Classes Of Antimicrobial Drugs Research Articles

Acinetobacter baumannii strains isolated from patients in intensive care units in Goiânia, Brazil: Molecular and drug susceptibility profiles.

Resistance to antimicrobial agents is increasing worldwide and imposes significant life-threatening risks to several different populations, especially those in intensive care units (ICUs). Bacteria can quickly develop or acquire resistance to antimicrobial drugs, and combined with their intrinsic potential to cause disease in humans, these bacteria can become deadly. Among Gram-negative bacteria, Acinetobacter baumannii is notorious as a frequent opportunistic pathogen associated with critically ill patients, and understanding the genetic basis of A. baumannii resistance to beta-lactams among patients in ICUs will result in better protocols to prevent the development of resistance as well as improved treatment regimens. In this study, we assessed 1333 patients in five ICUs, 56 of whom developed A. baumannii infections. Most of the A. baumannii isolates were resistant to beta-lactam antimicrobial drugs, specifically, 3rd- and 4th-generation cephalosporins and carbapenems, and 91.1% of the isolates were multi-drug resistant (MDR). The most frequent OXA gene present was OXA-23 (55.1%), which is significantly associated with MDR strains. Most of the A. baumannii isolates (76.8%) were capable of forming a biofilm. The antimicrobial drug classes that were effective against most of these isolates were polymyxins and tigecycline. The molecular profile of the isolates allowed detection of 12 different clusters comprising 2 to 8 isolates each. In conclusion, our data indicate a high incidence of resistance to carbapenems as well as MDR strains among the observed A. baumannii isolates, most of which exhibited a high prevalence of OXA-23 gene expression. Only a few selective drugs were effective, reinforcing the notion that bacterial resistance is an emerging problem that should be prioritized in every healthcare facility.

Antibióticos no setor avícola: uma revisão sobre a resistência microbiana

Since the first practical application of penicillin during World War II, the use of antibiotics has become an essential tool to treat infectious diseases and, after this event, many other drugs have been described, tested and used. However, the use of antimicrobials extends beyond the therapeutic treatment of animals and men, considering that, in some countries, these drugs are used in food producing animals with the objective of improving performance and reducing mortality. However, according to the World Health Organization, the use of antimicrobials in animal production should be controlled and restricted due to the risk of selecting resistant bacteria in different environments when these drugs are used indiscriminately. Therefore, the European Union prohibited the use of antibiotics as growth promoters in feed for production animals in 2006 as a precaution and this measure forced other countries, including Brazil, to adapt to this new demand in order to continue exporting products for this important economic bloc. Antimicrobial resistance may be coded by chromosomes or plasmids, which facilitates gene spreading. In addition, mechanisms of genetic interchange provide transmission from one bacterium to another, generating the occurrence of resistance to multiple antimicrobial drug classes, named multidrug resistance. This issue has been considered a major concern to the public health, since the transference of resistance to the human population by chicken meat is not clearly described. Therefore, this study reviewed the use of antibiotics in the poultry industry and, in order to do it so, information on the discovery and use of antimicrobials, mechanisms of action and resistance, as well as their impacts on the poultry industry were gathered. In addition, a lack in scientific literature has been observed in this study due to the low amount of papers addressing this theme in the poultry industry area.

Imidazoles Induce Reactive Oxygen Species in Mycobacterium tuberculosis Which Is Not Associated with Cell Death.

Azoles are a class of antimicrobial drugs used clinically to treat yeast and fungal infections. Against pathogenic yeast and fungi, azoles act by inhibiting the activity of the cytochrome P450 Cyp51, which is involved in the synthesis of a critical component of the yeast and fungal cell membrane. Azoles have antibacterial activity, including against mycobacteria, but the basis for this activity is not well-understood. We demonstrated that imidazoles are bactericidal to Mycobacterium tuberculosis. A marked increase in reactive oxygen species (ROS) was observed within imidazole-treated M. tuberculosis. The generation of ROS did not appear to be related to the mechanism of killing of imidazoles, as the addition of antioxidants or altered expression of detoxifying enzymes had no effect on growth. We examined the metabolic changes induced by econazole treatment in both wild-type and econazole-resistant mutant strains of M. tuberculosis. Econazole treatment induced changes in carbohydrates, amino acids, and energy metabolism in both strains. Notably, the untreated mutant strain had a metabolic profile similar to the wild-type drug-treated cells, suggesting that adaptation to similar stresses may play a role in econazole resistance.

