Modification Of Antibiotics Research Articles

Clinical outcomes of penicillin skin testing

Penicillin or cephalosporin allergy is a common problem with antibiotic drug prescribing in hospitalized patients. To study the various clinical outcomes of penicillin skin testing (PST) in a community teaching hospital and to determine the percentage of patients who have an antibiotic drug modification after PST. This study was a retrospective medical record review of all inpatients who underwent PST in 6.6 years. Information was collected on 101 patients using a detailed data collection form. Data were summarized using descriptive statistics, including frequencies and percentages. Of the 101 patients who underwent PST, 92 had a negative result and 5 had a positive result; in 4 patients the test result was indeterminate. There was a 96% (67/70) reduction in the use of vancomycin and a 96% (23/24) reduction in the use of fluoroquinolones after PST in patients with negative results. Forty-nine percent of patients with negative PST results were administered a penicillin-based drug, and 48% were given a cephalosporin. Cultures were positive most commonly for Staphylococcus aureus and enterococcus. There were no serious adverse reactions to PST or to the use of penicillins or cephalosporins after a negative PST result. Penicillin skin testing lowered the use of vancomycin and fluoroquinolones and increased the use of penicillin-based drugs and cephalosporins in patients with a history of beta-lactam drug allergies.

Infectious disease consultations and antibiotic usage in a Turkish university hospital

The aim of this study was to investigate the various features of infectious disease (ID) consultations and the usage of antibiotics in a Turkish university hospital. A total of 395 consultation requests were recorded during a three-year period. The departments most frequently requesting the consultation services of the ID department were Orthopedics (29.6%), Neurology (18.5%), Cardiology (11.8%) and Internal Medicine (10.4%). The main reasons were for diagnosis of unexplained fever (42.3%) and for antibiotic modification according to culture results (18%). Diagnoses made by the ID consultant were pneumonia (16.7%), urinary tract infections (9.3%), bone and joint prosthesis infections (9.1%) and in 15.7% of the investigated patients, no infectious focus was determined. It was recognized that the use of antibiotics had already been initiated in the great majority of patients (67.1%) before the consultation request. While the current therapy was changed in 57.4% of these patients, antibiotics were not necessary for 9.8%. Since the most common diagnoses were respiratory and urinary tract or bone and joint prosthesis infections, the ID specialists should have detailed knowledge of these problems. Usage of antibiotics without ID consultation was prevalent, therefore a continuous educational program is a necessity for healthcare workers in the hospital.

Phytoremediation Potential of Myriophyllum aquaticum and Pistia stratiotes to Modify Antibiotic Growth Promoters, Tetracycline, and Oxytetracycline, in Aqueous Wastewater Systems

Antibiotics are frequently used in the United States as feed efficiency promoters and medicines for livestock that is destined for human consumption. These antibiotics are released into the environment through the runoff and wastewater streams from animal feedlots and land applications of manure. The exposure of microorganisms to these antibiotics has reportedly resulted in the development of resistant species of microorganisms, which in turn can lead to human health hazards. Phytoremediation of these antibiotics can be a useful tool for countering this problem. Aquatic plants, Myriophyllum aquaticum (parrot feather) and Pistia stratiotes (water lettuce), were used for studying phytoremediation of tetracycline (TC) and oxytetracycline (OTC) from aqueous media. TC and OTC are two of the most commonly used tetracyclines in veterinary medicine. M. aquaticum and P. stratiotes gave high antibiotic modification rates of both antibiotics. Kinetic analyses dismiss direct enzyme catalysis; the modification rates decreased with increasing OTC concentrations. Sterile, cell-free root exudates (filtered through 0.2 μ m membranes) from both species also exhibited comparable antibiotic modification rates. The involvement of root-secreted metabolites in antibiotic modification is suggested. The changes in the UV absorbance spectra of OTC during treatment with the root exudates confirmed the modification.

Antibiotics: Actions, origins, resistance, by C. Walsh. 2003. Washington, DC: ASM Press. 345 pp. $99.95 (hardcover).

<i>Antibiotics: Actions, origins, resistance</i>, by C. Walsh. 2003. Washington, DC: ASM Press. 345 pp. $99.95 (hardcover).

