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PubMed2003

Antimicrobial formularies: can they minimize antimicrobial resistance?

The relationship between antimicrobial drug use and resistance rates and the implications for antimicrobial formularies are described. Efforts to restrict antimicrobial drug use to reduce resistance in certain microorganisms have been accompanied by increases in resistance in other microorganisms. Random cycling of a variety of antimicrobial agents to treat infections caused by the same microorganism in different patients within a health care institution has been advocated as a means to reduce antimicrobial resistance. Analysis of actual antimicrobial drug use and resistance data from a network of 40 hospitals revealed wide variability in antimicrobial use. The specific type and volume of antimicrobial agents used appear to play key roles in determining resistance rates. It may be feasible to optimize diversity in antimicrobial drug use and minimize resistance by making judicious changes to the antimicrobial formulary.

Anti-Infective Agents↗

PubMed2007

Relationship between antimicrobial drug usage and antimicrobial susceptibility of gram-positive mastitis pathogens.

The objective of this study was to analyze relationships between usage of antimicrobial drugs on dairy farms and results of antimicrobial susceptibility testing of mastitis pathogens. Exposure to selected antimicrobial drugs (n = 10) was standardized by calculation of the number of defined daily doses used per cow. Farms (n = 40) were categorized based on amount of antimicrobial exposure: organic (no usage); conventional-low usage (conventional farms not using or using less than or equal to the first quartile of use of each compound); and conventional-high usage (conventional farms using more than the first quartile of a particular compound). The minimum inhibitory concentration (MIC) of selected antimicrobial drugs was determined using a commercial microbroth dilution system for isolates of Staphylococcus aureus (n = 137), coagulase-negative staphylococci (CNS, n = 294), and Streptococcus spp. (n = 95) obtained from subclinical mastitis infections. Most isolates were inhibited at the lowest dilution tested of most antimicrobial drugs. Survival curves for Staph. aureus and CNS demonstrated heterogeneity in MIC based on the amount of exposure to penicillin and pirlimycin. For CNS, farm type was associated with the MIC of ampicillin and tetracycline. For Streptococcus spp., farm type was associated with MIC of pirlimycin and tetracycline. For all mastitis pathogens studied, the MIC of pirlimycin increased with increasing exposure to defined daily doses of pirlimycin. The level of exposure to most other antimicrobial drugs was not associated with MIC of mastitis pathogens. A dose-response effect between antimicrobial exposure and susceptibility was observed for some pathogen-antimicrobial combinations, but exposure to other antimicrobial drugs commonly used for prevention and treatment of mastitis was not associated with resistance.

Animals↗

PubMed2026

Evaluation of Oxford nanopore sequencing for antimicrobial resistance surveillance in Salmonella: comparison with phenotypic antimicrobial susceptibility in a large-scale study.

UNLABELLED: Salmonella is a major zoonotic foodborne pathogen, and antimicrobial resistance (AMR) in Salmonella presents a significant public health challenge. Compared with conventional antimicrobial susceptibility testing (AST), whole-genome sequencing (WGS) provides a more rapid and comprehensive approach to AMR characterization, thereby informing antimicrobial selection and supporting public health surveillance. In this study, Oxford Nanopore Technology (ONT)-based WGS was performed on 1,490 Salmonella isolates collected through nationwide surveillance in Taiwan in 2025. Genotypic resistance inferred from WGS data was compared with phenotypic AST results to assess the performance of ONT-WGS. Overall, WGS-inferred resistance showed high concordance with phenotypic resistance for most antimicrobials. However, major genotype-phenotype discordance was observed, attributed to four categories: (i) breakpoint-dependent classification, (ii) reduced or absent phenotypic expression of resistance genes, (iii) minimum inhibitory concentration (MIC) modulation by ramAp, and (iv) absence of known AMR determinants. Notable discrepancies included tigecycline resistance without known genetic determinants, nalidixic acid resistance linked to ramAp-mediated MIC elevation, and a high prevalence of colistin resistance (35.7%) in S. Enteritidis, with most resistant isolates lacking identifiable AMR determinants. Additionally, a significant proportion of ESBL- and AmpC-producing isolates were classified as susceptible or intermediate to cefotaxime and ceftazidime under CLSI criteria, highlighting the potential for misclassification and treatment failure. These findings demonstrate that ONT-WGS enables accurate and comprehensive AMR characterization by directly identifying resistance determinants and avoiding potential misclassification associated with breakpoint-based AST interpretations. When interpreted appropriately, WGS can support better antimicrobial selection and serve as a valuable alternative to conventional susceptibility testing. IMPORTANCE: Accurate prediction of antimicrobial resistance is essential for appropriate therapy and effective surveillance of Salmonella. However, discordance between genotype-based predictions and phenotypic antimicrobial susceptibility testing (AST) can complicate clinical interpretation. In this nationwide study of 1,490 Salmonella isolates, we show that Oxford Nanopore Technology-based whole-genome sequencing (ONT-WGS) provides rapid and comprehensive detection of antimicrobial resistance determinants with high concordance to phenotypic AST. We further identify four major mechanisms underlying genotype-phenotype discordance, including breakpoint-dependent classification, reduced or absent phenotypic expression of resistance genes, minimum inhibitory concentration (MIC) modulation by ramAp, and the absence of known AMR determinants. These findings demonstrate how WGS can complement conventional AST, improve interpretation of challenging susceptibility results, and strengthen genomic surveillance of emerging antimicrobial-resistant Salmonella.