Treatment of Staphylococcus aureus Infections.

Staphylococcus aureus, although generally identified as a commensal, is also a common cause of human bacterial infections, including of the skin and other soft tissues, bones, bloodstream, and respiratory tract. The history of S. aureus treatment is marked by the development of resistance to each new class of antistaphylococcal antimicrobial drugs, including the penicillins, sulfonamides, tetracyclines, glycopeptides, and others, complicating therapy. S. aureus isolates identified in the 1960s were sometimes resistant to methicillin, a ß-lactam antimicrobial active initially against a majority S. aureus strains. These MRSA isolates, resistant to nearly all ß-lactam antimicrobials, were first largely confined to the health care environment and the patients who attended it. However, in the mid-1990s, new strains, known as community-associated (CA-) MRSA strains, emerged. CA-MRSA organisms, compared with health care-associated (HA-) MRSA strain types, are more often susceptible to multiple classes of non ß-lactam antimicrobials. While infections caused by methicillin-susceptible S. aureus (MSSA) strains are usually treated with drugs in the ß-lactam class, such as cephalosporins, oxacillin or nafcillin, MRSA infections are treated with drugs in other antimicrobial classes. The glycopeptide drug vancomycin, and in some countries teicoplanin, is the most common drug used to treat severe MRSA infections. There are now other classes of antimicrobials available to treat staphylococcal infections, including several that have been approved after 2009. The antimicrobial management of invasive and noninvasive S. aureus infections in the ambulatory and in-patient settings is the topic of this review. Also discussed are common adverse effects of antistaphylococcal antimicrobial agents, advantages of one agent over another for specific clinical syndromes, and the use of adjunctive therapies such as surgery and intravenous immunoglobulin. We have detailed considerations in the therapy of noninvasive and invasive S. aureus infections. This is followed by sections on specific clinical infectious syndromes including skin and soft tissue infections, bacteremia, endocarditis and intravascular infections, pneumonia, osteomyelitis and vertebral discitis, epidural abscess, septic arthritis, pyomyositis, mastitis, necrotizing fasciitis, orbital infections, endophthalmitis, parotitis, staphylococcal toxinoses, urogenital infections, and central nervous system infections.

Short history of regulations and approved indications of antimicrobial drugs for food animals in the USA.

We review historical availability and regulation, and recent indications of antimicrobial drugs for food animals in the USA. We summarize the timeline of introduction of individual antimicrobial drug classes from the 1930s to present, history of regulation of antimicrobial drugs from the 1930s to present and indications of antimicrobial drugs in 1996-2014 for food animals in the USA. The history of antimicrobial drug regulation demonstrates a historical precedent for harmonized regulations of antimicrobials 'for human and other animals' in the USA.

Activity of Scorpion Venom-Derived Antifungal Peptides against Planktonic Cells of Candida spp. and Cryptococcus neoformans and Candida albicans Biofilms.

The incidence of fungal infections has been increasing in the last decades, while the number of available antifungal classes remains the same. The natural and acquired resistance of some fungal species to available therapies, associated with the high toxicity of these drugs on the present scenario and makes an imperative of the search for new, more efficient and less toxic therapeutic choices. Antimicrobial peptides (AMPs) are a potential class of antimicrobial drugs consisting of evolutionarily conserved multifunctional molecules with both microbicidal and immunomodulatory properties being part of the innate immune response of diverse organisms. In this study, we evaluated 11 scorpion-venom derived non-disulfide-bridged peptides against Cryptococcus neoformans and Candida spp., which are important human pathogens. Seven of them, including two novel molecules, showed activity against both genera with minimum inhibitory concentration values ranging from 3.12 to 200 μM and an analogous activity against Candida albicans biofilms. Most of the peptides presented low hemolytic and cytotoxic activity against mammalian cells. Modifications in the primary peptide sequence, as revealed by in silico and circular dichroism analyses of the most promising peptides, underscored the importance of cationicity for their antimicrobial activity as well as the amphipathicity of these molecules and their tendency to form alpha helices. This is the first report of scorpion-derived AMPs against C. neoformans and our results underline the potential of scorpion venom as a source of antimicrobials. Further characterization of their mechanism of action, followed by molecular optimization to decrease their cytotoxicity and increase antimicrobial activity, is needed to fully clarify their real potential as antifungals.

