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Introduction: Invasive Candida Infections (ICIs) have undergone a series of significant epidemiological, pathophysiological, and clinical changes during the last decades, with a shift toward non-albicans species, an increase in the rate of exogenous infections and clinical manifestations ranging from candidemia to an array of highly invasive and life-threatening clinical syndromes. The long-acting echinocandin rezafungin exhibits potent in-vitro activity against most wild-type and azole-resistant Candida spp. including C.auris ., Areas Covered: The following topics regarding candidemia only and ICIs were reviewed and addressed: i) pathogenesis; ii) epidemiology and temporal evolution of Candida species; iii) clinical approach; iv) potential role of the novel long-acting rezafungin in the treatment of ICIs., Expert Opinion: Authors' expert opinion focused on considering the potential role of rezafungin in the evolving context of ICIs. Rezafungin, which combines a potent in-vitro activity against Candida species, including azole-resistant strains and C.auris , with a low likelihood of drug-drug interactions and a good safety profile, may revolutionize the treatment of candidemia/ICI. Indeed, it may shorten the length of hospital stays when clinical conditions allow and extend outpatient access to treatment of invasive candidiasis, especially when prolonged treatment duration is expected.

Introduction: The choice of best therapeutic strategy for difficult-to-treat resistance (DTR) Gram-negative infections currently represents an unmet clinical need., Areas Covered: This review provides a critical reappraisal of real-world evidence supporting the role of pharmacokinetic/pharmacodynamic (PK/PD) optimization of novel beta-lactams in the management of DTR Gram-negative infections. The aim was to focus on prolonged and/or continuous infusion administration, penetration rates into deep-seated infections, and maximization of PK/PD targets in special renal patient populations. Retrieved findings were applied to the three most critical clinical scenarios of Gram-negative resistance phenotypes (i.e. carbapenem-resistant Enterobacterales ; difficult-to-treat resistant Pseudomonas aeruginosa , and carbapenem-resistant Acinetobacter baumannii )., Expert Opinion: Several studies supported the role of PK/PD optimization of beta-lactams in the management of DTR Gram-negative infections for both maximizing clinical efficacy and preventing resistance emergence. Optimizing antimicrobial therapy with novel beta-lactams based on the so called 'antimicrobial therapy puzzle' PK/PD concepts may represent a definitive jump into the future toward a personalized patient management of DTR Gram negative infections. Establishing a dedicated and coordinated multidisciplinary team and implementing a real-time TDM-guided personalized antimicrobial exposure optimization of novel beta-lactams based on expert clinical pharmacological interpretation, could represent crucial cornerstones for the proper management of DTR Gram-negative infections.

Introduction: Prompt implementation of appropriate targeted antibiotic therapy representsa valuable approach in improving clinical and ecological outcome in critically septic patients. Thismultidisciplinary opinion article aims to develop evidence-based algorithms for targeted antibiotictherapy of infection-related ventilator associated complications (IVACs) caused by  Enterobacterales ,which are among the most common pathogens associated with these conditions., Areas Covered: A multidisciplinary team of four experts had several rounds of assessment for developingalgorithms devoted to targeted antimicrobial therapy of IVACs caused by  Enterobacterales .A literature search was performed on PubMed-MEDLINE (until March 2021) to provide evidence forsupporting therapeutic choices. Quality and strength of evidence was established according toa hierarchical scale of the study design. Six different algorithms with associated recommendations concerning therapeutic choice and dosing optimization were suggested according to the susceptibilitypattern of Enterobacterales: multi-susceptible, extended-spectrum beta-lactamase (ESBL)-producing,AmpC beta-lactamase-producing,  Klebsiella pneumoniae  carbapenemase (KPC)-producing, OXA-48-producing, and metallo-beta-lactamase (MBL)-producing  Enterobacterales ., Expert Opinion: The implementation of algorithms focused on prompt revision of antibiotic regimensguided by results of conventional and rapid diagnostic methodologies, appropriate place in therapy ofnovel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and PK/PD optimization of antibiotic dosing regimens is strongly suggested.

Introduction : New diagnostics may be useful in clinical practice, especially in contexts of high prevalence of multidrug-resistant organisms (MDRO). However, misuse of diagnostic tools may lead to increased costs and worse patient outcome. Conventional and new techniques should be appropriately positioned in diagnostic algorithms to guide an appropriate use of antimicrobial therapy. Areas covered : A panel of experts identified 4 main areas in which the implementation of diagnostic stewardship is needed. Among chronic infections, bone and prosthetic joint infections and subacute-chronic intravascular infections and endocarditis represent common challenges for clinicians. Among acute infections, bloodstream infections and community-acquired pneumonia may be associated with high mortality and require appropriate diagnostic approach. Expert opinion : Diagnostic stewardship aims to improve the appropriate use of microbiological diagnostics to guide therapeutic decisions through appropriate and timely diagnostic testing. Here, diagnostic algorithms based on different patient profiles are proposed for chronic and acute clinical syndromes. In each clinical scenario, combining conventional and new diagnostic techniques is crucial to make a rapid and accurate diagnosis and to guide the selection of antimicrobial therapy. Barriers related to the implementation of new rapid diagnostic tools, such as high initial costs, may be overcome through their rational and structured use.

