Community-Acquired Pneumonia in Canada During Coronavirus Disease 2019.

Dealing with coronavirus disease 2019 (COVID-19) has been a monumental test of medical skills and resources worldwide. The management of community-acquired pneumonia (CAP) can at times be difficult, but treating CAP in the setting of COVID-19 can be particularly trying and confusing and raises a number of challenging questions relating to etiology, diagnosis, and treatment. This article is based on the authors' experiences and presents an overview of how CAP during COVID-19 is handled in Canada. We touch on the issues of microbial etiology in patients with CAP in the setting of COVID-19 as well as diagnostic, site of care, and treatment approaches. Published guidelines are the basis of management of CAP and are discussed in the context of Canadian data. We also outline the usual treatment approaches to COVID-19, particularly in patients who have been hospitalized.

Lefamulin: A Novel Oral and Intravenous Pleuromutilin for the Treatment of Community-Acquired Bacterial Pneumonia.

Lefamulin is a novel oral and intravenous (IV) pleuromutilin developed as a twice-daily treatment for community-acquired bacterial pneumonia (CABP). It is a semi-synthetic pleuromutilin with a chemical structure that contains a tricyclic core of five-, six-, and eight-membered rings and a 2-(4-amino-2-hydroxycyclohexyl)sulfanylacetate side chain extending from C14 of the tricyclic core. Lefamulin inhibits bacterial protein synthesis by binding to the 50S bacterial ribosomal subunit in the peptidyl transferase center (PTC). The pleuromutilin tricyclic core binds to a pocket close to the A site, while the C14 side chain extends to the P site causing a tightening of the rotational movement in the binding pocket referred to as an induced-fit mechanism. Lefamulin displays broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria as well as against atypical bacteria that commonly cause CABP. Pleuromutilin antibiotics exhibit low rates of resistance development and lack cross-resistance to other antimicrobial classes due to their unique mechanism of action. However, pleuromutilin activity is affected by mutations in 23S rRNA, 50S ribosomal subunit proteins rplC and rplD, ATP-binding cassette (ABC)-F transporter proteins such as vga(A), and the methyltransferase cfr. The pharmacokinetic properties of lefamulin include: volume of distribution (Vd) ranging from 82.9 to 202.8 L, total clearance (CLT) of 19.5 to 21.4 L/h, and terminal elimination half-life (t1/2) of 6.9-13.2 h; protein binding of lefamulin is high and non-linear. The oral bioavailability of lefamulin has been estimated as 24% in fasted subjects and 19% in fed subjects. A single oral dose of lefamulin 600 mg administered in fasted patients achieved a maximum plasma concentration (Cmax) of 1.2-1.5 mg/L with a time of maximum concentration (Tmax) ranging from 0.8 to 1.8 h, and an area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) of 8.5-8.8 mg h/L. The pharmacodynamic parameter predictive of lefamulin efficacy is the free plasma area under the concentration-time curve divided by the minimum inhibitory concentration (fAUC24h/MIC). Lefamulin efficacy has been demonstrated using various animal models including neutropenic murine thigh infection, pneumonia, lung infection, and bacteremia. Lefamulin clinical safety and efficacy was investigated through a Phase II clinical trial of acute bacterial skin and skin structure infection (ABSSSI), as well as two Phase III clinical trials of CABP. The Phase III trials, LEAP 1 and LEAP 2 established non-inferiority of lefamulin to moxifloxacin in both oral and IV formulations in the treatment of CABP. The United States Food and Drug Administration (FDA), European Medicines Agency (EMA), and Health Canada have each approved lefamulin for the treatment of CABP. A Phase II clinical trial has been completed for the treatment of ABSSSI, while the pediatric program is in Phase I. The most common adverse effects of lefamulin include mild-to-moderate gastrointestinal-related events such as nausea and diarrhea. Lefamulin represents a safe and effective option for treating CABP in cases of antimicrobial resistance to first-line therapies, clinical failure, or intolerance/adverse effects to currently used agents. Clinical experience and ongoing clinical investigation will allow clinicians and antimicrobial stewardship programs to optimally use lefamulin in the treatment of CABP.

The burden of community-acquired bacterial pneumonia in the era of antibiotic resistance.

INTRODUCTION: Community-acquired pneumonia (CAP) is a significant global health problem and leading cause of death and hospitalization in both the US and abroad. Increasing macrolide resistance among Streptococcus pneumoniae and other pathogens results in a greater disease burden, along with changing demographics and a higher preponderance of comorbid conditions. Areas covered: This review summarizes current data on the clinical and economic burden of CAP, with particular focus on community-acquired bacterial pneumonia (CABP). Incidence, morbidity and mortality, and healthcare costs for the US and other regions of the world are among the topics covered. Major factors that are believed to be contributing to the increased impact of CABP, including antimicrobial resistance, the aging population, and the incidence of comorbidities are discussed, as well as unmet needs in current CABP management. Expert commentary: The clinical and economic burden of CABP is staggering, far-reaching, and expected to increase in the future as new antibiotic resistance mechanisms emerge and the world's population ages. Important measures must be initiated to stabilize and potentially decrease this burden. Urgent needs in CABP management include the development of new antimicrobials, adjuvant therapies, and rapid diagnostics.

Community-acquired pneumonia: An overview.