Life aquatic: the amazing self-purifying properties of the Ganges River.

The Ganges is India’s holiest and most revered river. Often referred to as “Mother Ganges”, this river originates from the Gangotri glacier in the Himalayas, and provides a lifeline for the millions of people living along its banks, before emptying into the Bay of Bengal. Today, the river is among the world’s most polluted, filled with untreated sewage, industrial waste and pesticides. Amazingly, in spite of the pressures posed by modern India, the Ganges River supports a surprising amount of biodiversity thanks to its remarkable self–purifying and regeneration properties. Studies from as far back as 1896 have shown the unique antimicrobial properties of the Ganges against Vibrio cholera–the causative agent of cholera–which died within 3 hours in Ganges water, but persisted for 48 hours in distilled water. French scientist Félix d’Herelle later attributed this mystic characteristic to the action of bacteriophages–bacteria killing viruses. Besides just being fascinating science, bacteriophages may hold important implications in modern medicine. We live in an era where antibiotic resistance could become a global crisis, owing to the liberal and widespread use of antibiotics. Studies have shown that bacteriophages can be modified to target specific bacteria and provide long-lasting treatment for a vast array of infections. Scientists are now hopeful that the Ganges might provide clues for the design and synthesis of a new class of antimicrobial drugs.

Exploring Post-Treatment Reversion of Antimicrobial Resistance in Enteric Bacteria of Food Animals as a Resistance Mitigation Strategy.

Antimicrobial drug use in food animals is associated with an elevation in relative abundance of bacteria resistant to the drug among the animal enteric bacteria. Some of these bacteria are potential foodborne pathogens. Evidence suggests that at least in the enteric nontype-specific Escherichia coli, after treatment the resistance abundance reverts to the background pre-treatment levels, without further interventions. We hypothesize that it is possible to define the distribution of the time period after treatment within which resistance to the administered drug, and possibly other drugs in case of coselection, in fecal bacteria of the treated animals returns to the background pre-treatment levels. Furthermore, it is possible that a novel resistance mitigation strategy for microbiological food safety could be developed based on this resistance reversion phenomenon. The strategy would be conceptually similar to existing antimicrobial drug withdrawal periods, which is a well-established and accepted mitigation strategy for avoiding violative drug residues in the edible products from the treated animals. For developing resistance-relevant withdrawals, a mathematical framework can be used to join the necessary pharmacological, microbiological, and animal production components to project the distributions of the post-treatment resistance reversion periods in the production animal populations for major antimicrobial drug classes in use. The framework can also help guide design of empirical studies into the resistance-relevant withdrawal periods and development of mitigation approaches to reduce the treatment-associated elevation of resistance in animal enteric bacteria. We outline this framework, schematically and through exemplar equations, and how its components could be formulated.

Antimicrobial Susceptibility of Enteric Gram Negative Facultative Anaerobe Bacilli in Aerobic versus Anaerobic Conditions.

Antimicrobial treatments result in the host’s enteric bacteria being exposed to the antimicrobials. Pharmacodynamic models can describe how this exposure affects the enteric bacteria and their antimicrobial resistance. The models utilize measurements of bacterial antimicrobial susceptibility traditionally obtained in vitro in aerobic conditions. However, in vivo enteric bacteria are exposed to antimicrobials in anaerobic conditions of the lower intestine. Some of enteric bacteria of food animals are potential foodborne pathogens, e.g., Gram-negative bacilli Escherichia coli and Salmonella enterica. These are facultative anaerobes; their physiology and growth rates change in anaerobic conditions. We hypothesized that their antimicrobial susceptibility also changes, and evaluated differences in the susceptibility in aerobic vs. anaerobic conditions of generic E. coli and Salmonella enterica of diverse serovars isolated from cattle feces. Susceptibility of an isolate was evaluated as its minimum inhibitory concentration (MIC) measured by E-Test® following 24 hours of adaptation to the conditions on Mueller-Hinton agar, and on a more complex tryptic soy agar with 5% sheep blood (BAP) media. We considered all major antimicrobial drug classes used in the U.S. to treat cattle: β-lactams (specifically, ampicillin and ceftriaxone E-Test®), aminoglycosides (gentamicin and kanamycin), fluoroquinolones (enrofloxacin), classical macrolides (erythromycin), azalides (azithromycin), sulfanomides (sulfamethoxazole/trimethoprim), and tetracyclines (tetracycline). Statistical analyses were conducted for the isolates (n≥30) interpreted as susceptible to the antimicrobials based on the clinical breakpoint interpretation for human infection. Bacterial susceptibility to every antimicrobial tested was statistically significantly different in anaerobic vs. aerobic conditions on both media, except for no difference in susceptibility to ceftriaxone on BAP agar. A satellite experiment suggested that during first days in anaerobic conditions the susceptibility changes with time. The results demonstrate that assessing effects of antimicrobial treatments on resistance in the host’s enteric bacteria that are Gram negative facultative Anaerobe Bacilli requires data on the bacterial antimicrobial susceptibility in the conditions resembling those in the intestine.

