility. With this approach in mind, single-gene variants of the Australian sheep blowfly, Lucilia cuprina, resistant to dieldrin, diazinon and malathion, were selected in the laboratory after mutagenesis of susceptible strains. The genetic and molecular bases of resistance in these variants were identical to those that had previously evolved in natural populations. Given this predictive capacity for known resistances, the approach was extended to anticipate possible mechanisms of resistance to cyromazine, an insecticide to which L. cuprina populations remain susceptible after almost 20 years of exposure. Analysis of the laboratory-generated resistant variants provides an explanation for this observation. The variants show low levels of resistance and a selective advantage over susceptibles for only a limited concentration range. These results are discussed in the context of the choice of insecticides for control purposes and of delivery strategies to minimize the evolution of resistance.

Animals↗
PubMed2003

Tritrophic choice experiments with bt plants, the diamondback moth (Plutella xylostella) and the parasitoid Cotesia plutellae.

Parasitoids are important natural enemies of many pest species and are used extensively in biological and integrated control programmes. Crop plants transformed to express toxin genes derived from Bacillus thuringiensis (Bt) provide high levels of resistance to certain pest species, which is likely to have consequent effects on parasitoids specialising on such pests. A better understanding of the interaction between transgenic plants, pests and parasitoids is important to limit disruption of biological control and to provide background knowledge essential for implementing measures for the conservation of parasitoid populations. It is also essential for investigations into the potential role of parasitoids in delaying the build-up of Bt-resistant pest populations. The diamondback moth (Plutella xylostella), a major pest of brassica crops, is normally highly susceptible to a range of Bt toxins. However, extensive use of microbial Bt sprays has led to the selection of resistance to Bt toxins in P. xylostella. Cotesia plutellae is an important endoparasitoid of P. xylostella larvae. Although unable to survive in Bt-susceptible P. xylostella larvae on highly resistant Bt oilseed rape plants due to premature host mortality, C. plutellae is able to complete its larval development in Bt-resistant P. xylostella larvae. Experiments of parasitoid flight and foraging behaviour presented in this paper showed that adult C. plutellae females do not distinguish between Bt and wildtype oilseed rape plants, and are more attracted to Bt plants damaged by Bt-resistant hosts than by susceptible hosts. This stronger attraction to Bt plants damaged by resistant hosts was due to more extensive feeding damage. Population scale experiments with mixtures of Bt and wildtype plants demonstrated that the parasitoid is as effective in controlling Bt-resistant P. xylostella larvae on Bt plants as on wildtype plants. In these experiments equal or higher numbers of parasitoid adults emerged per transgenic as per wildtype plant. The implications for integrated pest management and the evolution of resistance to Bt in P. xylostella are discussed.

Animals↗
PubMed1995

Epidemiology of antibiotic resistance in Haemophilus influenzae.

During the last 10 years, a continuous increase in the incidence of beta-lactamase-producing Haemophilus influenzae has been observed; in addition, beta-lactamase-negative ampicillin-resistant strains are better identified and more frequently isolated. During the same period, resistance to tetracyclines and chloramphenicol decreased to a very low level. The incidence of resistant bacteria is highly variable according to the site of infection, patient's age, type of Haemophilus, and country or region, according to local epidemiological factors. Follow-up multicenter studies are needed to monitor the evolution of resistance to these antibiotics and also emergence and spread of resistance to other antibiotics, such as new fluoroquinolones, new beta-lactams, and new macrolides.

Anti-Bacterial Agents↗
PubMed2002

HIV in Africa (Communication arising): chemokine-receptor genes and AIDS risk.

Schliekelman et al. have provided a model to quantify the speed at which HIV-resistance haplotypes can become enriched in a susceptible population through a delay in the onset of AIDS, permitting greater lifetime reproduction and the selection of AIDS-delaying haplotypes. But we question their conclusion that there could be a rapid evolution of resistance to AIDS onset in some African populations if the current HIV epidemic persists, as this depends on an untested assumption: that variant forms of the chemokine-receptor-5 (CCR5) gene impart selective advantages or disadvantages in Africa that are comparable to those reported for African Americans. Here we test this premise in a large Ugandan population, and find that CCR5 variants are not associated with HIV/AIDS disease risk in Africa--the origin and centre of the current AIDS pandemic. This gene may therefore not be subject to rapid evolutionary change as a result of the HIV epidemic in Africa.

Acquired Immunodeficiency Syndrome↗
PubMed1998

[Microbiologic diagnosis of Helicobacter pylori and its resistance to antibiotics].