Introduction: The COVID-19 pandemic has dramatically challenged the national health systems worldwide in the last months. Dalbavancin is a novel antibiotic with a long plasmatic half-life and simplified weekly administration regimens, thus representing a promising option for the outpatient treatment of Gram-positive infections and the early discharge of hospitalized patients. Dalbavancin is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Many preliminary data seem to support its use in other indications, such as osteomyelitis, prosthetic joint infections, and infective endocarditis., Areas Covered: A search in the literature using validated keywords (dalbavancin, Gram-positive infections, Gram-positive cocci, ABSSSI, intravenous treatment, and long-acting antibiotics) was conducted on biomedical bibliographic databases (PubMed and Embase) from 2004 to 30 September 2020. Results were analyzed during two consensus conferences with the aim to review the current evidence on dalbavancin in Gram-positive infections, mainly ABSSSI, osteomyelitis, and infective endocarditis, highlight the main limitations of available studies and suggest possible advantages of the molecule., Expert Opinion: The board identifies some specific subgroups of patients with ABSSSIs who could mostly benefit from a treatment with dalbavancin and agrees that the design of homogenous and robust studies would allow a broader use of dalbavancin even in other clinical settings.

Introduction : Acute bacterial skin and skin-structure infections (ABSSSI) are a subgroup of skin and soft tissue infections and are a common source of morbidity in both the community and the hospital setting. The most common cause of ABSSSI is Staphylococcus aureus , which also includes methicillin-resistant S. aureus (MRSA), together with beta-hemolytic streptococci, enterococci, and Gram-negative bacteria. Since the emergence of MRSA, the management of ABSSSI has become more challenging. Novel therapies alternative to teicoplanin and vancomycin, intravenous agents commonly used against MRSA and employed in hospitalized patients, and to other antibiotics which are used as standard of care for MRSA infection, with a higher efficacy and safer profile are worth evaluating. Areas covered : This review presents and discusses current evidence on the use of dalbavancin in the treatment of ABSSSI. Expert opinion : Dalbavancin represents a promising therapeutic choice in patients with ABSSSI, thanks to its favorable pharmacokinetic profile, valuable antimicrobial spectrum, and good safety profile.

Introduction : The management of acute wounds may be affected by malpractices leading to poor outcome, prolonged hospital stay and inappropriate use of antibiotic therapy. Areas covered : Acute wound infections are represented by surgical site and post-traumatic infections. The aim of this expert opinion is to identify a list of inadvisable actions and to provide a guide for an optimal management of acute wound infections. A literature search using Pubmed/MEDLINE database was performed. Articles pertaining to areas covered published until December 2019 were selected. We identified the most common malpractices in this setting and, using the Choosing Wisely methodology, we proposed a list of "Don'ts" for an easy use in clinical practice. Expert opinion : Malpractices may occur from the surgical prophylaxis to the discharge of patient. A prolonged surgical prophylaxis, the underestimation of signs and symptoms, the omission of source control, the inappropriate collection of wound swab, the improper use of clinical microbiology and pharmacology, the lack of hygiene measures and the delay of discharge are all factors that may lead to unfavorable outcome. A multidisciplinary approach is needed to optimally manage these patients. The "Don'ts" refer to all professional figures involved in the management of patients with acute wound infections.

Introduction : The epidemiology of carbapenem-resistant Enterobacterales (CRE) is increasingly worldwide. Production of carbapenemases is the most common and efficient mechanism of carbapenem resistance, and could theoretically be overcome by optimizing the pharmacokinetic/pharmacodynamic (PK/PD) behavior of meropenem. Areas covered : This article overviews the available literature concerning the potential role that meropenem may still have in the treatment carbapenem-resistant Enterobacteriaceae infections. Clinical studies published in English language until June 2019 were searched on PubMed database. Expert commentary : High-dose continuous infusion meropenem-based combination regimens could still represent a valuable option for treating CRE infections in specific circumstances. Knowledge of the local prevalent mechanisms of carbapenem resistance, of patient clinical severity, of the site of infection, of an accurate minimum inhibitory concentration (MIC) value, coupled with the possibility of carrying-out a real-time therapeutic drug monitoring (TDM)-based PK/PD optimization of drug exposure must all be considered as fundamental for properly pursuing this goal.