Microbial Sensitivity Tests↗

PubMed2004

Computerized antimicrobial decision support: an offline evaluation of a database-driven empiric antimicrobial guidance program in hospitalized patients with a bloodstream infection.

INTRODUCTION: We developed a computerized antimicrobial guidance program based on the last 5 years of our laboratory culture data augmented by expert infectious disease logic. The program is designed to assist physicians with the targeting of empiric antimicrobials for hospitalized patients by tracking pathogenic bacteria and their evolving antimicrobial resistance profiles. Costs, toxicities, and environmental impact of antimicrobial use also influence the final recommendations. We undertook the following analysis to verify its potential safety and efficacy in hospitalized patients with a bloodstream infection. METHODS: We retrospectively enrolled all inpatients with a positive blood culture for a previously undetermined pathogen during the first 6 months of 2002 and determined the empiric therapy initiated within the 12h before and after the time of culture. Antimicrobial recommendations from the microbiologic decision support tool were then determined by matching specimen (blood), hospital unit, community- versus hospital-acquired category, age category, and gender. Generated antimicrobial recommendations were tailored to patient allergies, age category, and presence of pregnancy, lactation, or hepatic impairment. RESULTS: The microbiology laboratory recorded 226 unique patient/pathogen blood cultures during the study period. Physicians initiated effective empiric therapy in 150 of the 226 cases, for an effectiveness rate of 66%. The computer-guided therapy was effective in 195 of the 226 cases for a rate of 86%. A contingency table analysis showed 55 cases where the computer recommendation was effective but the physicians' selection was not, and eight cases where the physicians' antimicrobials were effective but the computer's were not (P < 0.0001). DISCUSSION: For patients with a bloodstream infection, we found that our computer-guided statistically-derived antimicrobial therapy would potentially improve the rate of effectiveness of empirically chosen antimicrobials.

Anti-Bacterial Agents↗

PubMed2006

[Surveillance of antimicrobial resistance and antimicrobial use in a university-affiliated hospital: implementation of a computerized system].

UNLABELLED: After half a century of antibiotic use, the increasing problem of the emergence and spread of antimicrobial-resistant pathogens has created a problem of public health. The causes of this problem are multifactorial, but the excessive and inappropriate use of antimicrobials is the principal cause. The current guidelines for the control of antimicrobial resistance in hospitals recommend the implementation of a surveillance system of antimicrobial use and antimicrobial resistance data. AIM OF THE STUDY: The objective of our project was to develop a computerised tool to survey the antibiotic consumption data and the antimicrobial resistance. MATERIALS AND METHODS: We have collected antimicrobial resistance data from the software of the bacteriology laboratory, antibiotic use data from the pharmacy and demographical data from the hospital's admission department. These data were integrated in a database server and available with a web application. Antimicrobial resistance data of 15 major microorganisms were extracted and expressed as a frequency with elimination of repeats by using time criteria (7, 14 or 28 days). Antibiotic use data were converted into defined daily doses (DDD) and expressed per 1000 patient-days. RESULTS: Data are available for consultation in the form of tables or graphs per unit, type of units (medicine, surgery, pediatrics, intensive care units) or in the whole hospital. The system allows the confrontation on the same graph of antimicrobial resistance and antibiotic use data. CONCLUSION: Our surveillance system constitutes a needed prerequisite to the implementation of a global strategy of antibiotic use improvement in our hospital.

