Antibiotic therapy for nonfermenting Gram-negative bacilli infections: future perspectives.

PURPOSE OF REVIEW: Serious infections caused by nonfermenting Gram-negative bacteria (NF-GNB) pose a significant challenge for clinicians due to the limited treatment options available, which are frequently associated with issues of toxicity and unfavourable pharmacokinetic profiles. The aim of this review is to provide a brief overview of the existing data concerning the ongoing development of antiinfective agents targeting NF-GNB. RECENT FINDINGS: Several agents exhibiting efficacy against NF-GNB are under clinical investigation. Durlobactam-sulbactam and cefepime-taniborbactam emerge as promising therapeutic avenues against carbapenem-resistant Acinetobacter baumanii . Cefepime-zidebactam may serve as a suitable treatment option for urinary tract infections caused by a wide range of NF-GNB. Cefepime-enmetazobactam demonstrates potent in vitro activity against various NF-GNB strains; however, its role as an anti- Pseudomonal agent is inadequately substantiated by available data. Xeruborbactam is a wide ß-lactamase inhibitor that can be associated with a range of agents, enhancing in-vitro activity of these against many NF-GNB, including those resistant to newer, broader spectrum options. Lastly, murepavadin appears to be a potential pathogen-specific solution for severe Pseudomonas infections; however, additional investigation is necessary to establish the safety profile of this compound. SUMMARY: Each of the novel molecules reviewed possesses an interesting range of in-vitro activity against NF-GNB. In addition, some of them have already been proved effective in vivo, underscoring their potential as future treatment options.

Delafloxacin for the treatment of adult patients with community-acquired bacterial pneumonia.

INTRODUCTION: Delafloxacin is a novel fluoroquinolone with peculiar characteristics such as a weak acid character, frequent in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA), and a low potential for resistance selection compared with other fluoroquinolones. AREAS COVERED: The present narrative review summarizes the available data on the use of delafloxacin for the treatment of community-acquired bacterial pneumonia (CABP). EXPERT OPINION: Delafloxacin is a novel fluoroquinolone with a unique profile and some interesting characteristics for the treatment of CABP, such as its marked activity against gram-positive bacteria, including MRSA, the possible use as monotherapy (owing to anti-Gram-negative and anti-atypical bacteria activity), the retained activity against many Gram-positive organisms resistant to other fluoroquinolones, and the availability of both oral and intravenous formulations. The results of the DEFINE-CABP phase-3 randomized controlled trial have shown noninferiority of delafloxacin vs. moxifloxacin for the treatment of CABP, thereby providing a further option for this indication. Against this background, future post-marketing experiences remain of crucial importance for further refining the place in therapy of delafloxacin in the real-life management algorithms of CABP, either as first-line option or step-down/outpatient treatment.

Therapeutic options for difficult-to-treat Acinetobacter baumannii infections: a 2020 perspective.

INTRODUCTION: Treatment of severe infections due to Acinetobacter baumannii with difficult-to-treat resistance (DTR-AB), which exhibits resistance to all ß-lactams, ß-lactam/ß-lactamases inhibitor combinations, and fluoroquinolones, remains a challenge for clinicians. AREAS COVERED: The present perspective provides a personal view on both current and future agents for the treatment of severe DTR-AB infections. EXPERT OPINION: We currently are in a transition era for the treatment of DTR-AB infections, where in the past 20 years, polymyxin-based regimens have become the most used approach (although possibly suboptimal, there were few or no alternatives) and where in the next 20 years, polymyxins will likely be replaced by less toxic novel agents as first-line choices. Two novel antimicrobial agents have been recently approved that show activity against DTR-AB, cefiderocol and eravacycline, while durlobactam/sulbactam is in phase-3 of clinical development. In the near future, these agents could become important first-line choices for the treatment of DTR-AB within approved indications, or for off-label indications in the absence of dependable alternatives. Good-quality post-marketing experiences remain necessary for arising clinically relevant questions and guiding the design of further dedicated randomized controlled trials to stably optimize the use of novel agents for DTR-AB infections in the next decades.

The role of new antimicrobials for Gram-negative infections in daily clinical practice.

PURPOSE OF REVIEW: To discuss a possible clinical reasoning for treating resistant Gram-negative bacteria (GNB) infections in daily clinical practice, as well as developing a research agenda for the field. RECENT FINDINGS: Novel agents, both belonging to ß-lactams and to other classes of antimicrobials, have recently become available, likely replacing polymyxins or polymyxin-based combination regimens as the preferred choices for the first-line treatment of severe resistant GNB infections in the near future. SUMMARY: The peculiar characteristics of novel agents for severe resistant GNB infections have abruptly made the structure of previous therapeutic algorithms somewhat obsolete, in view of the differential activity of most of them against different classes of carbapenemases. Furthermore, other agents showing activity against resistant GNB are in late phase of clinical development. Optimizing the use of novel agents in order both to guarantee the best available treatment to patients and to delay the emergence and spread of resistance is an important task that cannot be postponed, especially considering the unavailability of well tolerated and fully efficacious options for treating resistant GNB infections that we faced in the last 15 years.