Introduction : Ceftobiprole is a fifth-generation cephalosporin with a broad spectrum of antimicrobial activity, including also methicillin-resistant Staphylococcus aureus (MRSA). Ceftobiprole is approved for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia, in several European and non-European countries. Areas covered : In this narrative review, we discuss the current place in therapy of ceftobiprole, both within and outside approved indications. An inductive MEDLINE/PubMed search of the available literature was conducted. Expert opinion : There are three main reasons which render ceftobiprole an attractive option for the empirical and targeted treatment of CAP and HAP: ( i ) its broad spectrum of activity; ( ii ) its activity against MRSA; ( iii ) its good safety profile. For these indications, ceftobiprole should be employed thoughtfully, in those scenarios in which its intrinsic advantages could be maximized. The use of ceftobiprole outside approved indications could be justified in specific scenarios, such as when other approved alternatives are ineffective, when the risk of toxicity due to other agents is unacceptable, and for salvage therapy. In the near future, ongoing phase 3 studies and further observational experiences could both enlarge the current panel of approved indications and enrich our knowledge on the use of ceftobiprole for off-label indications.

Introduction: Ceftolozane/tazobactam (C/T) is a new antibiotic resulting from the combination of a novel cephalosporin, structurally similar to ceftazidime, with tazobactam, a well-known beta-lactamase inhibitor. C/T remains active against extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae and multi-drug resistant (MDR) P. aeruginosa, and has been recently approved for the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). A trial on hospital-acquired pneumonia is ongoing. Areas covered: The place in therapy of C/T is delineated by addressing the following main topics: (i) antimicrobial properties; (ii) pharmacological properties; (iii) results of clinical studies. Expert commentary: C/T is approved for cIAI and cUTI. However, the drug has a special value for clinicians in any kind of infectious localization for two main reasons. The first is that C/T is especially valuable in suspected or documented severe infections due to MDR P. aeruginosa, which is not a rare occurrence in many countries. The second is that C/T may provide an alternative to carbapenems for the treatment of infections caused by ESBL-producers, thus allowing a carbapenem-sparing strategy. Reporting of off-label use is mandatory to increase the body of evidence and the clinicians' confidence in using it for indications other than cIAI and cUTI.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most challenging bacterial pathogens responsible for severe infections among hospitalized patients. In recent years there is increasing evidence that the clinical efficacy of vancomycin is progressively decreasing. Although daptomycin and linezolid are valuable alternatives to vancomycin for the treatment of MRSA-related bloodstream infections and pneumonia, respectively, a great deal of debate exists about their role in daily clinical practice due to cost-effectiveness issues. In this article we put into perspective the importance of pharmacokinetic/pharmacodynamic (PK/PD) considerations based on recent experimental and clinical data to argue whether they could be helpful in identifying clinical conditions in which these agents could be advantageous as compared to vancomycin.

Community-acquired pneumonia (CAP) represents one of the most common reasons for hospitalization in elderly people. Because older persons are the fastest growing segment of the population, a further increase of the incidence of CAP is expected in the next few years. Due to the high frequency, the different epidemiology, the atypical clinical presentation and the age-related modifications in drug metabolism that complicate the treatment, infections in the elderly people represent a major challenge for physicians. Despite the peculiarity of the management of CAP in the elderly people, no specific recommendations for antimicrobial treatment are provided in the international guidelines. The aim of this review is to give an update of the current antibiotic options for CAP in the elderly people reporting available data on the CAP etiology and risk factors, and tolerability, toxicity and pharmacokinetics/pharmacodynamic of antimicrobial agents used for elderly patients.

Candida infections represent challenging causes of severe sepsis and/or of septic shock in the critically ill patients. Knowledge of current pharmacological concepts may promote a more wise use of echinocandins in the management of Candida infections in this setting. Echinocandins have some advantages over azoles, both pharmacodynamically (rapid fungicidal activity, anti-biofilm activity, unmodified activity against Candida isolates with decreased susceptibility to azoles and anti-cytokine/anti-chemokine activity) and pharmacokinetically (low interindividual variability, low potential for drug-drug interactions), that may influence the timing and the choice of therapy of Candida diseases in the critically ill patients. However, concerns exist in regards to the feasibility of fixed dosing regimens of echinocandins in all of the different patient populations and in regards to the effectiveness of echinocandin monotherapy in some clinical settings. In presence of deep-seated infections, voriconazole or liposomal amphotericin B may be valuable alternatives or add-on therapy.

Hospital infection due to multidrug-resistant Gram-positive bacteria may often represent a life-threatening challenge; thus, to appropriately combat them, clinicians should be confident and systematically apply several important pharmacodynamic concepts. The concept of 'correct antibiotic treatment' should include, in addition to an appropriate choice in terms of antimicrobial susceptibility, an appropriate dosage and administration schedule consistent with the pharmacodynamic principles. In the next few years, it is expected that some of the anti-Gram-positive antimicrobial agents that are currently under investigation will be added to the therapeutic armamentarium. However, optimization of the usage of old drugs still remains a clinical priority and a scientific challenge, whose dignity may be considered of similar importance to that of the assessment of the possible therapeutic role of the new compounds.