Anti-Infective Agents↗

PubMed2004

Antimicrobial use in agriculture: controlling the transfer of antimicrobial resistance to humans.

Salmonella and Campylobacter infections occur commonly in children. Some of these infections are severe, requiring treatment with antimicrobial agents. Many classes of antimicrobial agents that are used in humans also are used in food animals for growth promotion, disease prevention, and therapy. The use of such antimicrobial agents in food animals increases the likelihood that human bacterial pathogens that have food animal reservoirs, such as Salmonella or Campylobacter, will develop cross-resistance to drugs approved for use in human medicine. Resistance determinants also may be transmitted from food animals to humans through the food supply with bacteria that usually are commensal, such as Escherichia coli and enterococci. Clinicians should be aware that antimicrobial resistance is increasing in food-borne pathogens and that patients who are taking antimicrobial agents for any reason are at increased risk for acquiring antimicrobial-resistant food-borne infections. Several European countries have demonstrated that restricting the use of antimicrobial agents in food animals can be followed by a decrease in antimicrobial resistance in humans without compromising animal health or significantly increasing the cost of production. Appropriate use of antimicrobial agents in humans and food animals is an important factor in maintaining their effectiveness.

Animal Feed↗

PubMedDate not supplied

Improving antimicrobial use: longitudinal assessment of an antimicrobial team including a clinical pharmacist.

BACKGROUND: Inappropriate antimicrobial utilization in hospitalized patients has been associated with adverse effects, emergence of resistant bacteria, and increased health care cost. Participation of clinical pharmacists, working as an integral part of a hospital antimicrobial management team (AMT), has been shown to improve antimicrobial use; however, the long-term impact of such a team on antimicrobial use is unclear. OBJECTIVE: Our primary objective was to evaluate whether the number of recommendations to improve antimicrobial use made by a hospital AMT decreased over time. Our secondary objective was to identify and evaluate the acceptance of AMT recommendations with respect to the clinical service, site of infection, and category of suboptimal use. METHODS: We retrospectively reviewed antimicrobial utilization data collected by the team for the 3-year period from July 1996 to June 1999 at the Veterans Affairs Medical Center in Louisville, Kentucky. The total number of antimicrobial treatment episodes and the number of recommendations were grouped into periods of 6 months each during the 3 years. The type of recommendation, type of infection, and clinical service (medicine versus surgery) were reviewed for the entire 3-year period. RESULTS: The number of antimicrobial treatment episodes for each of the 6-month consecutive periods was 404, 526, 406, 549, 507, and 612. The proportion of episodes requiring team recommendations was constant over the 5 consecutive periods: 39%, 37%, 36%, 36%, 35%, and 37%. (P = 0.8). Acceptance rates of AMT recommendations by the internal medicine and general surgery services remained stable over the length of the study, 84% and 69%, respectively. The distribution of patients treated by the site of infection also remained stable over the study period. CONCLUSION: Our results demonstrate that despite the long-term presence of an AMT, the proportion of antimicrobial episodes requiring intervention and the percentage of accepted recommendations remained constant over a 3-year period. Having new resident physicians in teaching hospitals or staff turnover in managed care organizations may necessitate the continued presence of an active AMT.

Anti-Infective Agents↗

PubMed1997

The impact of antimicrobial use on the emergence of antimicrobial-resistant bacteria in hospitals.

Abundant evidence suggests a relationship between antimicrobial resistance and use, including models, consistent associations between resistance and antimicrobial use in hospitals, concomitant variation in resistance as antimicrobial use varies, and a dose-response relationship for many pathogen/antimicrobial combinations. Much of the evidence is from studies performed in single hospitals. Most multicenter studies on resistance have not included data on antimicrobial usage. Despite this substantial body of evidence, some studies have not demonstrated an association between antimicrobial resistance and use, suggesting other contributing factors such as cross transmission, interhospital transfer of resistance, a community contribution to resistance, or a complex relationship between resistance and the use of a variety of antimicrobials. Understanding the problem of antimicrobial resistance in a hospital cannot be achieved without knowledge of the hospital's pattern of antimicrobial use.

Anti-Bacterial Agents↗

PubMed2002

Analysis of antimicrobial resistance among gram-negative bacilli and antimicrobial use in intensive care unit patients for 5 years in a Veterans Affairs medical center.

