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PubMed2001

Will tuberculosis become resistant to all antibiotics?

The discovery of high prevalences of antibiotic resistance in some pathogens, in some parts of the world, has provoked fears of a widespread loss of drug efficacy. Here, we use a mathematical model to investigate the evolution of resistance to four major anti-tuberculosis drugs (isoniazid, rifampicin, ethambutol and streptomycin) in 47 sites around the world. The model provides a new method of estimating the relative risk of treatment failure for patients carrying drug-resistant strains and the proportion of patients who develop resistance after failing treatment. Using estimates of these two quantities together with other published data, we reconstructed the epidemic spread of isoniazid resistance over the past 50 years. The predicted median prevalence of resistance among new cases today was 7.0% (range 0.9-64.3%), close to the 6.3% (range 0-28.1%) observed. Predicted and observed prevalences of resistance to isoniazid plus rifampicin (multidrug-resistant or MDR-TB) after 30 years of combined drug use were also similar, 0.9% (0.1-5.9%) and 1.0% (range 0-14.1%), respectively. With current data, and under prevailing treatment practices, it appears that MDR-TB will remain a localized problem, rather than becoming a global obstacle to tuberculosis control. To substantiate this result, further measurements are needed of the relative fitness of drug-resistant strains.

Antitubercular Agents↗

PubMed1987

Co-adaptation of Escherichia coli and coliphage lambda vir in continuous culture.

Populations of the bacterium Escherichia coli and of its phage lambda vir appeared to equilibrate in continuous cultures. The bacterial end-populations were heterogeneous in respect of their resistance to lambda vir and their ability to utilize maltose. The most competitive of the selected bacteria were mutants which had a reduced rate of synthesis of lambda-receptor so as to become highly, but not totally, resistant to the phage. The coexisting phage had an increased affinity for the receptor and an altered antigenic specificity, suggesting adaptation of its adsorption site in response to the evolution of resistance in the bacteria.

Adaptation, Physiological↗

PubMed1983

Characterization of plasmids in aminocyclitol-resistant Staphylococcus aureus: electron microscopic and restriction endonuclease analysis.

Plasmid species isolated from aminocyclitol-resistant Staphylococcus aureus have been analyzed by restriction endonuclease digestion and electron microscopy. These plasmids can be divided into two interrelated groups; intergroup variability is due to the gain or loss of defined DNA sequences. Plasmids pSJ1 and pSJ24 are related to staphylococcal penicillinase plasmid pI524 which was first described over 20 years ago. Both pSJ1 and pSJ24 differ from pI524 by the acquisition of 8 and 4 kbp, respectively, and encode additional resistance to the antibiotics erythromycin and kanamycin. The gain of these resistance determinants suggests that the evolution of staphylococcal resistance plasmids parallels that observed for plasmids of gram-negative bacteria and has serious implications for the spread of antibiotic resistance among the staphylococci.

Aminoglycosides↗

PubMed2005

Human immunodeficiency virus mutagenesis during antiviral therapy: impact of drug-resistant reverse transcriptase and nucleoside and nonnucleoside reverse transcriptase inhibitors on human immunodeficiency virus type 1 mutation frequencies.

