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The increasing incidence of infections caused by extended-spectrum beta-lactamase (ESBL)/AmpC-producing bacteria leads to increasing use of carbapenems and risk of carbapenem resistance. Treatment success of carbapenem-sparing beta-lactams (CSBs) for ESBL infections is unclear. The aim of this study was to appraise the clinical cure rate and estimate the cost-effectiveness of meropenem vs. CSBs (piperacillin-tazobactam, temocillin, ceftazidime-avibactam, and ceftolozane-tazobactam) for urinary tract infections (UTIs) or intra-abdominal infections (IAIs) due to ESBL/AmpC-producing bacteria. A systematic literature search of the Cochrane library, EMBASE, PubMed, and Web of Science was conducted to identify studies assessing the clinical cure rate of the antibiotics. To assess the cost-effectiveness of CSBs vs. meropenem, a combined decision analytic and Markov model was probabilistically analysed over a 5-year period. The main outcome was presented as the incremental cost-effectiveness ratio and evaluated with a threshold of €20 000 per life year gained (LYG). From 656 identified articles, 17 and 14 studies were included in the qualitative synthesis and quantitative synthesis, respectively. A clinical cure of ceftazidime-avibactam and ceftolozane-tazobactam was comparable to meropenem in patients with complicated IAIs (cIAIs) due to ESBL (Risk ratio [RR]=1·04, 95% confidence interval [CI]=0·95-1·13). Both temocillin and ceftolozane-tazobactam were deemed cost-effective compared to meropenem with €157·58 and €13 398·34 per LYG, respectively, in patients with UTIs due to ESBL. However, only ceftazidime-avibactam (plus metronidazole) was cost-effective for the treatment of IAIs, with €16 916·77 per LYG. These results show that several CSBs can be considered as viable candidates for the treatment of UTIs and IAIs caused by ESBL., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Patients admitted to Intensive Care Units (ICUs) are at very high risk of developing severe nosocomial infections. Consequently, antimicrobials are among the most important and commonly prescribed drugs in the management of these patients. Critically ill patients in ICUs include representatives of all age groups with a range of organ dysfunction related to severe acute illness that may complicate long-term illness. The range of organ dysfunction, together with drug interactions and other therapeutic interventions (e.g. haemodynamically active drugs and continuous renal replacement therapies), may strongly impact on antimicrobial pharmacokinetics in critically ill patients. In the last decade, it has become apparent that the intrinsic pharmacokinetic (PK) and pharmacodynamic (PD) properties are the major determinants of in vivo efficacy of antimicrobial agents. PK/PD parameters are essential in facilitating the translation of microbiological activity into clinical situations, ensuring a successful outcome. In this review, we analyse the typical patterns of antimicrobial activity and the corresponding PK/PD parameters, with a special focus on a PK/PD dosing approach of the antimicrobial agent classes commonly utilised in the ICU setting.

This study is the first of its type to evaluate sources, patterns and appropriateness of antibacterial drug consumption within the Jordanian population. It uses a structured random interview to customers arriving at community pharmacy stores seeking antibacterial medication for systemic infections. Dispensed antibacterial drugs belonged to eight different main classes of systemically used antibacterial drugs in accordance with the Anatomical Therapeutic Chemical (ATC) classification system. Just less than one-half of all dispensed antibacterial drugs were without a prescription (46%), either via self-medication (23.2%) or pharmacist recommendation (23.1%). Inappropriateness in use was seen in 29.9% and 34% of the prescribed and non-prescribed (over-the-counter) antibacterial drugs, respectively. No uniformity in the treatment profile of the different treated complaints was seen. Our study shows great misuse and abuse of antibacterial drugs and hence there is a need to force regulations to control community use of antibacterial drugs and to increase awareness of the consequences of their inappropriate and uncontrolled use.