Antimicrobial Resistance Profiles in Escherichia coli O157 Isolates from Northern Colorado Dairies

Escherichia coli O157 (EcO157) infections can lead to serious disease and death in humans. Although the ecology of EcO157 is complex, ruminant animals serve as an important reservoir for human infection. Dairy cattle are unique because they may be a source of contamination for milk, meat, and manure-fertilized crops. Foodborne dairy pathogens such as EcO157 are of primary importance to public health. Antimicrobial resistance (AMR) is a complex phenomenon that complicates the treatment of serious bacterial infections and is of increasing concern. In the face of recommended use restrictions for antimicrobial agents in livestock operations, current AMR patterns in known foodborne pathogens should be documented. The objective of this study was to document AMR patterns in EcO157 isolates from dairies in northern Colorado using antimicrobial agents commonly found on dairies and representative of medically important antimicrobial drug classes. Seventy-five EcO157 isolates were recovered from three dairies. Six isolates were resistant to at least 1 of the 10 tested antimicrobial agents: four were resistant to streptomycin, sulfisoxazole, and tetracycline; one was resistant to streptomycin and tetracycline; and one was resistant to only tetracycline. All resistant isolates were from a single dairy. Overall, a low prevalence (8%) of AMR was observed among the 75 EcO157 isolates. No significant effects on AMR profiles due to virulence genes, parity, or previous antimicrobial treatments within the current lactation period were detected. The results of this study provide background information for future comparative studies investigating AMR trends. Future studies should include more participating farms and more samples and should control for potential confounding factors of AMR that may underlie individual farm variation.

Biological Efficacy and Application of Essential Oils in Foods-A Review

:Food contamination with pathogenic microbes have increased dramatically during the last few decades, and going to be a major public health concern in many developing countries. Foodborne pathogens cause severe diseases to human beings including infants. Although a large number of foodbornepathogens exist, the overall increase in the number of infections is of relatively few emerging serotypes and phage types. A variety of foodborne pathogens have risen and fallen within large geographic regions, associated with several meta-outbreaks. Recently the emergence of resistance of foodborne pathogens to the antimicrobial drugs appears to pose a particular health risk. Several reports have indicated that infection due to the consumption of food contaminated with foodborne pathogens is associated with increased risk for invasive illness, and death. In general, antimicrobial drug resistance occurs frequently in zoonotic foodborne pathogens and is largely promoted by using antimicrobial drugs in food practices. Foodborne pathogens have become a matter of great concern because of their rapid dissemination and their ability to readily acquire additional resistance traits to other clinically important antimicrobial drug classes. There has been an increasing interest worldwide on versatile potential of natural products in controlling foodborne pathogens in food commodities using essential oils, especially from plant origin. This review deals with the novel findings on essential oils and their compounds for their possible applications in food industry against the foodborne pathogens.A reliable amount of description on the practical applications of essential oils in food practices has been described. We have also described the chemical nature and mode of action of essential oils. A brief summary on the use of essential oils in food system as future perspectives has also been discussed. Although an adequate information from literature is presented, this review mainly focusses on the food application of essential oils and their active compounds as natural antimicrobial agents.