BACKGROUND: Gram-negative bacilli antimicrobial resistance remains a significant problem for patients in the intensive care unit (ICU). Patterns of antimicrobial use may be a contributing factor. METHODS: Gram-negative bacilli from ICU patients of a Veterans Affairs (VA) medical center were tested to determine in vitro antimicrobial susceptibility (205 isolates in 1995 and 209 in 1999). Antimicrobial use was calculated from 1995 through 1999. RESULTS: For Pseudomonas aeruginosa, significant declines in susceptibility to ciprofloxacin (medical ICU [MICU] individually and all units) and aztreonam (all units) were noted. For gram-negative bacilli that was non-P aeruginosa, significant increases in susceptibility to ceftazidime (MICU, surgical ICU, and all units), gentamicin (all units), and ticarcillin/clavulanate (MICU) were noted. The most notable trends in antimicrobial usage were sharp increases in fluoroquinolone use in the MICU and surgical ICU and substantial decreases in the use of third-generation cephalosporins, monobactams, and aminoglycosides. In each instance of significant change in the susceptibility of a group of organisms to an antibiotic, there was a corresponding inverse change in the use of the antibiotic and/or its antimicrobial category (except for aztreonam). CONCLUSIONS: Significant changes in antimicrobial use may affect certain gram-negative bacilli antimicrobial susceptibilities in ICUs.

Anti-Bacterial Agents↗

PubMed2006

Antimicrobial drug utilisation in Dunedin Hospital, New Zealand, and its association with antimicrobial resistance.

INTRODUCTION: Antimicrobial resistance (AR) to a drug can be considered a natural response to the selection pressure of that drug, with over prescribing being one of the major causes. Few investigations have evaluated the relationships between antimicrobial drug use in a hospital and antimicrobial resistance. METHOD AND MATERIALS: Antimicrobial drug utilisation (AU) data were collated for Dunedin Hospital, New Zealand, and expressed as defined daily doses per 1000 patient days according to the World Health Organization's definition. The drug groups studied were glycopeptides, carbapenems, third and fourth generation cephalosporins and fluoroquinolones. Antibiograms were also analysed and possible associations between antimicrobial utilisation and resistance were investigated. The reduction of antimicrobial utilisation has also been explored by various means. RESULTS: The utilisation of fluoroquinolones at Dunedin Hospital was high compared with hospitals in South Australia, increasing from 1999 to 2003 then decreasing in 2004 and 2005. The Spearman rank correlation coefficients for the associations between fluoroquinolone utilisation and resistance to ciprofloxacin were: rs = 0.79, p = 0.06 for Pseudomonas aeruginosa and rs = -0.37, p = 0.5 for Escherichia coli. CONCLUSION: The findings of antimicrobial drug utilisation studies in hospital can serve to describe the pattern of drug use in the institution, to detect areas of concern, and to evaluate the impact of interventions taken to influence the use of drugs, especially when this use is associated with increasing antimicrobial drug resistance.

Anti-Bacterial Agents↗

PubMed2004

Antimicrobial use and the influence of inadequate empiric antimicrobial therapy on the outcomes of nosocomial bloodstream infections in a neonatal intensive care unit.

OBJECTIVE: To evaluate antimicrobial use and the influence of inadequate empiric antimicrobial therapy on the outcomes of nosocomial bloodstream infections (BSIs). DESIGN: Prospective cohort study with nested case-control analysis. SETTING: Neonatal intensive care unit (NICU). METHODS: All patients weighing 2,000 g or less were enrolled. Data collection included risk factors for nosocomial BSI, admission severity of illness, microbiology, antimicrobial therapy, and outcomes. Inadequate empiric antimicrobial therapy was defined as the use of antibiotics for more than 48 hours after the day that blood cultures were performed that did not cover the microorganisms causing the bacteremia or administration of antibiotics that failed to cover resistant microorganisms. RESULTS: Two hundred twenty-nine patients were enrolled. Forty-five developed nosocomial BSIs. The BSI rates were 11.2, 2.8, and 0 per 1,000 catheter-days for patients weighing 1,000 g or less, between 1,001 and 1,500 g, and between 1,501 and 2,000 g, respectively. After adjustment for severity of illness, the mortality in patients with nosocomial BSI receiving inadequate empiric antimicrobial therapy was higher than in those receiving adequate therapy (adjusted odds ratio [AOR], 5.3; 95% confidence interval [CI95], 1.2-23.2). By multivariate analysis, nosocomial BSI attributed to Candida species (AOR, 6.3; CI95, 1.4-28.0) and invasive procedure prior to onset of BSI (AOR, 6.4; CI95, 1.0-39.0) were associated with administration of inadequate empiric antimicrobial therapy. CONCLUSIONS: Administration of inadequate empiric antimicrobial therapy among NICU patients with nosocomial BSI was associated with higher mortality. Additional studies on the role of inadequate empiric antimicrobial therapy and the outcomes of BSIs among NICU patients are needed.