De-escalation therapy in ventilator-associated pneumonia*

To evaluate de-escalation of antibiotic therapy in patients with ventilator-associated pneumonia. Prospective observational study during a 43-month period. Medical-surgical intensive care unit. One hundred and fifteen patients admitted to the intensive care unit with clinical diagnosis of ventilator-associated pneumonia. All the episodes of ventilator-associated pneumonia received initial broad-spectrum coverage followed by reevaluation according to clinical response and microbiology. Quantitative cultures obtained by bronchoscopic examination or tracheal aspirates were used to modify therapy. : None. One hundred and twenty-one episodes of ventilator-associated pneumonia were diagnosed. Change of therapy was documented in 56.2%, including de-escalation (the most frequent cause) in 31.4% (increasing to 38% if isolates were sensitive). Overall intensive care unit mortality rate was 32.2%. Inappropriate antibiotic therapy was identified in 9% of cases and was associated with 14.4% excess intensive care unit mortality. Quantitative tracheal aspirates and bronchoscopic samples (58 protected specimen brush and three bronchoalveolar lavage) were associated with 32.7% and 29.5% intensive care unit mortality and 29.3% and 34.4% de-escalation rate. De-escalation was lower (p < .05) in the presence of nonfermenting Gram-negative bacillus (2.7% vs. 49.3%) and in the presence of late-onset pneumonia (12.5% vs. 40.7%). When the pathogen remained unknown, half of the patients died and de-escalation was not performed. De-escalation was the most important cause of antibiotic modification, being more feasible in early-onset pneumonia and less frequent in the presence of nonfermenting Gram-negative bacillus. The impact of quantitative tracheal aspirates or bronchoscopic techniques was comparable in terms of mortality.

Cell envelope analysis of insensitive, susceptible or resistant strains of Leuconostoc and Weissella genus to Leuconostoc mesenteroides FR 52 bacteriocins

Mesenterocins 52A and 52B belong to class II of lactic acid bacteria bacteriocins. To study susceptibility, insensitivity and resistance to these mesenterocins, four wild-type bacterial strains and four resistant strains, all from Leuconostoc or Weissella genus, were compared. Several cell envelope features were investigated: susceptibilities to antibiotics and to lysozyme, cell morphology and membrane phospholipids contents. The strain insensitive to the two mesenterocins appeared to be resistant to lysozyme and exhibited the highest resistance to antibiotics. Resistant strains displayed cell morphology modifications, several increases in antibiotic resistance and modifications in lysozyme susceptibility. Moreover, mesenterocin 52A-resistant strains displayed modifications in their membrane phospholipids, leading to a more cationic membrane. Insensitivity and resistance of Leuconostoc or Weissella strains seem to be due to various minor modifications of the membrane and/or of the cell wall.

Gentamicin supplementation of polyvinylidenfluoride mesh materials for infection prophylaxis

Hernia repair evolved from pure tissue repair to mesh repair due to decreased recurrence rates. However, concern exists about mesh-related infections occurring even several years after initial operation. Therefore, a polyvinylidenfluoride (PVDF) mesh material was constructed and surface modified by plasma-induced graft polymerization of acrylic acid (PVDF+PAAc). Antimicrobial treatment was sought by binding of gentamicin (PVDF+PAAc+Gentamicin). In vitro efficacy and cytotoxicity was measured by agar diffusion test, L929 cytotoxicity testing and by analyzing the amount of gentamicin release from the mesh surface. In vivo biocompatibility was evaluated in 45 Sprague–Dawley rats. 7, 21 and 90 days after mesh implantation the amount of inflammatory and connective tissue as well as the percentage of proliferating (Ki67) and apoptotic cells (TUNEL) were analyzed at the perifilamentary region. Agar diffusion tests showed sufficient local antimicrobiotic effects against the bacteria tested after 24 h of incubation. No signs of cytotoxicity could be identified by L929 testing. Furthermore, surface modification did not affect the in vivo biocompatibility. At the end of the observation period, no significant differences were found for the perifilamentary amount of inflammatory cells and connective tissue and the percentage of Ki67 and TUNEL positive stained cells. The presented data confirm that an antibiotic surface modification of PVDF mesh samples is feasible. By analyzing cytotoxicity in vitro as well as biocompatibility in vivo no side effects were observed.

Functional annotation of putative aminoglycoside antibiotic modifying proteins in Mycobacterium tuberculosis H37Rv.

