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Concept: Beta-lactam antibiotic

160

Beta-lactam antibiotics form the backbone of treatment for Gram-negative pneumonia in mechanically ventilated patients in the intensive care unit. However, this beta-lactam antibiotic backbone is increasingly under pressure from emerging resistance across all geographical regions, and health-care professionals in many countries are rapidly running out of effective treatment options. Even in regions that currently have only low levels of resistance, the effects of globalization are likely to increase local pressures on the beta-lactam antibiotic backbone in the near future. Therefore, clinicians are increasingly faced with a difficult balancing act: the need to prescribe adequate and appropriate antibiotic therapy while reducing the emergence of resistance and the overuse of antibiotics. In this review, we explore the burden of Gram-negative pneumonia in the critical care setting and the pressure that antibiotic resistance places on current empiric therapy regimens (and the beta-lactam antibiotic backbone) in this patient population. New treatment approaches, such as systemic and inhaled antibiotic alternatives, are on the horizon and are likely to help tackle the rising levels of beta-lactam antibiotic resistance. In the meantime, it is imperative that the beta-lactam antibiotic backbone of currently available antibiotics be supported through stringent antibiotic stewardship programs.

Concepts: Beta-lactam, Intensive care medicine, Antibiotics, Bacteria, Antibiotic resistance, Beta-lactam antibiotic, Antibiotic, Penicillin

159

Approaches to controlling emerging antibiotic resistance in health care settings have evolved over time. When resistance to broad-spectrum antimicrobials mediated by extended-spectrum β-lactamases (ESBLs) arose in the 1980s, targeted interventions to slow spread were not widely promoted. However, when Enterobacteriaceae with carbapenemases that confer resistance to carbapenem antibiotics emerged, directed control efforts were recommended. These distinct approaches could have resulted in differences in spread of these two pathogens. CDC evaluated these possible changes along with initial findings of an enhanced antibiotic resistance detection and control strategy that builds on interventions developed to control carbapenem resistance.

Concepts: Microorganism, Beta-lactam antibiotic, Antibiotics, United Kingdom, Medicine, Penicillin, Antibiotic resistance, Bacteria

28

Photodegradation may be the most important elimination process for cephalosporin antibiotics in surface water. Cefazolin (CFZ) and cephapirin (CFP) underwent mainly direct photolysis (t(½) = 0.7, 3.9 h), while cephalexin (CFX) and cephradine (CFD) were mainly transformed by indirect photolysis, which during the process a bicarbonate-enhanced nitrate system contributed most to the loss rate of CFX, CFD, and cefotaxime (CTX) (t(½) = 4.5, 5.3, and 1.3 h, respectively). Laboratory data suggested that bicarbonate enhanced the phototransformation of CFD and CFX in natural water environments. When used together, NO(3)(-), HCO(3)(-), and DOM closely simulated the photolysis behavior in the Jingmei River and were the strongest determinants in the fate of cephalosporins. TOC and byproducts were investigated and identified. Direct photolysis led to decarboxylation of CFD, CFX, and CFP. Transformation only (no mineralization) of all cephalosporins was observed through direct photolysis; byproducts were found to be even less photolabile and more toxic (via the Microtox test). CFZ exhibited the strongest acute toxicity after just a few hours, which may be largely attributed to its 5-methyl-1,3,4-thiadiazole-2-thiol moiety. Many pharmaceuticals were previously known to undergo direct sunlight photolysis and transformation in surface waters; however, the synergistic increase in toxicity caused by this cocktail (via pharmaceutical photobyproducts) cannot be ignored and warrants future research attention.

Concepts: Beta-lactam antibiotic, Cefalotin, Toxicology, Medicine, Surface water, Water, Cephalosporin antibiotics, Cephalosporin

27

Beta-lactam antibiotics are largely administered by bolus dosing, despite displaying time-dependent pharmacokinetics and pharmacodynamics and there being a strong rationale for continuous administration. The randomised controlled trials conducted to date comparing the mode of betalactam administration have been inconclusive and limited by non-equivalent dosing, unblinded administration and small sample sizes.