From March 1995 to February 1996 a total of 386 gastroduodenal biopsies were processed for microbiological diagnosis of Helicobacter pylori which included culture, Gram staining and urease test. For susceptibility studies to five antimicrobial agents, 35 additional gastroduodenal biopsies (n = 421) were added. There were 272 (70.4%) positive cultures, 220 (56.9%) samples with positive urase test and 244 (63.2%) with positive result in Gram-staining; both tests were statistically significant compared with culture (p < 0.05). Considering culture as the reference method, sensitivity and specificity values for the urease test were 77.0% and 92.1% and for Gram staining 86.7% and 92.9%, respectively. A total of 11 isolates were recovered from the 35 biopsies processed only for culture. Susceptibility testing of 283 isolates (272 + 11) was performed to the following antimicrobials: amoxicillin, metronidazole, clarithromycin, azythromycin and tetracycline. Resistance to metronidazole was 25.4% and the corresponding values for clarithromycin and azithromycin 9.5%. No resistance to amoxicillin or tetracycline was observed. Urease test and Gram staining are two easy-to-perform tests and when taken together allow the microbiological diagnosis of Helicobacter pylori infection. Culture should be performed to know the evolution of resistance to antimicrobials used for treatment of this infection.

Biopsy↗
PubMed2004

[A 7-year survey of strains identified in blood cultures in a clinical hematology unit].

GOAL: This study had for aim to analyze the epidemiology of strains identified in blood cultures (hôpital d'instruction des armées Percy, Clamart, France, hematology unit) to compare the rate of identified micro-organisms with literature data, and to search for a possible correlation between antibiotherapy management and evolution of resistance profiles. MATERIAL AND METHODS: All the micro-organisms (N = 690) collected over seven years (January 1996 to December 2002), from blood cultures of hospitalized patients in conventional and sterile sector were studied. RESULTS: Gram positive cocci rate (GPC) was 62.6% and Gram negative bacilli (GNB) 31.3%. Evolution in time showed a decrease of GPC and an increase of GNB, notably the non fermenting Gram negative bacilli, leading to an equal rate by 2001-2002. The most frequently identified species were Staphylococcus epidermidis (36.4%), Escherichia coli (8.7%), Pseudomonas aeruginosa (6.8%), and Staphylococcus aureus (4.9%). The rate of methicillin-resistant staphylococci was 63.6%. Fifty-five percent of E. coli strains had a penicillinase phenotype. Pseudomonas aeruginosa resistance was 8.5, 8.5, 6.4 and 8.5%, respectively for ceftazidime, piperacillin-tazobactam, imipenem, and amikacin. CONCLUSION: This study showed a tendency to inversion of former bacteremia epidemiology with increasing negative Gram bacilli. It justifies the antibiotherapy protocols adopted in the hematology unit.

Anti-Bacterial Agents↗
PubMed2006

Quantitative genetics of preference and performance on chickpeas in the noctuid moth, Helicoverpa armigera.

If a novel, resistant host-plant genotype arises in the environment, insect populations utilising that host must be able to overcome that resistance in order that they can maintain their ability to feed on that host. The ability to evolve resistance to host-plant defences depends upon additive genetic variation in larval performance and adult host-choice preference. To investigate the potential of a generalist herbivore to respond to a novel resistant host, we estimated the heritability of larval performance in the noctuid moth, Helicoverpa armigera, on a resistant and a susceptible variety of the chickpea, Cicer arietinum, at two different life stages. Heritability estimates were higher for neonates than for third-instar larvae, suggesting that their ability to establish on plants could be key to the evolution of resistance in this species; however, further information regarding the nature of selection in the field would be required to confirm this prediction. There was no genetic correlation between larval performance and oviposition preference, indicating that female moths do not choose the most suitable plant for their offspring. We also found significant genotype by environment interactions for neonates (but not third-instar larvae), suggesting that the larval response to different plant genotypes is stage-specific in this species.

Adaptation, Biological↗
PubMed2000

Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance.

Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response </=28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.

Antimalarials↗
PubMed2005

Genetic basis of resistance to Cry1Ac and Cry2Aa in Heliothis virescens (Lepidoptera: Noctuidae).