Anti-Infective Agents↗

PubMed2000

Economic justification of antimicrobial management programs: implications of antimicrobial resistance.

The relationship between the problem of antimicrobial resistance and efforts to control antimicrobial costs is explored. Antimicrobial drug management typically centers around controlling costs and controlling antimicrobial resistance. Selection of therapeutic alternatives without adherence to a well-developed program or without a rationale based on data from the medical literature may promote antimicrobial resistance. Attempts to select alternatives can produce cost shifting rather than cost containment. The annual cost associated with antimicrobial resistance in the United States is estimated to be as high as $47 billion. In one study, patients with bacteremia caused by methicillin-resistant Staphylococcus aureus had an average length of stay 2.7 days longer than patients with susceptible strains and a mean cost of care that was $3500 higher. Infection control is one of the most important duties of health care practitioners. Given today's prevailing reimbursement structure, hospitals with high rates of nosocomial and resistant infections are likely to lose money. A basic problem with the current approach to controlling resistance is that the two most common strategies, highly restrictive formularies and drug cycling, work in opposition. Antimicrobial management programs should be directed at ensuring the most appropriate use of antimicrobials rather than focusing on limiting choices.

Anti-Bacterial Agents↗

PubMed1995

Structural and charge requirements for antimicrobial and hemolytic activity in the peptide PKLLETFLSKWIG, corresponding to the hydrophobic region of the antimicrobial protein bovine seminalplasmin.

Several analogs of the 13-residue antimicrobial and hemolytic peptide PKLLETFLSKWIG (SPF), which is the most hydrophobic region of the 47-residue antimicrobial protein seminalplasmin [Sitaram, N. & Nagaraj, R. (1990) J. Biol. Chem. 265, 10438-10442] have been synthesized. The antimicrobial and hemolytic properties of the peptides were investigated with a view to gain a insight into the structural and charge requirements for these activities of SPF. Peptides in which E was replaced by K exhibited considerably improved antimicrobial activity with no concomitant increase in hemolytic activity. A peptide in which the aromatic amino acids were replaced by leucine exhibited antimicrobial activity like those of the peptides which had aromatic amino acids. Interchange in the positions of E and K and total replacement of K by E resulted in complete loss of activity. The peptides having antimicrobial activity like those of the peptides which had aromatic amino acids. Interchange in the positions of E and K and total replacement of K by E resulted in complete loss activity. The peptides having antimicrobial activities showed appreciable helical content in a hydrophobic environment, whereas inactive peptides did not. Thus, by suitable 'engineering' the biological activity of a short 13-residue peptide can be altered by yield peptides specifically having only antimicrobial activity with increased potency.

Amino Acid Sequence↗

PubMed2000

In vitro antimicrobial susceptibilities of three Porphyromonas spp and in vivo responses in the oral cavity of cats to selected antimicrobial agents.