Concepts: Epidemiology, ClinicalTrials.gov, Beta-lactam, Pharmacology, Penicillin, Beta-lactam antibiotic, Sample size, Randomized controlled trial

27

Bacterial production of beta-lactamases, which hydrolyze beta-lactam type antibiotics, is a common antibiotic resistance mechanism. Antibiotic resistance is a high priority intervention area and one strategy to overcome resistance is to administer antibiotics with beta-lactamase inhibitors in the treatment of infectious diseases. Unfortunately, beta-lactamases are evolving at a rapid pace with new inhibitor resistant mutants emerging every day, driving the design and development of novel beta-lactamase inhibitors. Here, we examined the inhibitor recognition mechanism of two common beta-lactamases using molecular dynamics simulations. Binding of beta-lactamase inhibitor protein (BLIP) caused changes in the flexibility of regions away from the binding site. One of these regions was the H10 helix, which was previously identified to form a lid over an allosteric inhibitor binding site. Closer examination of the H10 helix using sequence and structure comparisons with other beta-lactamases revealed the presence of a highly conserved Trp229 residue, which forms a stacking interaction with two conserved proline residues. Molecular dynamics simulations on the Trp229Ala mutants of TEM-1 and SHV-1 resulted in decreased stability in the apo form, possibly due to loss of the stacking interaction as a result of the mutation. The mutant TEM-1 beta-lactamase had higher H10 fluctuations in the presence of BLIP, higher affinity to BLIP and higher cross-correlations with BLIP. Our results suggest that the H10 helix and specifically W229 are important modulators of the allosteric communication between the active site and the allosteric site.

Concepts: Escherichia coli, Enzyme inhibitor, Bacteria, Beta-lactamase, Penicillin, Clavulanic acid, Beta-lactam antibiotic, Antibiotic resistance

25

In 2010, the Clinical Laboratory Standards Institute (CLSI) lowered the minimum inhibitory concentration (MIC) breakpoints for many beta-lactam antibiotics to enhance detection of known resistance among Enterobacteriaceae. The decision to implement these new breakpoints, both 2010 and 2014, can have significant impact on both microbiology laboratories and antimicrobial stewardship programs. In this commentary, we discuss the changes and how implementation of these updated CLSI breakpoints requires partnership between antimicrobial stewardship programs and the microbiology laboratory, including data on the impact the changes had on antibiotic usage at our own institution.

Concepts: Chemistry, Bacteria, Antibiotic, Medical laboratory, Laboratory, Beta-lactam antibiotic, Penicillin, Medicine

24

An appropriate antibiotherapy is crucial for the safety and recovery of patients. Depending on the clinical conditions of patients, the required dose to effectively eradicate an infection may vary. An inadequate dosing not only reduces the efficacy of the antibiotic, but also promotes the emergence of antimicrobial resistances. Therefore, a personalized therapy is of great interest for improved patients' outcome and will reduce in long-term the prevalence of multidrug-resistances. In this context, on-site monitoring of the antibiotic blood concentration is fundamental to facilitate an individual adjustment of the antibiotherapy. Herein, we present a bioinspired approach for the bedside monitoring of free accessible ß-lactam antibiotics, including penicillins (piperacillin) and cephalosporins (cefuroxime and cefazolin) in untreated plasma samples. The introduced system combines a disposable microfluidic chip with a naturally occurring penicillin-binding protein, resulting in a high-performance platform, capable of gauging very low antibiotic concentrations (less than 6 ng ml(-1)) from only 1 µl of serum. The system’s applicability to a personalized antibiotherapy was successfully demonstrated by monitoring the pharmacokinetics of patients, treated with ß-lactam antibiotics, undergoing surgery.

Concepts: Virus, Antibiotic resistance, Antibiotic, Bacteria, Medicine, Beta-lactam antibiotic, Cephalosporin, Penicillin