The development of antiviral drug resistance is an important problem in the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Potent antiretroviral therapy is currently used for treatment, and typically consists of at least two reverse transcriptase (RT) inhibitors. We have previously reported that both drugs and drug-resistant RT mutants can increase virus mutation frequencies. To further assess the contributions of nucleoside RT inhibitors (NRTIs), nonnucleoside RT inhibitors (NNRTIs), and drug-resistant RTs to HIV mutagenesis, a new high-throughput assay system was developed. This assay system was designed to specifically detect frameshift mutations in the luciferase gene in a single virus replication cycle. New drug-resistant RTs were identified that significantly altered virus mutation frequencies. Consistent with our previous observations of NRTIs, abacavir, stavudine, and zalcitabine increased HIV-1 mutation frequencies, supporting the general hypothesis that the NRTIs currently used in antiviral drug therapy increase virus mutation frequencies. Interestingly, similar observations were made with NNRTIs. This is the first report to show that NNRTIs can influence virus mutation frequencies. NNRTI combinations, NRTI-NNRTI combinations, and combinations of drug and drug-resistant RTs led to significant changes in the virus mutation frequencies compared to virus replication of drug-resistant virus in the absence of drug or wild-type virus in the presence of drug. This indicates that combinations of RT drugs or drugs and drug-resistant virus created during the evolution of drug resistance can act together to increase HIV-1 mutation frequencies, which would have important implications for drug therapy regimens. Finally, the influence of drug-resistant RT mutants from CRF01_AE viruses on HIV-1 mutation frequencies was analyzed and it was found that only a highly drug resistant RT led to altered virus mutation frequencies. The results further suggest that high-level drug-resistant RT can significantly influence virus mutation frequencies. A structural model that explains the mutation frequency data is discussed.

Anti-HIV Agents↗

PubMed2004

Can mutation and selection explain virulence in human P. falciparum infections?

BACKGROUND: Parasites incur periodic mutations which must ultimately be eliminated to maintain their genetic integrity. METHODS: It is hypothesised that these mutations are eliminated not by the conventional mechanisms of competition between parasites in different hosts but primarily by competition between parasites within the same infection. RESULTS: This process is enhanced by the production of a large number of parasites within individual infections, and this may significantly contribute to parasitic virulence. CONCLUSIONS: Several features of the most virulent human malaria parasite Plasmodium falciparum can usefully be re-interpreted in this light and lend support to this interpretation. More generally, it constitutes a novel explanation for the evolution of virulence in a wider range of microparasites.

Animals↗

PubMed2001

[Susceptibility of non-typhi Salmonella spp. at the Galdakao Hospital (1992-1998)].

Non-typhi Salmonella spp. are a common cause of gastroenteritis. In patients with a greater risk of bacteremia (those with immunosuppression, cardiovascular abnormalities, prostheses, those older than 50, especially those with atherosclerosis, and neonates) the need for antibiotic treatment may be affected by the presence of resistance. We retrospectively studied the evolution of antibiotic resistance of 917 strains isolated from feces, during the period between January 1992 and May 1998. Resistances of 32.1% to ampicillin, 14.6% to amoxicillin- clavulanic acid, 14.8% to chloramphenicol, 3.5% to trimethoprim-sulfamethoxazole and 1.8% to gentamicin were found. All the strains were susceptible to cefotaxime and ciprofloxacin. There was a distinct increase in the ampicillin resistance (12.9% in 1992 to 52.5% in 1998), amoxicillin-clavulanic acid (8.3% in 1992 to 23% in 1998), chloramphenicol (8.3% in 1994 to 23% in 1998) and trimethoprim-sulfamethoxazole (0% in 1992 to 6.6% in 1998). The typhimurium serotype showed higher resistance levels than the enteritidis serotype. Ciprofloxacin and trimethoprim-sulfamethoxazole (in children), used as first-choice antibiotics in patients with intestinal infections caused by non-typhi Salmonella spp., show excellent activity in our area.

Hospitals↗

PubMed2003

[Mechanism of carbapenems resistance in Acinetobacter baumannii].