The high level of consumption of systemic antibiotics in our country prompted a study of factors affecting the geographical variations in this consumption. Several parameters explain the uneven distribution of consumption: (a) the epidemiology of the infections, (b) population-dependent factors and (c) factors dependent on the prescribing doctor. The aim of this study was to study population-dependent parameters (type of population and age). A retrospective longitudinal study was made from antibiotic consumption data provided by International Marketing Services (IMS) between 1 January 1996 and 31 December 2000. The consumption indicator used was the number of defined daily doses per 1000 inhabitants per day (DID). Global consumption in regions under study varied by 5.7 DID: Medina del Campo (25.9 DID), Valladolid city (23.4 DID), Laguna de Duero (22.6 DID), Northern Region (22.4 DID), Southern Region (21.4 DID) and lastly Central Region (20.2 DID). The specific consumption per area showed a greater consumption of amoxicillin in the three urban areas, amoxicillin-clavulanic acid and the main macrolides in Medina del Campo, quinolones antibiotics in the Northern Region and tetracyclines and sulphonamides in Valladolid City. Significant area-dependent global consumption differences were observed with the most marked in urban areas. The differences were more marked when studying the geographical distribution of consumption of the commonly used antibiotics.

Antimicrobial peptides (AMPs) are an important component of the natural defences of most living organisms against invading pathogens. These are relatively small (< 10kDa), cationic and amphipathic peptides of variable length, sequence and structure. During the past two decades several AMPs have been isolated from a wide variety of animals, both vertebrates and invertebrates, and plants as well as from bacteria and fungi. Most of these peptides are obtained from different sources like macrophages, neutrophils, epithelial cells, haemocytes, fat body, reproductive tract, etc. These peptides exhibit broad-spectrum activity against a wide range of microorganisms including Gram-positive and Gram-negative bacteria, protozoa, yeast, fungi and viruses. A few peptides have also been found to be cytotoxic to sperm and tumour cells. AMPs are classified based on the three dimensional structural studies carried out with the help of NMR. The peptides are broadly classified into five major groups namely (a) peptides that form alpha-helical structures, (b) peptides rich in cysteine residues, (c) peptides that form beta-sheet, (d) peptides rich in regular amino acids namely histatin, arginine and proline and (e) peptides composed of rare and modified amino acids. Most of these peptides are believed to act by disrupting the plasma membrane leading to the lysis of the cell. AMPs have been found to be excellent candidates for developing novel antimicrobial agents and a few of these peptides show antimicrobial activity against pathogens causing sexually transmitted infection (STI), including HIV/HSV. Peptides, namely magainin and nisin have been shown to demonstrate contraceptive properties in vitro and in vivo. A few peptides have already entered clinical trials for the treatment of impetigo, diabetic foot ulcers and gastric helicobacter infections. In this review, we discuss the source, structures and mode of action with special reference to therapeutic considerations of various AMPs.

Increasing resistance in Pseudomonas aeruginosa to multiple antibiotics has been observed and is posing therapeutic dilemmas. Antibiotic utilization is one factor that has been associated with the emergence of antimicrobial resistance. We examined the overall and specific antimicrobial use in relation to changes in susceptibility patterns in P. aeruginosa. Regression analysis was performed to explore the relationships between annual antibiotic use and the incidence of resistant P. aeruginosa. There were statistically significant relationships between increasing anti-pseudomonal cephalosporin and levofloxacin use and the increasing incidence of ciprofloxacin resistant P. aeruginosa. However, there was not an association between other fluoroquinolone or overall fluoroquinolone use and this change. In addition, there was no association between increasing anti-pseudomonal cephalosporin use and cefepime resistant P. aeruginosa. No statistical relationship was seen with overall antibiotic use and the development of resistance in P. aeruginosa, suggesting that the development of resistance is associated with the use of individual agents, rather than overall antibiotic consumption.

Bacterial spread between patients may contribute to the high prevalence of antibiotic-resistant pathogens within ICUs. The aim of this study was to evaluate the fate of Pseudomonas aeruginosa during the different antibiotic regimens. Susceptibility patterns and genotyping were performed to determine whether there was a predominant clone and to track the spread of resistant strains within the unit. Twenty-eight different ribotypes were found among 82 Pseudomonas isolates. Four ribotypes accounted for 42 (51%) isolates and were designated the "major clones" occurring throughout multiple cycles. The ribotypes with multiple occurrences were more resistant to antibiotics than ribotypes that appeared only once. The correlation of antibiotic use with antibiotic resistance and the finding of a large number of ribotypes suggested that de novo development of antibiotic resistance is a likely event in P. aeruginosa. In addition, ribotypes associated with antibiotic resistance appeared to have a survival advantage and can become frequent colonizers in the ICU.