The growing availability of sequences of bacterial genomes has revealed a number of open reading frames predicted by sequence alignment to encode antibiotic resistance proteins. The presence of these putative resistance genes within bacterial genomes raises important questions regarding potential reservoirs of resistance elements and their evolution. Here we examine four gene products encoding predicted aminoglycoside-aminocyclitol antibiotic modifying enzymes, two phosphotransferases and two acetyltransferases, derived from analysis of the genome sequence of Mycobacterium tuberculosis strain H37Rv with the goal of assigning biochemical function by purification of each protein and characterization of their ability to modify aminoglycoside antibiotics. Only one of these enzymes, the previously characterized aminoglycoside acetyltransferase AAC(2')-Ic, displayed compelling aminoglycoside modifying activity. While the putative phosphotransferase encoded by the Rv3225c gene did display low levels of aminoglycoside kinase activity, the predicted kinase encoded by the Rv3817 gene lacked any such activity. A potential aminoglycoside 6'-acetyltransferase, encoded by the Rv1347c gene, did not show antibiotic acylation activity but did demonstrate selective thioesterase activity with numerous acyl-CoAs. This activity, together with the genomic environment of the Rv1347c gene in a likely polyketide synthesis cluster, suggests a role for this protein in secondary metabolism and not in antibiotic modification. It was thus shown that only one of four putative aminoglycosides modifying enzymes derived from the whole genome sequencing of M. tuberculosis H37Rv showed sufficient predicted enzyme activity to be annotated as an aminoglycoside resistance element. This study demonstrates the necessity of biochemical annotation methods as a follow up to in silico sequence alignment-based methods of assigning gene product function.

HIV-1 RNA Dimerization Initiation Site Is Structurally Similar to the Ribosomal A Site and Binds Aminoglycoside Antibiotics

Human immunodeficiency virus (HIV) genomic RNA is packaged into virions as a dimer. The first step of dimerization is the formation of a kissing-loop complex at the so-called dimerization initiation site (DIS). We found an unexpected and fortuitous resemblance between the HIV-1 DIS kissing-loop complex and the eubacterial 16 S ribosomal aminoacyl-tRNA site (A site), which is the target of aminoglycoside antibiotics. Similarities exist not only at the primary and secondary structure level but also at the tertiary structure level, as revealed by comparison of the respective DIS and A site crystal structures. Gel shift, inhibition of lead-induced cleavage, and footprinting experiments showed that paromomycin and neomycin specifically bind to the kissing-loop complex formed by the DIS, with an affinity and a geometry similar to that observed for the A site. Modeling of the aminoglycoside-DIS complex allowed us to identify antibiotic modifications likely to increase the affinity and/or the specificity for the DIS. This could be a starting point for designing antiviral drugs against HIV-1 RNA dimerization.

Functional Analysis of the Lipoglycodepsipeptide Antibiotic Ramoplanin

The peptide antibiotic ramoplanin is highly effective against several drug-resistant gram-positive bacteria, including vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), two important opportunistic human pathogens. Ramoplanin inhibits bacterial peptidoglycan (PG) biosynthesis by binding to Lipid intermediates I and II at a location different than the N-acyl-D-Ala-D-Ala dipeptide site targeted by vancomycin. Lipid I/II capture physically occludes these substrates from proper utilization by the late-stage PG biosynthesis enzymes MurG and the transglycosylases. Key structural features of ramoplanin responsible for antibiotic activity and PG molecular recognition have been discovered by antibiotic semisynthetic modification in conjunction with NMR analyses. These results help define a minimalist ramoplanin pharmacophore and introduce the possibility of generating ramoplanin-derived peptide or peptidomimetic antibiotics for use against VRE, MRSA, and related pathogens.

Streptogramin Antibiotics: Mode of Action and Resistance

The streptogramin antibiotics were discovered over 40 years ago but are only now emerging as important therapeutic agents for the treatment of infection caused by a variety of bacteria. The streptogramins consist of mixtures of two structurally distinct compounds, type A and type B, which are separately bacteriostatic, but bactericidal in appropriate ratios. These antibiotics act at the level of inhibition of translation through binding to the bacterial ribosome. Resistance to streptogramins occurs through a number of mechanisms including target modification, efflux, and enzyme catalyzed antibiotic modification. This review describes the current understanding of streptogramin function and resistance with emphasis on molecular mechanism and epidemiology.