OBJECTIVE: To investigate the mechanism of carbapenems resistance in Acinetobacter baumannii. METHODS: WHONET-5 software was used to analyze the trend of carbapenem resistance in Acinetobacter baumannii collected from 1999 to 2001 at Peking Union Medical College Hospital. Analytical isoelectric focusing was used to measure the pI of the beta-lactamase. Conjugation experiment was used to study the transfer of carbapenem resistance and plasmid DNA was extracted and purified with Qiagen Plasmid Mini Kit. The homology of the isolates was determined by pulsed field gel electrophoresis (PFGE). Integrase genes and blaIMP-, blaVIM-, blaOXA- genes for resistant isolates were amplified and sequenced. RESULTS: Imipenem resistance in A. baumannii was ranged from 1.8%-8.5%, but only 9 resistant isolates were viable. They were co-resistant to other carbapenems, ceftazidime, aztreonam, and gentamicin, and four isolates were resistant to ciprofloxacin. Impipenem resistance could not be transferred to susceptible strains. No plasmid was extracted. Each isolate produced TEM-1, AmpC, and two enzymes (pI 6.7, 6.0), which can not be inhibited by cloxacillin and clavulanic acid. Each isolate had class I intergase gene. Nine isolates were all negative for PCR of blaIMP- and blaVIM- genes, but positive for blaOXA-23 specific PCR. Sequencing found 100% homology with blaOXA-23. PFGE found 3 clones (A type: 5 isolates; B type: 3 isolates; C type: 1 isolate). Control isolates (imipenem-susceptible, but ceftazidime, ciprofloxacin, and gentamicin resistant) were also A clone. CONCLUSIONS: Production of OXA-23 carbapenemase in A. baumannii was one of the main mechanisms of carbapenems resistance at our hospital. It brings concern that imipenem-resistant clone has evoluted from nosocomial multiple-resistant strains.

Acinetobacter baumannii↗

PubMed1995

[In vitro activity of carbapenems (biapenem, imipenem and meropenem) and some other antibiotics against strict anaerobic bacteria].

During 1994, the in vitro antibiotic susceptibility of 306 anaerobic bacteria was performed in 4 hospitals, by the reference agar dilution method. Among the 129 B. fragilis group strains, only two B. fragilis strains were resistant to the three carbapenems and all beta-lactams, even combined with beta-lactamase-inhibitors while metronidazole resistance could not be detected. Evolution in antibiotic resistance rates could be assessed only for piperacillin whose resistance rates increased to 20%. beta-lactamase production was detected respectively for 27% of Prevotella and 17% of Fusobacterium strains. No beta-lactamase activity was seen among Gram positive anaerobes. On the whole anaerobic strains resistance rates were: biapenem, imipenem, meropenem and piperacillin-tazobactam 0.7, amoxicillin-clavulanic acid or metronidazole 2, piperacillin 11.3, amoxicillin 31%, respectively. The three carbapenems demonstrated a good in vitro activity against most anaerobes with few differences between them.

Bacteroides fragilis↗

PubMed1994

[Susceptibility of strict anaerobic bacteria to antibiotics in France: a multicenter study].

During 1992, the in vitro antibiotic susceptibility of 462 anaerobic bacteria was performed in 7 hospitals, by the reference agar dilution method. Among the 222 Bacteroides fragilis group strains, only one Bacteroides fragilis strain was resistant to imipenem and all bêtalactams, even combined with bêtalactamase-inhibitors while metronidazole resistance could not be detected. One major outer membrane protein (probably a porin) was lacking in some of the six amoxicillin-clavulanic acid resistant Bacteroides fragilis group strains. Evolution in antibiotic resistance rates could be assessed only for clindamycin and piperacillin whose resistance rates increased to 14 and 15.8 p. cent, respectively. On the whole anaerobic strains resistance rates were: imipenem 0.2, ticarcillin-clavulanic acid 0.5, amoxicillin-clavulanic acid or metronidazole 1.5, piperacillin 9.1, cefotaxime-sulbactam 9.7, cefoxitin 12.8, clindamycin 13.7, cefotaxime 27.2, amoxicillin 45 and ciprofloxacin 70, respectively.

Anti-Bacterial Agents↗

PubMed2005

Delayed resistance to transgenic cotton in pink bollworm.

