Andrea Novelli

The containment of the phenomenon of resistance towards antimicrobials is a priority, especially in preserving molecules acting against Gram-negative pathogens, which represent the isolates more frequently found in the fragile population of patients admitted to Intensive Care Units. Antimicrobial therapy aims to prevent resistance through several actions, which are collectively known as “antimicrobial stewardship”, to be taken together, including the application of pharmacokinetic/pharmacodynamic (PK/PD) principles. PK/PD application has been shown to prevent the emergence of resistance in numerous experimental studies, although a straight translation to the clinical setting is not possible. Individualized antibiotic dosing and duration should be pursued in all patients, and even more especially when treating intensive care unit (ICU) septic patients in whom optimal exposure is both difficult to achieve and necessary. In this review, we report on the available data that support the application of PK/PD parameters to contain the development of resistance and we give some practical suggestions that can help to translate the benefit of PK/PD application to the bedside.

Background: New insights into the diagnosis, treatment and prevention of acute otitis media (AOM) have been gained in recent years. For this reason, the Italian Paediatric Society has updated its 2010 guidelines. Methods: A literature search was carried out on PubMed. Only pediatric studies published between January 1, 2010 and December 31, 2018 in English or Italian were included. Each included study was assessed according to the GRADE methodology. The quality of the systematic reviews was assessed using AMSTAR 2. The recommendations were formulated by a multidisciplinary panel of experts. Results: Prompt antibiotic treatment is recommended for children with otorrhea, intracranial complications and/or a history of recurrence and for children under the age of 6 months. For children 6 months to 2 years of age, prompt antibiotic treatment is recommended for all forms of unilateral and bilateral AOM, whether mild or severe. Prompt antibiotic treatment is also recommended for children over 2 years with severe bilateral AOM. A watchful-waiting approach can be applied to children over 2 years with mild or severe unilateral AOM or mild bilateral AOM. High doses of amoxicillin, or amoxicillin-clavulanic acid for patients with a high risk of infection by Beta-lactamase producing strains, remain the first-line antibiotics. Conclusions: AOM should be managed on a case-by-case basis that takes account of the child’s age, the severity of the episode and whether it is unilateral or bilateral. In patients under 2 years, prompt antibiotic treatment is always recommended.

Ceftolozane-tazobactam (C/T) pharmacokinetics during extracorporeal membrane oxygenation (ECMO) has not been previously studied. In this work we report on the C/T plasmatic levels in a lung transplant (LTX) recipient during ECMO, treated with C/T (i.v., 2 g ceftolozane and 1 g tazobactam, every 8 hours]) for a Pseudomonas aeruginosa pulmonary infection.

Background and Objective The Rifampicin (RF) ‐ Clindamycin (CL) combination is recommended as first line therapy in moderate to severe Hidradenitis Suppurativa (HS) by European S1 guidelines. Although prolonged use of RF should be discouraged, there are currently few alternatives to this combination therapy. The aim of this study was to assess retrospectively the efficacy of oral CL monotherapy in patients diagnosed with HS. Methods In the period January 2017 ‐ May 2018 31 HS patients who received a 300 mg b.i.d. oral dose of CL were studied retrospectively. Efficacy of the treatment was evaluated by comparing the main HS severity scores (Sartorius score modified by J.E. Revuz, Hidradenitis Suppurativa Physician Global Assessment/HS‐PGA and International Hidradenitis Suppurativa Severity Score System/IHS4) before (W0) and after (W12) CL oral therapy. Results CL efficacy was demonstrated by the extreme and significant reduction of all three disease severity parameters during the 12‐week period (p≤0.01). There was also a statistically significant change in the mean VAS for pain. Conclusions This study demonstrates the efficacy of oral CL monotherapy as RF‐sparing regimen alternative to RF‐CL combination in a selected group of patients.

Due to the so‐called “antibiotic resistance crisis” new antibacterial agents are urgently sought to treat multidrug‐resistant pathogens. A group of gold‐ or silver‐based complexes, of general formula [M(PEt₃)X] (with M=Au or Ag, and X=Cl, Br or I), alongside with three complexes bearing a positive or negative charge—[Au(PEt₃)₂]Cl, K[Au(CN)₂] and [Ag(PEt₃)₂]NO₃—were prepared and comparatively tested with auranofin on a representative panel of pathogens including Gram‐positive, Gram‐negative and Candida strains. Interestingly, all the gold and silver complexes tested were active on Gram‐positive strains, with the gold complexes having greater efficacy. The effects of the gold compounds were potentiated to a larger extent than silver compounds when tested in combination with a permeabilizing agent. A number of relevant structure–activity relationships emerged from the comparative analysis of the observed antibacterial profiles, shedding new light on the underlying molecular mechanisms of the action of these compounds.

Ceftolozane-tazobactam pharmacokinetics during extracorporeal membrane oxygenation (ECMO) has not been previously studied. In this work we report on the ceftolozane and tazobactam plasmatic levels in a lung transplant recipient during ECMO, treated with ceftolozane-tazobactam (2g/1g, intravenously every 8 h, 1 h infusion) for a Pseudomonas aeruginosa pulmonary infection. Ceftolozane Cmax and Cmin, monitored during 96 hrs, remained above 60 and 20 μg/mL, respectively, with optimal drug exposure (100% % T _MIC ). Tazobactam levels were above 1.9 μg/mL.

This study aimed to assess the predictors of acute kidney injury (AKI) during colistin therapy in a cohort of patients with bloodstream infections (BSI) due to colistin-susceptible Gram-negative bacteria, focusing on the role of serum albumin levels. The study consisted of two parts: (1) a multicentre retrospective clinical study to assess the predictors of AKI during colistin therapy, defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria; and (2) bioinformatic and biochemical characterization of the possible interaction between human serum albumin and colistin. Among the 170 patients included in the study, 71 (42%), 35 (21%), and 11 (6%) developed KDIGO stage 1 (K1-AKI), KDIGO stage 2 (K2-AKI), and KDIGO stage 3 (K3-AKI), respectively. In multivariable analyses, serum albumin <2.5 g/dL was independently associated with K1-AKI (subdistribution hazard ratio [sHR] 1.85, 95% confidence interval [CI] 1.17–2.93, p = 0.009) and K2-AKI (sHR 2.37, 95% CI 1.15–4.87, p = 0.019). Bioinformatic and biochemical analyses provided additional information nurturing the discussion on how hypoalbuminemia favors development of AKI during colistin therapy. In conclusion, severe hypoalbuminemia independently predicted AKI during colistin therapy in a large cohort of patients with BSI due to colistin-susceptible Gram-negative bacteria. Further study is needed to clarify the underlying causal pathways.