Modulation of Antibiotic Efflux in Bacteria

Bacteria develop resistance to antibiotics by receptor alteration, antibiotic modification and by drug efflux, whereby the antibiotic is removed from intracellular compartments by efflux proteins. This article gives an overview of the chemical and biological properties of the major efflux proteins found within resurgent pathogens, their activity in creating resistance, and the effect of inhibitors of these proteins. The major families of efflux protein inhibitors against bacteria include tetracyclines, indanes, ginsensosides, indoles, reserpine and reserpine analogues, dipeptides, peptidomimetic heterocycles and heterocycles, flavones, and benastatins. Their effect on both Gram-positive and Gram-negative bacteria efflux proteins and bacterial growth is detailed.

Antimicrobial resistance mechanisms: what's hot and what's not in respiratory pathogens.

Community respiratory tract pathogens comprise Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and a few other select, but less frequent, species such as atypical bacteria, staphylococci, and some gram-negative organisms. In addition to an array of virulence factors, these bacteria have also developed a propensity to withstand a range of antimicrobial agents. These resistance mechanisms occur as either target site or antibiotic modifications or antibiotic transportation changes (prevention of cell entry or agent efflux). The genetic coding for these changes can be transmitted to progeny every 20 minutes or can be acquired from the normal flora via transformation. Presently, it is this acquisition of naked DNA by pneumococci that is a "hot" topic and the realization that unless antimicrobials are used more thoughtfully, then new agents can be rapidly rendered redundant. Other potential, but as yet unfounded, resistance scenarios include the acquisition of extended spectrum beta-lactamases by H. influenzae and the development of ribosomal changes to obviate the ketolides and oxazolidinones. To prevent the continued escalation of antimicrobial resistance, new approaches to antimicrobials must be implemented soon.

Structural basis for selectivity and toxicity of ribosomal antibiotics.

Ribosomal antibiotics must discriminate between bacterial and eukaryotic ribosomes to various extents. Despite major differences in bacterial and eukaryotic ribosome structure, a single nucleotide or amino acid determines the selectivity of drugs affecting protein synthesis. Analysis of resistance mutations in bacteria allows the prediction of whether cytoplasmic or mitochondrial ribosomes in eukaryotic cells will be sensitive to the drug. This has important implications for drug specificity and toxicity. Together with recent data on the structure of ribosomal subunits these data provide the basis for development of new ribosomal antibiotics by rationale drug design.

Modification and inhibition of vancomycin group antibiotics by formaldehyde and acetaldehyde.

It is shown that several vancomycin group antibiotics (vancomycin, eremomycin, and avoparcin) undergo spontaneous chemical modifications when kept at room temperature at neutral pH in aqueous solutions containing traces of formaldehyde or acetaldehyde. This chemical modification predominantly results in a mass increase of 12 Da in the reaction with formaldehyde and 26 Da in the case of acetaldehyde. By using tandem mass spectrometry the modification can unambiguously be identified as originating from the formation of a ring-closed 4-imidazolidinone moiety at the N-terminus of the glycopeptide antibiotics, that is, near the receptor binding pocket of the glycopeptide antibiotics. Bioaffinity mass spectrometry shows that this ring-closure results in a dramatically decreased affinity for the peptidoglycan-mimicking D-alanyl-D-alanine receptor. Additionally, in vitro inhibition measurements on two different strains of bacteria have revealed that the modified antibiotics display reduced antibacterial activity. The ring-closure is also shown to have a dissociative effect on the dimerization of the vancomycin-analogue eremomycin. The spontaneous reaction of vancomycin with formaldehyde or acetaldehyde may have implications not only for the clinical use of this class of antibiotics, but also for the effectiveness of these antibiotics when they are used in chiral separation chromatography or capillary electrophoresis.

Review of macrolides and ketolides: focus on respiratory tract infections.