Transgenic crops producing Bacillus thuringiensis (Bt) toxins kill some key insect pests and thus can reduce reliance on insecticides. Widespread planting of such Bt crops increased concerns that their usefulness would be cut short by rapid evolution of resistance to Bt toxins by pests. Pink bollworm (Pectinophora gossypiella) is a major pest that has experienced intense selection for resistance to Bt cotton in Arizona since 1997. We monitored pink bollworm resistance to Bt toxin for 8 years with laboratory bioassays of strains derived annually from 10-17 cotton fields statewide. Bioassay results show no net increase from 1997 to 2004 in the mean frequency of pink bollworm resistance to Bt toxin. A synthesis of experimental and modeling results suggests that this delay in resistance can be explained by refuges of cotton without Bt toxin, recessive inheritance of resistance, incomplete resistance, and fitness costs associated with resistance.

Animals↗

PubMed2005

Stochastic modeling of drug resistance in cancer.

One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. Employing multi-drug therapeutic strategies is a promising way to prevent resistance and improve the chances of treatment success. We formulate and analyse a stochastic model for multi-drug resistance and investigate the dependence of treatment outcomes on the initial tumor load, mutation rates and the turnover rate of cancerous cells. We elucidate the general principles of the emergence and evolution of resistant cells inside the tumor, before and after the start of treatment. We discover that for non-mutagenic drugs, pre-existence contributes more to resistance generation than the treatment phase; this result holds for the case where all drugs are applied simultaneously, and is not applicable for sequential therapy models. The application of mathematical modelling to aspects of adjuvant chemotherapy scheduling. J. Math. Biol. 48(4), 375-422]. Also, we find that treatment success is independent on the turnover rate for one drug, and it depends strongly on it for multi-drug therapies. For low-turnover rates, increasing the number of drugs will increase the probability of successful therapy. For very high-turnover rates, increasing the number of drugs used does not significantly increase the chances of treatment success.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Evolution of antiretroviral phenotypic and genotypic drug resistance in antiretroviral-naive HIV-1-infected children treated with abacavir/lamivudine, zidovudine/lamivudine or abacavir/zidovudine, with or without nelfinavir (the PENTA 5 trial).

PURPOSE AND METHODS: To describe the evolution of resistance to zidovudine (ZDV), lamivudine (3TC), abacavir (ABC) and nelfinavir (NFV), 113 previously untreated children in the PENTA 5 trial had resistance assayed at baseline, rebound and/or 24, 48, 72 weeks (VIRCO: phenotyping and genotyping with 'Virtual Phenotype' interpretation). RESULTS: At baseline, few reverse transcriptase mutations and no primary protease inhibitor mutations were observed. Time to detectable HIV-1 RNA with reduced phenotypic susceptibility to any drug was shortest in the ZDV+3TC arm (overall logrank P=0.02). Through a median follow-up of 55 weeks, at their last assessment 11 (28%), 16 (40%) and 13 (32%) children with detectable HIV-1 RNA and a resistance test available had mutations conferring resistance to none, one, or two or more trial drugs, respectively, according to the virtual phenotype. Reduced phenotypic susceptibility to ABC only occurred in the 3TC+ABC arm and required K65R and/or L74V in addition to M184V. NFV-resistant virus was selected slowly through D30N or L90M pathways, and selection of ZDV-resistant virus was rare. CONCLUSIONS: Selection of 3TC-resistant virus was most frequent, followed by NFV and/or ABC; selection of ZDV-resistant virus was rare. Importantly, although in vitro, ABC selects for M184V as the first mutation, ABC did not select for M184V when combined with ZDV without 3TC. The most sustained HIV-1 RNA response was in the 3TC+ABC arm, but mutations conferring reduced susceptibility to 3TC and/or ABC evolved more frequently if virological failure occurred with 3TC+ABC than with ZDV+ABC.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Cytochrome b gene structure and consequences for resistance to Qo inhibitor fungicides in plant pathogens.