OBJECTIVES: To determine in vitro susceptibility of Porphyromonas gingivalis, P salivosa and P circumdentaria to seven antimicrobial agents by agar dilution and Epsilometer test methods and to assess the effectiveness of these antimicrobial agents in reducing the numbers of each Porphyromonas spp in the oral cavity of 16 domestic cats. DESIGN: A two-part prospective study involving in vitro antimicro-bial studies using Porphyromonas spp obtained from naturally occurring feline infections and in vivo antimicrobial response studies using client-owned cats with naturally occurring periodontal disease. PROCEDURE: Isolates (n = 25) of three feline Porphyromonas spp from the oral cavity and oral-associated disease were tested for their in vitro susceptibility to amoxycillin, amoxycillin-clavulanate, benzylpenicillin, clindamycin, doxycycline, erythromycin and metronidazole, using agar dilution and Epsilometer test methods. Digoxigenin-labelled whole chromosomal DNA probes directed against P gingivalis VPB 3492, P circumdentaria NCTC 12469T and P salivosa VPB 3313 were used to quantify organisms taken from two sample sites at the gingival margins of these cats prior to, and 5 days after, treatment with one of four commonly used antimicrobial products (amoxycillin-clavulanate, clindamycin, doxycycline or spiramycin-metronidazole). The response to treatment was assessed clinically for each cat. RESULTS: All isolates were susceptible in vitro to all seven antimicrobial agents using both methods. The numbers of P gingivalis were not reduced at the gingival sample sites by administration of amoxycillin-clavulanate for 5 days, although this treatment reduced the numbers of P salivosa and P circumdentaria to below detection levels in six of eight and two of three of sample sites, respectively; clinical improvement was not observed in cats treated with amoxycillin-clavulanate. Treatment with clindamycin, doxycycline or spiramycin-metronidazole resulted in clinical improvement and a marked reduction of all Porphyromonas isolates at the sample sites. CONCLUSION: The Epsilometer test is a simple and accurate method for determining the minimum inhibitory concentration for P gingivalis, P salivosa and P circumdentaria. All strains were susceptible in vitro to all the antimicrobial agents tested although clinical improvement of gingival disease was not noted with amoxycillin-clavulanate when given for 5 days at usual doses. This appears to be the first report of the disparity between the in vivo and in vitro susceptibility of oral bacterial strains to amoxycillin-clavulanate in the veterinary dental literature. This also appears to be the first report in which clinical and microbiological responses to commonly used antimicrobial agents for periodontal disease in cats has been documented and quantified. It was shown that treatment with clindamycin, spiramycin-metronidazole or doxycycline not only produced a substantial reduction in the number of Porphyromonas spp (in the majority of cases to below detection levels), but also resulted in substantial clinical improvement. This would indicate that these antimicrobial agents are useful adjunctive therapy to mechanical debridement in domestic cats.

Animals↗

PubMedDate not supplied

[Consensus for antimicrobial susceptibility testing for Enterobacteriaceae. Subcommittee on Antimicrobials, SADEBAC (Argentinian Society of Clinical Bacteriology), Argentinian Association of Microbiology].

Taking into account previous recommendations from the National Committee for Clinical Laboratory Standards (NCCLS), the Antimicrobial Committee, Sociedad Argentina de Bacteriología Clínica (SADEBAC), Asociación Argentina de Microbiología (AAM), and the experience from its members and some invited microbiologists, a consensus was obtained for antimicrobial susceptibility testing and interpretation in most frequent enterobacterial species isolated from clinical samples in our region. This document describes the natural antimicrobial resistance of some Enterobacteriaceae family members, including the resistance profiles due to their own chromosomal encoded beta-lactamases. A list of the antimicrobial agents that should be tested, their position on the agar plates, in order to detect the most frequent antimicrobial resistance mechanisms, and considerations on which antimicrobial agents should be reported regarding to the infection site and patient characteristics are included. Also, a description on appropriate phenotypic screening and confirmatory test for detection of prevalent extended spectrum beta-lactamases in our region are presented. Finally, a summary on frequent antimicrobial susceptibility profiles and their probably associated resistance mechanisms, and some infrequent antimicrobial resistance profiles that deserve confirmation are outlined.

Anti-Bacterial Agents↗

PubMed2003

Antimicrobial peptides from hylid and ranin frogs originated from a 150-million-year-old ancestral precursor with a conserved signal peptide but a hypermutable antimicrobial domain.

The dermal glands of frogs produce antimicrobial peptides that protect the skin against noxious microorganisms and assist in wound repair. The sequences of these peptides are very dissimilar, both within and between species, so that the 5000 living anuran frogs may produce approximately 100 000 different antimicrobial peptides. The antimicrobial peptides of South American hylid frogs are derived from precursors, the preprodermaseptins, whose signal peptides and intervening sequences are remarkably conserved, but their C-terminal domains are markedly diverse, resulting in mature peptides with different lengths, sequences and antimicrobial spectra. We have used the extreme conservation in the preproregion of preprodermaseptin transcripts to identify new members of this family in Australian and South American hylids. All these peptides are cationic, amphipathic and alpha-helical. They killed a broad spectrum of microorganisms and acted in synergy. 42 preprodermaseptin gene sequences from 10 species of hylid and ranin frogs were analyzed in the context of their phylogeny and biogeography and of geophysical models for the fragmentation of Gondwana to examine the strategy that these frogs have evolved to generate an enormous array of peptide antibiotics. The hyperdivergence of modern antimicrobial peptides and the number of peptides per species result from repeated duplications of a approximately 150-million-year-old ancestral gene and accelerated mutations of the mature peptide domain, probably involving a mutagenic, error-prone, DNA polymerase similar to Escherichia coli Pol V. The presence of antimicrobial peptides with such different structures and spectra of action represents the successful evolution of multidrug defense by providing frogs with maximum protection against infectious microbes and minimizing the chance of microorganisms developing resistance to individual peptides. The hypermutation of the antimicrobial domain by a targeted mutagenic polymerase that can generate many sequence changes in a few steps may have a selective survival value when frogs colonizing a new ecological niche encounter different microbial predators.