The mutant prevention concentration (MPC) of fluoroquinolones, linezolid, rifabutin, rifampicin and macrolides was determined in 16 nontuberculous Mycobacterium species in order to compare the incidence of resistant mutant occurrence for different antibiotics. Linezolid showed good activity against Mycobacterium gordonae and Mycobacterium kansasii. Rifabutin had a lower MPC values than rifampicin. The fluoroquinolones were more active against M. gordonae and Mycobacterium chelonae. Clarithromycin had better MPC values than azithromycin but its intracellular concentration was high. Mutant prevention concentration may help to establish a better clinico-microbiological correlation, the sub-populations of drug-resistant micro-organisms may be detected by that method. It is still important to administer correct drug doses, to use combined therapies and to find new drugs that are useful in the treatment of these infections.

The frequency of resistance to antibiotics among common community-acquired pathogens, and the number of drugs to which they are resistant have been increasing worldwide. The relationship between antibiotic usage and resistance is strongly supported by data from several studies. Countries with the highest per capita antibiotic consumption have the highest resistance. The emergence of penicillin-resistant Streptococcus pneumoniae is related to high consumption of antibiotics in general, as well as to increased use of aminopenicillins and/or probably to wider use of oral cephalosporins. Increased consumption of macrolides, especially the long-acting ones, correlates significantly with the level of macrolide resistance of group A streptococci and S. pneumoniae while increased use of oral cephalosporins might be associated with the increase of beta-lactamase-producing strains of Moraxella catarrhalis. Trimethoprim/sulphamethoxazole resistance is strongly associated with resistance to penicillin. A rise in consumption of fluoroquinolones is consonant with a higher rate of resistance to quinolones of S. pneumoniae, Escherichia coli and other Gram-negative bacteria. Paediatric bacterial isolates are more often resistant to various antimicrobial agents than isolates from adult patients; this higher resistance rate may be due to more frequent antimicrobial treatments in children, and extensive child to child transmission. Reliable data on antimicrobial consumption and resistance should form a basis for national policies devised to reduce the resistance of microorganisms to antibiotics.

The study was designed to evaluate rational antibiotic use in relation to diagnosis and bacteriological findings. All hospitalized patients who received antibiotics were evaluated by a cross-sectional study. Of the 713 patients hospitalized, 281 (39.4%) patients received 377 antibiotics. Among 30 different antibiotics the most frequently requested were first generation cephalosporins (19.9%), ampicillin-sulbactam (19.1%) and aminoglycosides (11.7%). Antibiotic use was appropriate in 64.2% of antibiotic requests. In analysis of appropriate use, a request after an infectious diseases consultation was a frequent reason (OR=14, P<0.001, CI=0.02-0.24). Antibiotics requested in conjunction with susceptibility results were found to be more appropriate than those ordered empirically (OR=4.5, P=0.017, CI=0.06-0.76). Inappropriate antibiotic use was significantly higher among unrestricted antibiotics than restricted ones (P<0.001). Irrational antibiotic use was high for unrestricted antibiotics. Additional interventions such as postgraduate training programmes and elaboration of local guidelines could be beneficial.

The macrolide class of antibiotics is well established and often recommended for use in the treatment of community-acquired respiratory tract infections. A number of agents with varying antimicrobial activity have been developed via chemical modification of the core macrolide structure, a macrocyclic lactam ring. Although structurally diverse, the macrolides share a common ability to bind to the bacterial 50S ribosome subunit and inhibit protein synthesis, thereby preventing bacterial multiplication. Resistance in the clinic is due to modification of the 50S subunit in the area of the peptidyl transferase center or to an efflux pump. The newer macrolides, and in particular azithromycin, with their broad-spectrum microbiological profile have extended the therapeutic uses of this class of antibiotics and ensured that they remain an integral part of the clinician's armamentarium.

The macrolides are generally well tolerated when used for the treatment of acute infections. Even when given long term for prophylaxis, there are few discontinuations due to side-effects. There are isolated reports of QT(c) prolongation in patients treated with erythromycin and other 14-membered-ring macrolides. Since the 14-membered-ring macrolides are metabolized by P450 isoenzymes, there is the potential for interaction with other therapeutic agents also metabolized in this way. Pharmacokinetic studies have demonstrated interactions between either erythromycin or clarithromycin and cyclosporin, cisapride, pimozide, disopyramide, astemizole, carbamazepine, midazolam, digoxin, hydroxymethylglutaryl-coenzyme A reductase inhibitors (i.e. 'statins') and warfarin. In patients receiving such concurrent therapy, azithromycin may be superior to erythromycin and clarithromycin.