23

The mortality of patients with sepsis and septic shock is still unacceptably high. An effective antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality; therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed focus and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account for selection of anti-infection treatment. Many pathophysiological alterations influence the pharmacokinetics of antibiotics during sepsis. The principle of standard dosing should be abandoned and replaced by an individual treatment approach with stronger weighting of the pharmacokinetics/pharmacodynamics (PK/PD) index of the substance groups. Although this is not yet the clinical standard, prolonged (or continuous) infusion of beta-lactam antibiotics and therapeutic drug monitoring (TDM) can help to achieve defined PK targets. Prolonged infusion is sufficient without TDM but for continuous infusion TDM is basically necessary. A further argument for individual PK/PD-oriented antibiotic approaches is the increasing number of infections due to multidrug resistant pathogens (MDR) in the intensive care unit. For effective treatment antibiotic stewardship teams (ABS team) are becoming more established. Interdisciplinary cooperation of the ABS team with infectiologists, microbiologists and clinical pharmacists leads not only to a rational administration of antibiotics but also has a positive influence on the outcome. The gold standards for pathogen detection are still culture-based detection and microbiological resistance testing for the various antibiotic groups. Despite the rapid investigation time, novel polymerase chain reaction (PCR)-based procedures for pathogen identification and resistance determination, are currently only an adjunct to routine sepsis diagnostics due to the limited number of studies, high costs and limited availability. In complicated septic courses with multiple anti-infective treatment or recurrent sepsis, PCR-based procedures can be used in addition to therapy monitoring and diagnostics. Novel antibiotics represent potent alternatives in the treatment of MDR infections. Due to the often defined spectrum of pathogens and the practically absent resistance, they are suitable for targeted treatment of severe MDR infections (therapy escalation).

Concepts: Antibiotic resistance, Beta-lactam antibiotic, Intensive care medicine, Microbiology, Penicillin, Antibiotic, Sepsis, Bacteria

22

Amoxicillin has become a major antimicrobial substance in pig medicine for the treatment and control of severe, systemic infections such as Streptococcus suis. The minimum inhibitory concentration 90% (MIC 90) is 0.06 μg amoxicillin/ml, and the proposed epidemiological cut-off value (ECOFF) is 0.5 μg/ml, giving only 0.7% of isolates above the ECOFF or of reduced susceptibility. Clinical breakpoints have not been set for amoxicillin against porcine pathogens yet, hence the use of ECOFFs. It has also been successfully used for bacterial respiratory infections caused by Actinobacillus pleuropneumoniae and Pasteurella multocida. The ECOFF for amoxicillin against A. pleuropneumoniae is also 0.5 μg/ml demonstrating only a reduced susceptibility in 11.3% of isolates. Similarly, P. multocida had an ECOFF of 1.0 μg/ml and a reduced susceptibility in only 2.6% of isolates. This reduced susceptibility disappears when combined with the beta-lactamase inhibitor, clavulanic acid, demonstrating that it is primarily associated with beta-lactamase production. In contrast, amoxicillin is active against Escherichia coli and Salmonella species but using ECOFFs of 8.0 and 4.0 μg/ml, respectively, reduced susceptibility can be seen in 70.9% and 67.7% of isolates. These high levels of reduced susceptibility are primarily due to beta-lactamase production also, and most of this resistance can be overcome by the combination of amoxicillin with clavulanic acid. Currently, amoxicillin alone is considered an extremely valuable antimicrobial in both human and animal medicine and remains in the critically important category of antibiotics alongside the fluoroquinolones and macrolides by the World Health Organization as well as the third- and fourth-generation cephalosporins, but these cephalosporins show marked resistance to basic beta-lactamase production and are only destroyed by the extended-spectrum beta-lactamases. Amoxicillin alone and in combination with clavulanic acid are currently classed together in Category 2 in the European Union. By reviewing the pharmacodynamic data and comparing this with pharmacokinetic data from healthy and infected animals and clinical trial data, it can be seen that the product has a good efficacy against S. suis and A. pleuropneumoniae, in spite of usage over many years. However, it may be much less efficacious on its own against E. coli, due to reduced susceptibility and resistance associated with beta-lactamase production, which is largely overcome by the use of clavulanic acid. It is felt that this differentiation may be useful in future classification of amoxicillin alone, in comparison with its combined use with clavulanic acid and thereby preserve the use of the more critically important antibiotics in veterinary medicine and reducing the risk of their resistance being transmitted to human.

Concepts: Clinical trial, Medicine, Bacteria, Microbiology, Beta-lactam antibiotic, Escherichia coli, Beta-lactamase, Clavulanic acid

11

Emerging resistance to antibiotics renders therapy of Typhoid Fever (TF) increasingly challenging. The current single-drug regimens exhibit prolonged fever clearance time (FCT), imposing a great burden on both patients and health systems, and potentially contributing to the development of antibiotic resistance and the chronic carriage of the pathogens. The aim of our study was to assess the efficacy of combining third-generation cephalosporin therapy with azithromycin on the outcomes of TF in patients living in an endemic region.

Concepts: Antibiotic, Malaria, Ceftriaxone, Beta-lactam antibiotic, Bacteria, Penicillin, Antibiotic resistance, Medicine