The first macrolide, erythromycin A, demonstrated broad-spectrum antimicrobial activity and was used primarily for respiratory and skin and soft tissue infections. Newer 14-, 15- and 16-membered ring macrolides such as clarithromycin and the azalide, azithromycin, have been developed to address the limitations of erythromycin. The main structural component of the macrolides is a large lactone ring that varies in size from 12 to 16 atoms. A new group of 14-membered macrolides known as the ketolides have recently been developed which have a 3-keto in place of the L-cladinose moiety. Macrolides reversibly bind to the 23S rRNA and thus, inhibit protein synthesis by blocking elongation. The ketolides have also been reported to bind to 23S rRNA and their mechanism of action is similar to that of macrolides. Macrolide resistance mechanisms include target site alteration, alteration in antibiotic transport and modification of the antibiotic. The macrolides and ketolides exhibit good activity against gram-positive aerobes and some gram-negative aerobes. Ketolides have excellent activity versus macrolide-resistant Streptococcus spp. Including mefA and ermB producing Streptococcus pneumoniae. The newer macrolides, such as azithromycin and clarithromycin, and the ketolides exhibit greater activity against Haemophilus influenzae than erythromycin. The bioavailability of macrolides ranges from 25 to 85%, with corresponding serum concentrations ranging from 0.4 to 12 mg/L and area under the concentration-time curves from 3 to 115 mg/L x h. Half-lives range from short for erythromycin to medium for clarithromycin, roxithromycin and ketolides, to very long for dirithromycin and azithromycin. All of these agents display large volumes of distribution with excellent uptake into respiratory tissues and fluids relative to serum. The majority of the agents are hepatically metabolised and excretion in the urine is limited, with the exception of clarithromycin. Clinical trials involving the macrolides are available for various respiratory infections. In general, macrolides are the preferred treatment for community-acquired pneumonia and alternative treatment for other respiratory infections. These agents are frequently used in patients with penicillin allergies. The macrolides are well-tolerated agents. Macrolides are divided into 3 groups for likely occurrence of drug-drug interactions: group 1 (e.g. erythromycin) are frequently involved, group 2 (e.g. clarithromycin, roxithromycin) are less commonly involved, whereas drug interactions have not been described for group 3 (e.g. azithromycin, dirithromycin). Few pharmacoeconomic studies involving macrolides are presently available. The ketolides are being developed in an attempt to address the increasingly prevalent problems of macrolide-resistant and multiresistant organisms.

Low-dose continuous-infusion ceftazidime monotherapy in low-risk febrile neutropenic patients.

One hundred and thirty-five cancer patients admitted with low-risk neutropenic fever received a low-dose schedule of ceftazidime as infusional monotherapy over a total of 180 episodes. Ceftazidime was administered as a 1-g bolus followed by a continuous infusion of 2 g per day. In this patient population the ceftazidime was both practical and well tolerated. Sixty-eight percent of patients responded with clinical improvement and complete resolution of fever within 48 h. Overall, 95% of patients responded, although 18% subsequently required antibiotic modification for persistent fever. Only 5% of episodes were considered failures due to clinical deterioration, and over the study period there was only 1 fatality due to respiratory failure. The median duration of hospitalisation was only 4 days (2-20). In conclusion, monotherapy with low-dose infusional ceftazidime appears safe and highly effective in this low-risk population of neutropenic patients and may reduce antibiotic costs appreciably.

Chemical modifications and structure activity studies of ziracin and related everninomicin antibiotics

Chemical modifications of everninomicin antibiotics, particularly ziracin ( 1), were carried out to study the SARs as well as the chemical properties of this class of compounds. Use of allyl ether group for protection and selective deprotection of phenolic groups provided access to a variety of novel analogs of the title compounds, some of which exhibited the same high in vitro potency as the parent compounds.

Antibacterial glycopeptide antibiotics (review)

The structures of the most important antibacterial glycopeptide antibiotics and the mechanisms of their activity and resistance to them are examined. Researches on the total synthesis of antibiotics and model compounds are discussed. The chemical modification of antibiotics (changing the amino acid composition) and also the modification of fragments of the molecule that do not take part in interaction with the target but make it possible to overcome the resistance of bacteria to antibiotics of this group are discussed.

1H-NMR analysis of copper-aminoglycoside complexes in solution and its implication for regioselective modification of multifunctional aminoglycoside antibiotics

A method for analysis of complexes of the cupric ion with aminoglycoside antibiotics based on the measurement of the paramagnetic contribution of the cupric ion to T 1 relaxation time on 1H-NMR spectra of the antibiotics is described. The information from the NMR experiments was supplemented by molecular modeling studies and proved valuable in predicting the reactivities of these complexes toward reagents for modification of amines, which were used in regioselective, and often regiospecific, derivatization of these important antibiotics.