The cytochrome b (cyt b) gene structure was characterized for different agronomically important plant pathogens, such as Puccinia recondita f sp tritici (Erikss) CO Johnston, P graminis f sp tritici Erikss and Hennings, P striiformis f sp tritici Erikss, P coronata f sp avenae P Syd & Syd, P hordei GH Otth, P recondita f sp secalis Roberge, P sorghi Schwein, P horiana Henn, Uromyces appendiculatus (Pers) Unger, Phakopsora pachyrhizi Syd & P Syd, Hemileia vastatrix Berk & Broome, Alternaria solani Sorauer, A alternata (Fr) Keissl and Plasmopara viticola (Berk & Curt) Berlese & de Toni. The sequenced fragment included the two hot spot regions in which mutations conferring resistance to QoI fungicides may occur. The cyt b gene structure of these pathogens was compared with that of other species from public databases, including the strobilurin-producing fungus Mycena galopoda (Pers) P Kumm, Saccharomyces cerevisiae Meyer ex Hansen, Venturia inaequalis (Cooke) Winter and Mycosphaerella fijiensis Morelet. In all rust species, as well as in A solani, resistance to QoI fungicides caused by the mutation G143A has never been reported. A type I intron was observed directly after the codon for glycine at position 143 in these species. This intron was absent in pathogens such as A alternata, Blumeria graminis (DC) Speer, Pyricularia grisea Sacc, Mycosphaerella graminicola (Fuckel) J Schröt, M fijiensis, V inaequalis and P viticola, in which resistance to QoI fungicides has occurred and the glycine is replaced by alanine at position 143 in the resistant genotype. The present authors predict that a nucleotide substitution in codon 143 would prevent splicing of the intron, leading to a deficient cytochrome b, which is lethal. As a consequence, the evolution of resistance to QoI fungicides based on G143A is not likely to evolve in pathogens carrying an intron directly after this codon.

Amino Acid Substitution↗

PubMed1986

Niche expansion in bacteria: can infectious gene exchange affect the rate of evolution?

Recombination occurs by infectious gene transfer in bacteria, at rates much lower than recombination by sexual reproduction in other organisms. Thus, recombination may accelerate evolution in bacteria only under restricted conditions, such as occur when mutations at several loci are required for the evolution of an expanded ecological niche. Mathematical ("chemostat") models of several such cases--evolution of independence from three limiting essential or "interactive-essential" resources; evolution of the ability to use three new substitutable resources; and evolution of resistance to three growth inhibitors--were analyzed by computer simulation. All combinations of three mutation rates (U) and four values for the "infectious gene transfer rate parameter" (chi) were considered. Recombination accelerated evolution most when U was low and chi was high, but was unlikely to have large effects when chi was low enough to be realistic for natural populations of Escherichia coli. Recombination had the largest effects when resources were substitutable, and in that case could have substantially reduced the chance of random loss of the favored "triple mutant" while it was still rare. The simulations also revealed some interesting features of selection for an expanded niche. Evolution of independence from essential resources occurred more rapidly when the resources were weakly complementary than when they did not interact. Selection for the ability to use all substitutable resources was weak after all intermediate types that used only one or two of the resources had arisen.

Anti-Bacterial Agents↗

PubMed2004

Continued production of drug-sensitive human immunodeficiency virus type 1 in children on combination antiretroviral therapy who have undetectable viral loads.

Highly active antiretroviral therapy (HAART) can suppress plasma human immunodeficiency virus type 1 (HIV-1) levels to below the detection limit of ultrasensitive clinical assays. However, HIV-1 persists in cellular reservoirs, and in adults, persistent low-level viremia is detected with more sensitive assays. The nature of this viremia is poorly understood, and it is unclear whether viremia persists in children on HAART, particularly those who start therapy shortly after birth. We therefore developed a reverse transcriptase PCR (RT-PCR) assay that allows genotyping of HIV-1 protease even when viremia is present at levels as low as 5 copies of HIV-1 RNA/ml. We demonstrated that viremia persists in children with plasma virus levels below the limit of detection of clinical assays. Viremia was detected even in children who began HAART in early infancy and maintained such strong suppression of viremia that HIV-1-specific antibody responses were absent or minimal. The low-level plasma virus lacked protease inhibitor resistance mutations despite the frequent use of nelfinavir, which has a low mutational barrier to resistance. Protease sequences resembled those of viruses in the latent reservoir in resting CD4(+) T cells. Thus, in most children on HAART with clinically undetectable viremia, there is continued virus production without evolution of resistance in the protease gene.