Ceftaroline for severe community-acquired pneumonia: A real-world two-centre experience in Italy and Spain.

BACKGROUND: Ceftaroline is one of latest additions to the armamentarium for treating community-acquired pneumonia (CAP). This study aimed to describe the outcome of severe CAP (SCAP) in a cohort of hospitalised patients treated with ceftaroline. METHODS: A retrospective, observational study of patients with SCAP treated with ceftaroline in two hospitals in Spain and Italy. The primary objective was to explore 30-day mortality after diagnosis of SCAP. RESULTS: During the study period the following were observed: there were 89 cases of SCAP treated with ceftaroline and 53 cases used in combination with other antibiotics (60%). Overall, 30-day mortality and clinical failure were 20% (18 of 89) and 36% (32 of 89), respectively. Independent predictors of 30-day mortality were: increasing age (OR for 1 year increase 1.0, 95% CI 1.0-1.1, P 0.043), presence of solid neoplasm (OR 4.0, 95% CI 1.0-15.1, P 0.044) and concomitant therapy with oseltamivir (OR 8.5, 95% CI 1.2°57.3, P 0.029). The only independent predictor of clinical failure was the time elapsing from SCAP diagnosis to ceftaroline therapy (OR for each passing day 1.5, 95% CI 1.1-1.9, P 0.003). The clinical success rate was 64% (57 of 89). In the subgroups of patients with proven Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) infection, clinical success was 83% (10 of 12), 75% (three of four) and 56% (five of nine), respectively. CONCLUSIONS: Considering its spectrum of activity, ceftaroline could represent an important therapeutic option for SCAP. Further studies are needed to identify the precise clinical success rate against MRSA in a larger cohort of patients with SCAP.

The role of fosfomycin for multidrug-resistant gram-negative infections.

PURPOSE OF REVIEW: In the last decade, an increasing interest in using fosfomycin for the treatment of multidrug-resistant gram-negative (MDR-GNB) infections have been registered, especially when none or only a few other active alternatives remained available. RECENT FINDINGS: Fosfomycin may remain active against a considerable proportion of MDR-GNB. In observational studies, a possible curative effect of oral fosfomycin monotherapy has been described for uncomplicated urinary tract infections (UTI) and bacterial prostatitis caused by MDR-GNB, whereas intravenous fosfomycin has been mostly used in combination with other agents for various type of severe MDR-GNB infections. The ZEUS randomized controlled trial (RCT) has started to provide high-level evidence about the possible use of fosfomycin for complicated UTI caused by extended-spectrum ß-lactamase-producing GNB, but no results of large RCT are currently available to firmly guide the use of fosfomycin for carbapenem-resistant GNB. SUMMARY: Fosfomycin is an important therapeutic option for MDR-GNB infections. Further pharmacokinetic/pharmacodynamic and clinical research is needed to optimize its use.

Pharmacokinetics of high-dose extended-infusion meropenem during pulmonary exacerbation in adult cystic fibrosis patients: a case series.

This case series explored the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of meropenem (MEM) in adult cystic fibrosis (CF) patients hospitalized for a pulmonary exacerbation. From January 2015 to June 2016, all adult patients with cystic fibrosis (CF) and chronic pulmonary infection due to meropenem (MEM)-susceptible/intermediate Pseudomonas aeruginosa who received at least 48 h of MEM as an extended 3-hour infusion for treating a pulmonary exacerbation were enrolled. MEM plasma concentrations were determined by high-performance liquid chromatography. Six adult CF patients with a median age of 47 years were included in the study. MEM showed a high Vd (mean 45.98 L, standard deviation [SD] ±34.45). A minimal PK/PD target of 40% T > minimum inhibitory concentration (MIC) with respect to the MEM MIC of P. aeruginosa strains isolated from sputum during exacerbation was achieved in 5/6 patients (83%). MEM failed to achieve this target only in one patient, whose strain showed the highest MEM MIC in our cohort (8 mg/L). In all patients, MEM was well tolerated, and no adverse events were reported. In conclusion, high-dose, extended-infusion MEM during pulmonary exacerbation showed a high Vd in six adult CF patients with high median age, and was well tolerated.

Meropenem for treating KPC-producing Klebsiella pneumoniae bloodstream infections: Should we get to the PK/PD root of the paradox?