Amino Acid Sequence↗

PubMed1985

Antimicrobial activity, bacterial resistance, and antimicrobial pharmacology. Is it possible to use new agents cost-effectively?

Perusal of the various journals devoted to antimicrobial agents and to the chemotherapy of infectious diseases reveals an increasing number of articles devoted to the analysis of the pharmacology of antimicrobial agents and the relationships of antimicrobial activity and pharmacologic properties. However, most attention to the pharmacokinetic properties of antimicrobial agents in the past decade has focused on the toxic properties of these agents, and there has been little work devoted to improving methods of administration. The availability of nontoxic antibiotics that are extremely active at low concentrations and of agents with markedly extended half-lives should cause us to reevaluate some of our current dosing practices. In many ways, a major adverse influence on appropriate antimicrobial therapy of ordinary infections has been the febrile neutropenic patient. Lessons learned from the care of these patients are inappropriately applied to the treatment of other patients. The neutropenic patient requires frequent administration of antibiotics at maximally tolerated doses. Many patients at risk for infection do not require antimicrobial therapeutic programs in which the antibiotic always exceeds the minimal inhibitory concentration. Indeed, the concept that the drug must be present in the serum well above the minimal inhibitory concentration for the entire interval of infection is derived from studies of neutropenic patients infected with Pseudomonas aeruginosa. Increasing resistance of hospital-acquired bacteria to older antibacterial agents will alter the initial and subsequent selection of antimicrobial agent. Combination drug therapy, which has a prominent role in the neutropenic patient, frequently results in greater cost to the health care system than is seen with single agents that are active against resistant bacteria. There are clear areas in which new antibacterial agents will be beneficial. We may be at a stage in which use of the older agents can no longer be viewed as the best clinically and economically. Better use of twice- or once-daily dosing programs of new agents coupled with use of intramuscular and oral administration of antibiotics can help reduce nosocomial infections that contribute to rising health costs.

Anti-Bacterial Agents↗

PubMed1998

Patterns of antimicrobial use and antimicrobial resistance among healthy children in Bolivia.

OBJECTIVE: To determine the incidence of antimicrobial-resistant, nonpathogenic Escherichia coli among healthy children aged 6-72 months in Camiri town and a rural village, Javillo, in south-eastern Bolivia. METHOD: A community-based survey: stool samples were obtained from 296 healthy children selected by modified cluster sampling in Camiri and all 25 eligible children in Javillo. E. coli isolates were tested for antimicrobial susceptibility according to the standard disc diffusion method. By a questionnaire survey of 12 pharmacies and by using simulated patients, we investigated the antimicrobial availability and the usage patterns in Camiri town. RESULTS: In Camiri, over 90%, and in Javillo over 70% of children carried E. coli resistant to ampicillin, trimethoprim-sulphamethoxazole (TMP/SMX) or tetracycline. Overall, 63% of children carried E. coli with multiple resistance to ampicillin, TMP/SMX, tetracycline and chloramphenicol. In the simulated patients study, antimicrobials were dispensed inappropriately for 92% of adults and 40% of children with watery diarrhoea, and were under-prescribed for males with urethral discharge (67%) or females with fever and dysuria (58%). The dose and/or duration of antimicrobials dispensed was almost always too low. CONCLUSION: Our study showed a disturbingly high prevalence of carriage of nonpathogenic E. coli resistant to antimicrobials. The prevalence of resistance to ampicillin and TMP/SMX was higher than that previously reported in developing countries. The existence of a large reservoir of resistance genes in healthy individuals in developing countries represents a threat to the success of antimicrobial therapy throughout the world. Programmes to improve rational and effective drug use in developing countries are urgently needed.

Adult↗