The spectrum of antibiotic susceptibility of Borrelia burgdorferi has been only partially defined. In the present study the effectiveness of 12 antimicrobials, belonging to six different antibiotic classes have been tested against Borrelia burgdorferi s.s. (N=3), Borrelia garinii (N=3), Borrelia afzelii (N=3), Borrelia valaisiana (N=1), and Borrelia bissettii (N=1) isolates. These isolates were analysed by a new standardised colorimetric minimal inhibitory concentration (MIC) method based upon colour changes that result from actively metabolizing spirochaetes after 72 h of incubation. Piperacillin (MIC90: 0.08 mg/l), ceftriaxone (MIC90: 0. 04 mg/l), cefotaxime (MIC90: 0.15 mg/l), azithromycin (MIC90: 0.015 mg/l), roxithromycin (MIC90: 0.05 mg/l) and quinupristin/dalfopristin (MIC90: 0.12 mg/l) gave the lowest MIC values. Minimal inhibibitory activity of amoxycillin (MIC90: 1.04 mg/l), cefixime (MIC90: 1.33 mg/l), cefoperazone (MIC90: 0.83 mg/l) tetracycline (MIC90: 0.29 mg/l) and minocycline (MIC90: 0.30 mg/l) was slightly lower, whereas borrelia were resistant to amikacin (MIC90: >128 mg/l). Mean minimal borreliacidal concentrations (MBCs) were representatively determined for piperacillin (MBC: 1.8 mg/l), ceftriaxone (MBC: 2.0 mg/l), azithromycin (MBC: 0.82 mg/ml), roxithromycin (MBC: 1.8 mg/l), quinupristin/dalfopristin (MBC: 5.0 mg/l), minocycline (MBC: 5.8 mg/l), and amikacin (MBC: >128 mg/l) by using conventional subculture for three weeks in combination with dark-field microscopy. B. garinii proved to be the most susceptible of the genospecies tested. Our study showed excellent in vitro antimicrobial activity of all classes of antibiotics tested, except the aminoglycosides and hence their suitability for therapy of Lyme disease.

Concern regarding antimicrobial resistance has led to proposals for the prudent use of antimicrobial agents. Whilst this is appropriate, it is not sufficient. This article proposes that dosage schedules should be developed to provide a basis for the rational use of antimicrobial drugs. This requires knowledge of resistance mechanisms and transfer, the biochemistry and structure of microorganisms and both the pharmacodynamics and pharmacokinetics of antimicrobial drugs. Dosage schedules should maintain concentrations at the site of infection in excess of MIC(90) for bacteriostatic drugs and bactericidal drugs acting primarily by time-dependent mechanisms whilst they should provide high AUIC and C(max)/minimum inhibitory concentration (MIC) values for agents acting mainly by concentration-dependent mechanisms. It is proposed that pharmacodynamic and population pharmacokinetic data should be integrated through use of the sigmoidal E(max) equation, together with mathematical modelling and appropriate statistical analyses, to take account of the natural variation in drug pharmacodynamics and pharmacokinetics.

The correlation between consumption of antimicrobials in humans and the emergence of resistance in bacteria is complex and has proved difficult to establish. Besides antimicrobial use, many other distinct contributing factors are also involved in the issue. Despite this complexity, there is a substantial body of evidence that the use of antibiotics in prophylaxis and in therapy is associated with the development of resistance in the hospital and in the community. Some examples are reviewed, including increase of resistance in enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp., Streptococcus pneumoniae, Staphylococcus aureus, Coagulase Negative Staphylococci and Streptococcus pyogenes after the use of beta-lactam antibiotics, aminoglycosides, fluoroquinolones and macrolides. Success in reversing the rise of resistant strains has been rarely described. Two examples are highlighted, the reduction in the incidence of nasal carriage of penicillin-resistant pneumococci in Icelandic children, and a significant decline in erythromycin resistance in S. pyogenes after the reduction in the use of macrolides in Finland.