Community-acquired pneumonia is still a significant cause of morbidity and mortality and is often misdiagnosed and inappropriately treated. Although it can be caused by a wide variety of micro-organisms, the pneumococcus, atypicals, such as Mycoplasma pneumoniae and Chlamydophila pneumoniae, Staphylococcus aureus and certain Gram-negative rods are the usual pathogens encountered. The site-of-care decision is critical in determining the site and type of care as well as the extent of diagnostic workup. Antimicrobial therapy should be started as soon as possible particularly in those requiring admission to hospital, but typically the physician does not know with any degree of certainty the identity of the etiologic pathogen. A number of national guidelines have been published to help the physician with this choice. The initial drug(s) can be modified if necessary if the pathogen and its antimicrobial susceptibility pattern becomes known. Adjunctive therapy such as pressors and fluid replacement are of value and macrolides appear to help as well, likely secondary to their immunomodulatory effects. Recent data also suggest a role for steroids.

Guidelines and quality measures: do they improve outcomes of patients with community-acquired pneumonia?

Community-acquired pneumonia (CAP) has a significant impact in terms of morbidity, mortality, and cost of care. Guidelines play an important role in the management of this disease, and evidence supporting the positive effects of guidelines on outcomes in patients with CAP is substantial. However, evidence supporting many of the CAP quality indicators is low, and pay-for-performance measures do not seem to influence clinically important outcomes. Future CAP quality indicators should incorporate evidence-based interventions.

Adjunctive therapy in community-acquired pneumonia.

Despite potent antibiotics, community-acquired pneumonia (CAP) remains the most common cause of death from infection and the eighth overall leading cause of death in the United States. For this reason, adjunctive therapeutic measures directed at the host response rather than the pathogen are attractive. The immunomodulatory effects of macrolide antibiotics may play a significant role in management of severe CAP. The existing literature does not demonstrate a clear benefit for corticosteroids, but larger prospective randomized trials are needed. Nonsteroidal antiinflammatory drugs may benefit oxygenation but have no documented effect on mortality. Statin use before CAP diagnosis is associated with improved outcome but requires further research to determine if initiation at the time of diagnosis will affect outcome positively. Activation of the coagulation system appears to be a major pathophysiological event in severe pneumonia, but neither drotrecogin alfa activated nor tifacogin (recombinant tissue factor pathway inhibitor) have demonstrated a survival benefit. Other therapies have theoretical benefit but are not yet in the stage of clinical trials.

Doripenem: a new carbapenem in the treatment of nosocomial infection.

Difficult-to-treat infections caused by gram-negative pathogens are common in the hospital setting, particularly those caused by Pseudomonas aeruginosa, Acinetobacter species, and extended-spectrum beta-lactamase-producing Enterobacteriaceae, all of which are capable of developing resistance to common antimicrobial agents. New drugs are urgently needed to combat this threat. In this supplement, researchers in infectious diseases discuss the role of doripenem, a newly approved carbapenem, in the treatment of serious nosocomial infections and review new data on doripenem for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia. The topics addressed include antimicrobial resistance and the available therapeutic options against gram-negative pathogens, the in vitro activity of doripenem, the efficacy and safety of intravenous infusion of doripenem, and the clinical and economic consequences of ventilator-associated pneumonia. Based on the strength of the clinical evidence presented, doripenem appears to provide broad-spectrum coverage and antipseudomonal activity, leading to advantageous clinical outcomes, particularly in patients at risk of infection with drug-resistant pathogens.

Spectrum of microbial etiology of community-acquired pneumonia in hospitalized patients: implications for selection of the population for enrollment in clinical trials.

The title of this article implies that knowledge of the etiological pathogen may be useful in selection of patients for clinical trials for community-acquired pneumonia (CAP). However, this remains to be seen. The clinical course of a patient with CAP admitted to the hospital but not to the intensive care unit depends on a number of variables, including the patient, the pathogen, and the hospital itself. The site-of-care decision can be based on 1 of 2 prediction rules. Neither of these rules, however, correlates with the etiology of CAP, and it is not clear whether they can be used to stratify patients according to prognostic factors. A pathogen may be found in only approximately one-third of hospitalized patients with CAP overall. An etiological diagnosis is more likely to be made for patients with CAP who are hospitalized in the intensive care unit (39%) than for those hospitalized in other wards (20%). The issue of randomization to treatment regimens and possible approaches to randomization are discussed. It seems clear, however, that randomization would have to take place immediately after entry of the patient into the study. The possibility of using risks for specific pathogens or risks for antimicrobial resistance is also addressed. However, there are no data to support the use of such risks as prognostic factors in CAP. The best approach for noninferiority trials involving hospitalized patients with CAP is to randomize patients who meet the inclusion criteria and to stratify them by hospital site, with block randomization within each site. Stratification by site takes into account local epidemiology and can balance differences in unmeasured confounders among sites.

Gemifloxacin once daily for 5 days versus 7 days for the treatment of community-acquired pneumonia: a randomized, multicentre, double-blind study.

OBJECTIVES: Short-course therapy has been advocated for the treatment of community-acquired pneumonia (CAP). We compared the efficacy and safety of 5 and 7 day courses of gemifloxacin for outpatient treatment of mild-moderate CAP. PATIENTS AND METHODS: In a multicentre, double-blind, parallel group study, patients were randomized to receive 320 mg of oral gemifloxacin once daily for 5 or 7 days. Over 95% of all patients in each cohort had a Fine score of