Acute Disease↗

PubMed1995

[Phenotypes of resistance to antibiotics of the most frequently isolated strains in five specialized hospital centers. Multicenter study].

Antibiotic susceptibility of 948 bacterial strains isolated from varied samples essentially proceeding from urinary infections in five Paris psychiatric Hospitals was determined by disk diffusion method. E. coli, P. mirabilis, Klebsiella spp., P. aeruginosa et S. aureus are the predominant bacteria. 40% of S. aureus are methicilline resistant. Enterobacteriaceae are progressively becoming resistant to aminopenicillines, but remain sensitive to third generation cephalosporines. They are still susceptible to first generation quinolones. At least, if no resistance of P. aeruginosa to imipeneme has been reported, 30% of strains are resistant to ciprofloxacine. Resistance phenotypes to antibiotics of the strains isolated in patients from psychiatric Hospitals are located between those observed in out patients and in patients from general Hospitals. However, we noticed a worrying evolution of resistance to those encontered in psychiatric Hospitals. Therefore, a multiresistant strains emergence monitoring must be carried out regulary.

4-Quinolones↗

PubMed2003

Arsenic resistance in the archaeon "Ferroplasma acidarmanus": new insights into the structure and evolution of the ars genes.

Arsenic resistance in the acidophilic iron-oxidizing archaeon " Ferroplasma acidarmanus" was investigated. F. acidarmanus is native to arsenic-rich environments, and culturing experiments confirm a high level of resistance to both arsenite and arsenate. Analyses of the complete genome revealed protein-encoding regions related to known arsenic-resistance genes. Genes encoding for ArsR (arsenite-sensitive regulator) and ArsB (arsenite-efflux pump) homologues were found located on a single operon. A gene encoding for an ArsA relative (anion-translocating ATPase) located apart from the arsRB operon was also identified. Arsenate-resistance genes encoding for proteins homologous to the arsenate reductase ArsC and the phosphate-specific transporter Pst were not found, indicating that additional unknown arsenic-resistance genes exist for arsenate tolerance. Phylogenetic analyses of ArsA-related proteins suggest separate evolutionary lines for these proteins and offer new insights into the formation of the arsA gene. The ArsB-homologous protein of F. acidarmanus had a high degree of similarity to known ArsB proteins. An evolutionary analysis of ArsB homologues across a number of species indicated a clear relationship in close agreement with 16S rRNA evolutionary lines. These results support a hypothesis of arsenic resistance developing early in the evolution of life.

Amino Acid Sequence↗

PubMed2005

A model of antibiotic-resistant bacterial epidemics in hospitals.

The emergence of drug-resistant strains of bacteria is an increasing threat to society, especially in hospital settings. Many antibiotics that were formerly effective in combating bacterial infections in hospital patients are no longer effective because of the evolution of resistant strains, which compromises medical care worldwide. In this article, we formulate a two-level population model to quantify key elements in nosocomial (hospital-acquired) infections. At the bacteria level, patients infected with these strains generate both nonresistant and resistant bacteria. At the patient level, susceptible patients are infected by infected patients at rates proportional to the total bacteria load of each strain present in the hospital. The objectives of this paper are to analyze the dynamic elements of nonresistant and resistant bacteria strains in epidemic populations in hospital environments and to provide understanding of measures to avoid the endemicity of resistant antibiotic strains.

Bacterial Infections↗