The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) ≥16 mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2 g every 8 hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1×MIC and T > 40% 4×MIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024 mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1×MIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64 mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32 mg/L.

Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study.

OBJECTIVES: Infections caused by Klebsiella pneumoniae (Kp) carbapenemase (KPC)-producing strains of Kp have become a significant threat in recent years. To assess their outcomes and identify risk factors for 14 day mortality, we conducted a 4 year (2010-13) retrospective cohort study in five large Italian teaching hospitals. METHODS: The cohort included 661 adults with bloodstream infections (BSIs; n = 447) or non-bacteraemic infections (lower respiratory tract, intra-abdominal structure, urinary tract or other sites) caused by a KPC-Kp isolate. All had received ≥48 h of therapy (empirical and/or non-empirical) with at least one drug to which the isolate was susceptible. RESULTS: Most deaths occurred within 2 weeks of infection onset (14 day mortality: 225/661, 34.1%). Logistic regression analysis identified BSI (OR, 2.09; 95% CI, 1.34-3.29), presentation with septic shock (OR, 2.45; 95% CI, 1.47-4.08), inadequate empirical antimicrobial therapy (OR, 1.48; 95% CI, 1.01-2.18), chronic renal failure (OR, 2.27; 95% CI, 1.44-3.58), high APACHE III score (OR, 1.05; 95% CI, 1.04-1.07) and colistin-resistant isolates (OR, 2.18; 95% CI, 1.37-3.46) as independent predictors of 14 day mortality. Combination therapy with at least two drugs displaying in vitro activity against the isolate was associated with lower mortality (OR, 0.52; 95% CI, 0.35-0.77), in particular in patients with BSIs, lung infections or high APACHE III scores and/or septic shock at infection onset. Combinations that included meropenem were associated with significantly higher survival rates when the KPC-Kp isolate had a meropenem MIC of ≤8 mg/L. CONCLUSIONS: KPC-Kp infections are associated with high mortality. Treatment with two or more drugs displaying activity against the isolate improves survival, mainly in patients who are critically ill.

Emergence of a KPC-3-Producing Escherichia coli ST69 as a Cause of Bloodstream Infections in Italy.

The spread of carbapenem-resistant gram negatives is a global emergency, and surveillance of new resistant clones is critical from both public health and clinical standpoints. Herein, we describe the emergence of a KPC-3-producing Escherichia coli ST69 as a cause of bloodstream infection in two Italian patients.

Management of ventilator-associated pneumonia: epidemiology, diagnosis and antimicrobial therapy.

Ventilator-associated pneumonia (VAP) is the most frequent infection among patients hospitalized in intensive care units, maintaining a high morbidity and mortality. The global incidence of VAP ranges from 8 to 28%. Early-onset VAP is mainly caused by community pathogens with a favorable pattern of antibiotic sensitivity, whereas late-onset VAP is often caused by multidrug-resistant pathogens, mainly methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter spp. and enteric Gram-negative bacilli. The diagnosis of VAP remains difficult to confirm, lacking both microbiological analysis and radiological signs of high specificity. The Clinical Infection Pulmonary Score has been proposed to overcome the difficulties related to the diagnosis, but is not applicable to all patient categories. A continuous evaluation of the antimicrobial therapeutic options, along with their pharmacodynamic and pharmacokinetic profiles, is mandatory to create therapeutic protocols and reduce VAP-related mortality.

Will new antimicrobials overcome resistance among Gram-negatives?

The spread of resistance among Gram-positive and Gram-negative bacteria represents a growing challenge for the development of new antimicrobials. The pace of antibiotic drug development has slowed during the last decade and, especially for Gram-negatives, clinicians are facing a dramatic shortage in the availability of therapeutic options to face the emergency of the resistance problem throughout the world. In this alarming scenario, although there is a shortage of compounds reaching the market in the near future, antibiotic discovery remains one of the keys to successfully stem and maybe overcome the tide of resistance. Analogs of already known compounds and new agents belonging to completely new classes of antimicrobials are in early stages of development. Novel and promising anti-Gram-negative antimicrobials belong both to old (cephalosporins, carbapenems, ß-lactamase inhibitors, monobactams, aminoglycosides, polymyxin analogues and tetracycline) and completely new antibacterial classes (boron-containing antibacterial protein synthesis inhibitors, bis-indoles, outer membrane synthesis inhibitors, antibiotics targeting novel sites of the 50S ribosomal subunit and antimicrobial peptides). However, all of these compounds are still far from being introduced into clinical practice. Therefore, infection control policies and optimization in the use of already existing molecules are still the most effective approaches to reduce the spread of resistance and preserve the activity of antimicrobials.