Rationality of utilization of antimicrobial agents in medical intensive care unit of a tertiary care hospital

Background: Patients admitted to intensive care unit receive multiple medications of different pharmacological classes due to various life threatening ailments. This study was conducted to assess the patterns of usage of antimicrobial agents in medical ICU of a tertiary care hospital and to suggest necessary modifications in prescribing patterns to achieve rational therapeutic practices. Methods: A cross-sectional observational study was carried out at ICU of the tertiary care hospital for 6 months. From the inpatient case record of ICU relevant data on prescription of each patient was collected. The demographic status, disease data and the utilization of different antimicrobial drug classes and individual drugs were analysed. Results: Of 753 patients admitted in the medical ICU during the study period, 640 consecutive patients were included for analysis. Male to female ratio was 1.45. Mean age was 63.32±17.93 years. Extensive poly-pharmacy (100%) and drugs with non-generic name (73%) noticed among the prescriptions.Average number of drugs per prescription was 12.1±2.13. Penicillins (51.87%) and cephalosporins (45.78%) were most commonly used antimicrobial drug classes. Piperacillin (37.03%), ceftriaxone (33.28%) and levofloxacin (22.5%) were commonly used antimicrobial drugs. A total of 181 prescriptions contained two and 138 contained three antimicrobial drugs. Piperacillin+tazobactam(37.03%) was the most common fixed dose combination noticed. Conclusions: Overall extensive poly-pharmacy and drugs with non-generic name noticed among the prescriptions. Few interventional programs should be aimed at control of infections, rational antimicrobial drug prescription to minimize adverse drug events, emergence of bacterial resistance and attenuating unnecessary cost.

Sulfoxides, Analogues of L-Methionine and L-Cysteine As Pro-Drugs against Gram-Positive and Gram-Negative Bacteria

The problem of resistance to antibiotics requires the development of new classes of broad-spectrum antimicrobial drugs. The concept of pro-drugs allows researchers to look for new approaches to obtain effective drugs with improved pharmacokinetic and pharmacodynamic properties. Thiosulfinates, formed enzymatically from amino acid sulfoxides upon crushing cells of genus Allium plants, are known as antimicrobial compounds. The instability and high reactivity of thiosulfinates complicate their use as individual antimicrobial compounds. We propose a pharmacologically complementary pair: an amino acid sulfoxide pro-drug and vitamin B6 - dependent methionine γ-lyase, which metabolizes it in the patient's body. The enzyme catalyzes the γ- and β-elimination reactions of sulfoxides, analogues of L-methionine and L-cysteine, which leads to the formation of thiosulfinates. In the present work, we cloned the enzyme gene from Clostridium sporogenes. Ionic and tautomeric forms of the internal aldimine were determined by lognormal deconvolution of the holoenzyme spectrum and the catalytic parameters of the recombinant enzyme in the γ- and β-elimination reactions of amino acids, and some sulfoxides of amino acids were obtained. For the first time, the possibility of usage of the enzyme for effective conversion of sulfoxides was established and the antimicrobial activity of thiosulfinates against Gram-negative and Gram-positive bacteria in situ was shown.

The antimicrobial activity of mecillinam, nitrofurantoin, temocillin and fosfomycin and comparative analysis of resistance patterns in a nationwide collection of ESBL-producing Escherichia coli in Norway 2010–2011

Background: The prevalence of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli in Norway has been steadily increasing during the last 10–15 years as part of a global pandemic. ESBL producers frequently express co-resistance to other important antimicrobial drug classes, limiting therapeutic options. This has led to regained interest in older antimicrobial agents. The aim of this study was to evaluate the antimicrobial activity of mecillinam, nitrofurantoin, temocillin and fosfomycin, as well as to perform a comparative analysis of resistance patterns in a nationwide collection of ESBL-producing E. coli. Methods: A nationwide collection of all 105 clinical isolates of ESBL-producing E. coli from the Norwegian Organisation for Surveillance of Antimicrobial Resistance (NORM) during 2010–2011 was analyzed. Detection and identification of ESBL-encoding genes were performed by PCR and sequencing for confirmation of ESBL variants of blaTEM and blaSHV (2010) or microarray (2011). Minimum inhibitory concentrations (MICs) or MIC correlates were determined using MIC gradient tests or VITEK 2, respectively. Comparative analysis of resistance patterns was performed. Results: All isolates were susceptible to fosfomycin, temocillin (urinary tract breakpoint) and meropenem. For mecillinam and nitrofurantoin, 6% and 9% of the isolates, respectively, were non-susceptible. A high level of susceptibility was also observed for amikacin (95%). In contrast, the non-susceptibility proportions to ampicillin (100%), cefotaxime (97%), ceftazidime (77%), aztreonam (87%), gentamicin (42%), tobramycin (52%), ciprofloxacin (76%) and trimethoprim-sulfamethoxazole (71%) were higher. Conclusions: Overall, the in vitro susceptibility to nitrofurantoin, fosfomycin, mecillinam and temocillin was high, indicating that these drugs are good options for treating uncomplicated urinary tract infections caused by ESBL-producing E. coli.