The development of pest resistance to transgenic crop plants producing insecticidal toxins from Bacillus thuringiensis Berliner (Bt) poses a major threat to their sustainable use in agriculture. "Pyramiding" two toxins with different modes of actions in the same plant is now being used to delay the evolution of resistance in the insects, but this strategy could fail if a single gene in a pest confers resistance to both toxins. The CP73 strain of the cotton pest Heliothis virescens (F.) is resistant to both Cry1Ac and Cry2Aa toxins from Bt. We explored the genetic basis of resistance in this strain with a backcross, split-family design. The gene with the largest effect on Cry1Ac resistance in CP73 (BtR-5) maps to linkage group 10 of H. virescens and thus differs from the previously described linkage group 9 BtR-4 resistance found in the YHD2 strain, involving mutation of the gene encoding a 12-domain cadherin-like binding target of the Cry1A toxins. Neither BtR-4 nor BtR-5 seems to confer significant resistance to Cry2Aa. A majority of the linkage groups studied in one backcross family made a small positive contribution to resistance for both toxins. Thus, the Cry2Aa resistance in CP73 is not caused by either of the two major Cry1Ac resistance-conferring genes but instead probably has a quantitative genetic basis.

Animals↗
PubMed2005

[Vancomycin-resistant Staphylococcus aureus].

The evolution and molecular mechanisms of vancomycin resistance in Staphylococcus aureus were reviewed. Case reports and research studies on biochemestry, electron microscopy and molecular biology of Staphylococcus aureus were selected from Medline database and summarized in the following review. After almost 40 years of successful treatment of S. aureus with vancomycin, several cases of clinical failures have been reported (since 1997). S. aureus strains have appeared with intermediate susceptibility (MIC 8-16 microg/ml), as well as strains with heterogeneous resistance (global MIC < or =4 microg/ml), but with subpopulations of intermediate susceptibility. In these cases, resistance is mediated by cell wall thickening with reduced cross linking. This traps the antibiotic before it reaches its major target, the murein monomers in the cell membrane. In 2002, a total vancomycin resistant strain (MIC > or =32 microg/ml) was reported with vanA genes from Enterococcus spp. These genes induce the change of D-Ala-D-Ala terminus for D-Ala-D-lactate in the cell wall precursors, leading to loss of affinity for glycopeptides. Vancomycin resistance in S. aureus has appeared; it is mediated by cell wall modifications that trap the antibiotic before it reaches its action site. In strains with total resistance, Enterococcus spp. genes have been acquired that lead to modification of the glycopeptide target.

Anti-Bacterial Agents↗
PubMed1999

[Cerebral panthrombophlebitis in a paucisymptomatic patient].

In most cases, extensive cerebral venous thrombosis present themselves with a severe clinical outcome and poor prognosis. We present the case of a 59-years-old patient with a slight rather unrevealing symptoms but suffering from a cerebral thrombosis impacting on both superficial and deep venous system. The etiologic assessment revealed activated protein C resistance. Clinical evolution under systemic anticoagulation was prompt, with complete repermeabilization of the various venous structures.

Activated Protein C Resistance↗
PubMed1999

Parasitism of Sympetrum dragonflies by Arrenurus planus mites: maintenance of resistance particular to one species.

Using field surveys and histological methods, we show that a dragonfly species (Sympetrum internum) has an effective resistance, not seen previously in other odonates, to a mite parasite (Arrenurus planus). This mite is a generalist parasite known to effectively engorge on several other odonate species. We argue that selection is likely weak, favouring counter adaptations of Arrenurus planus to Sympetrum internum, in part because other host species are available. We further argue that this pattern is possibly linked to the fact that the mode of resistance is relatively novel, and because Sympetrum internum is rare compared to another host species, Sympetrum obtrusum, at our study site. Although resistance of Sympetrum internum is quite effective against Arrenurus planus, Arrenurus planus larvae still attach to this species, but less often than they attach to Sympetrum obtrusum. Attachment to unsuitable hosts may reflect constraints operating on Arrenurus planus larvae during host discovery. Such factors influencing the evolution of resistance, when several potential host species exist, have not received much attention.

Animals↗
PubMed2005

Comment définir le potentiel de sélection de la résistance bactérienne aux antibiotiques ?

Evolution of bacterial resistance to antibiotics could be better controlled if we knew how to define the potential of evolution of bacterial resistance towards a given antibiotic, prospectively. No unique method allows to do it. Pieces of answers can be obtained by using diverse methods using bacteriological, ecological pharmaco-epidemiological techniques and experimental models. Association of the results obtained with these various techniques is mandatory to understand the evolution potential of resistance towards a given antibiotic when it is used in the clinical setting.

Journal Article↗