Prescription practices in acute pediatric infections and their implications on the worldwide antimicrobial resistance

A large proportion of antimicrobial agents are prescribed worldwide for acute respiratory infections, including colds, upper respiratory infections, acute bronchitis, pharyngo-tonsillitis, sinusitis, and acute otitis media [1–9]. Many of these infections are viral in nature, and antimicrobials are of no benefit. However, the widespread and inappropriate utilization of antimicrobials for such viral illnesses is the driving force behind the emergence of infections caused by antimicrobial drug-resistant organisms [10–12]. Antimicrobial drug – resistant strains of communityacquired pathogens, including Streptococcus pneumoniae, Haemophillus influenzae, and Staphylococcusaureus, have emerged as serious global health threats [13– 15]. In the United States the proportion of invasive infections caused by penicillin-nonsusceptible S. pneumoniae increased from 1% in 1992 to 27% in 2000 [10]. Multiple drug resistance of S. pneumoniae has also escalated in frequency as the proportion of S. pneumoniae isolates nonsusceptible to 3 classes of antimicrobial drugs increased from 7% in 1995 to 19% in 2000 [10].

Multidrug-Resistant Pseudomonas aeruginosa Keratitis: Risk Factors, Clinical Characteristics, and Outcomes

To identify risk factors for multidrug-resistant Pseudomonas aeruginosa (MDR-PA) keratitis and to report clinical characteristics and outcomes of this infection. Retrospective, case-control study. Ninety episodes of P. aeruginosa keratitis from a tertiary care eye institution from 2007 through 2014 were identified. Episodes of MDR-PA keratitis were taken as cases. Episodes of drug-sensitive P. aeruginosa keratitis during the same period were taken as controls. Chart review of cases and controls. Multidrug resistance was defined as resistance to 3 or more classes of antimicrobial drugs. Logistic regression analysis was used to determine association of baseline characteristics with multidrug resistance. Clinical characteristics and risk factors in each group also were compared. Risk factors for multidrug resistance, including age, gender, eye, duration of symptoms, topical steroid or lubricant ointment use, trauma, prior ocular surgery, presence of a compromised ocular surface, and bandage contact lens use. Twenty-three episodes of MDR-PA keratitis (cases) and 67 episodes of drug-sensitive P. aeruginosa keratitis (controls) were identified. In the multivariate analysis, lubricant ointment use, presence of a compromised ocular surface, and bandage contact lens use were associated with MDR-PA keratitis. Antimicrobial resistance in the MDR-PA keratitis isolates was least for colistin and imipenem (56.52% each). Corneal perforation was more common in cases (52.17% [12 of 23]) than in controls (11.94% [8 of 67]; P = 0.0001). Cyanoacrylate glue application was required in 47.82% of cases (11 of 23), compared with 22.38% of controls (15 of 67; P = 0.031). Keratoplasty was more commonly required in cases (47.82% [11 of 23]) than in controls (20.89% [14 of 67]; P = 0.017). Lubricant ointment use, a compromised ocular surface, and bandage contact lens use are associated with MDR-PA keratitis. Preservative-free lubricant ointment may act as a source or reservoir of infection. Outcomes are worse in MDR-PA keratitis compared with drug-sensitive P. aeruginosa keratitis.

The Antibiotic Era: Reform, Resistance, and the Pursuit of a Rational Therapeutics

There has been a flood of recent publications and media coverage on the current crisis relating to drug-resistant microorganisms. The Antibiotic Era: Reform, Resistance, and the Pursuit of a Rational Therapeuticstakes a unique approach by presenting a well-documented history, starting in the earliest days with the introduction of antimicrobial drugs to the present time. It is built around those reformers who recognized problems relating to the irrational use of these agents and the difficulties these reformers experienced over many years. Early chapters provide a firm foundation for the many issues that follow. They trace the development of the sulfa drugs and penicillin up to the period of World War II, and more important, the postwar introduction of the group of broad-spectrum “wonder-drug” antibiotics. The introduction of these drugs changed the practice of medicine but also stimulated the need for infectious disease experts to clarify their use and help counter the extreme and extensive marketing of these drugs by the pharmaceutical companies in the form of journal advertisements, supplements, and free physician samples. As the author notes, experts like Maxwell Finland became “therapeutic rationalists” or “reformers” to help fill the vacuum left by the American Medical Association and the Food and Drug Administration because they only dealt with drug safety, not efficacy, and did not want to dictate therapeutic choices to practicing physicians. It was the introduction of the fixed-dose combination antibiotics in the 1950s, especially Panalba (tetracycline/novobiocin), that reinforced the need for real reform, a movement that dragged on for several decades before coming to fruition with the acceptance of the requirement for controlled clinical studies to prove the efficacy, as well as the safety, of antimicrobial agents. Except for the last chapter, this well-researched book focuses exclusively on issues debated in the United States. This easy to read book is arranged in a logical chronologic order, and traces the complexity of newer antimicrobial drug classes and their related policy issues. The author provides 105 pages of references and documentation that makes this book a valuable source of information for historians of science, clinical microbiologists, and infectious disease physicians. If for no other reason, the extensive reference sections makes this book a wise investment for anyone researching or writing on these issues now or in the future, especially because many of the past issues are still being argued today.

Recent advances in C. Elegans as a model system for high throughput antimicrobial drug discovery

Multidrug resistance among pathogens has become a leading cause of health care concern since these pathogens have acquired resistance against most classes of antimicrobial drugs. Therefore there is urgent need for newer antimicrobial compounds and new treatment strategies. Unfortunately the pace of new antimicrobial drug discovery programs have slowed down due to rising cost of drug discovery coupled with the relatively unattractive markets for antimicrobial drugs compared to drugs for chronic diseases. In this background, invertebrate model organisms such as the nematode Caenorhabditis elegans and fruit fly Drosophila melanogaster are finding increasing use as models to study host-pathogen relationship and high throughput antimicrobial drug discovery. The focus of this review will be to give a brief outline of the C. elegans model for high throughput antimicrobial drug discovery.

Folded structure and insertion depth of the frog-skin antimicrobial Peptide esculentin-1b(1-18) in the presence of differently charged membrane-mimicking micelles.

Antimicrobial peptides (AMPs) are effectors of the innate immunity of most organisms. Their role in the defense against pathogen attack and their high selectivity for bacterial cells make them attractive for the development of a new class of antimicrobial drugs. The N-terminal fragment of the frog-skin peptide esculentin-1b (Esc(1-18)) has shown broad-spectrum antimicrobial activity. Similarly to most cationic AMPs, it is supposed to act by binding to and damaging the negatively charged plasma membrane of bacteria. Differently from many other AMPs, Esc(1-18) activity is preserved in biological fluids such as serum. In this work, a structural investigation was performed through NMR spectroscopy. The 3D structure was obtained in the presence of either zwitterionic or negatively charged micelles as membrane models for eukaryotic and prokaryotic membranes, respectively. Esc(1-18) showed a higher affinity for and deeper insertion into the latter and adopted an amphipathic helical structure characterized by a kink at the residue G8. These findings were confirmed by measuring penetration into lipid monolayers. The presence of negatively charged lipids in the bilayer appears to be necessary for Esc(1-18) to bind, to fold in the right three-dimensional structure, and, ultimately, to exert its biological role as an AMP.

Increased survival of experimentally evolved antimicrobial peptide-resistant Staphylococcus aureus in an animal host.

Antimicrobial peptides (AMPs) have been proposed as new class of antimicrobial drugs, following the increasing prevalence of bacteria resistant to antibiotics. Synthetic AMPs are functional analogues of highly evolutionarily conserved immune effectors in animals and plants, produced in response to microbial infection. Therefore, the proposed therapeutic use of AMPs bears the risk of ‘arming the enemy’: bacteria that evolve resistance to AMPs may be cross-resistant to immune effectors (AMPs) in their hosts. We used a panel of populations of Staphylococcus aureus that were experimentally selected for resistance to a suite of individual AMPs and antibiotics to investigate the ‘arming the enemy’ hypothesis. We tested whether the selected strains showed higher survival in an insect model (Tenebrio molitor) and cross-resistance against other antimicrobials in vitro. A population selected for resistance to the antimicrobial peptide iseganan showed increased in vivo survival, but was not more virulent. We suggest that increased survival of AMP-resistant bacteria almost certainly poses problems to immune-compromised hosts.