achn-490 and Gram-Negative-Bacterial-Infections

Antimicrobial resistance is a growing threat to public health and an increasingly common problem for acute care physicians to confront. Several novel antibiotics have been approved in the past decade to combat these infections; however, physicians may be unfamiliar with how to appropriately utilize them. The purpose of this review is to evaluate novel antibiotics active against resistant gram-negative bacteria and highlight clinical information regarding their use in the acute care setting. This review focuses on novel antibiotics useful in the treatment of infections caused by resistant gram-negative organisms that may be seen in the acute care setting. These novel antibiotics include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilistatin/relebactam, cefiderocol, plazomicin, eravacycline, and omadacycline. Acute care physicians should be familiar with these novel antibiotics so they can utilize them appropriately.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Cefiderocol; Ceftazidime; Cephalosporins; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Design; Drug Resistance, Multiple; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Heterocyclic Compounds, 1-Ring; Humans; Meropenem; Sisomicin; Tazobactam; Tetracyclines

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.. Novel agents, both belonging to β-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.. 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.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Azabicyclo Compounds; beta-Lactams; Carbapenems; Cefiderocol; Ceftazidime; Cephalosporins; Drug Combinations; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Humans; Imipenem; Microbial Sensitivity Tests; Polymyxins; Sisomicin; Tazobactam; Tetracyclines

Plazomicin is a novel aminoglycoside antibiotic that binds to the bacterial 30S ribosomal subunit, thus inhibiting protein synthesis in a concentration-dependent manner. Plazomicin displays a broad spectrum of activity against aerobic gram-negative bacteria including extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and organisms with aminoglycoside-modifying enzymes. In a large phase III clinical trial, plazomicin was shown to be noninferior to meropenem in the treatment of complicated urinary tract infections (cUTIs) with respect to the coprimary efficacy end points of the microbiologically modified intent-to-treat composite cure rate at day 5 (plazomicin 88% [168/191 subjects] vs meropenem 91.4% [180/197]) and at the test-of-cure visit (plazomicin 81.7% [156/191] vs meropenem 70.1% [138/197]). In a small phase III clinical trial, plazomicin was shown to be effective in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. It was associated with a lower all-cause mortality or significant disease-related complication rate (23.5% [4/17]) compared with colistin (50% [10/20]). The most common adverse reactions associated with plazomicin are decreased renal function, diarrhea, hypertension, headache, nausea, vomiting, and hypotension. As with other aminoglycosides, plazomicin may cause neuromuscular blockade, ototoxicity, and fetal harm in pregnant women. Due to limited efficacy and safety data, plazomicin is indicated for the treatment of cUTIs in adults with limited or no alternative treatment options, using a dosage regimen of 15 mg/kg intravenously every 24 hours for 4-7 days. Dosage reductions and therapeutic drug monitoring are warranted in patients with moderate or severe renal impairment. Plazomicin is not recommended in patients with severe renal impairment including those receiving renal replacement therapy. With the approval of plazomicin, clinicians now have an additional option for the treatment of adults with cUTIs, particularly those caused by multidrug-resistant gram-negative rods.

Topics: Adult; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Sisomicin; Urinary Tract Infections

Plazomicin is a novel semisynthetic parenteral aminoglycoside that inhibits bacterial protein synthesis. It was approved by the United States Food and Drug Administration for use in adults with complicated urinary tract infections (cUTI), including pyelonephritis. Plazomicin displays potent in vitro activity against Enterobacteriaceae, including both extended-spectrum β-lactamase-producing and carbapenem-resistant isolates. Plazomicin's enhanced Enterobacteriaceae activity is due to its stability to commonly encountered aminoglycoside-modifying enzymes that compromise the activity of traditional aminoglycosides. Plazomicin resistance in Enterobacteriaceae is via modification of the ribosomal binding site due to expression of 16S rRNA methyltransferases. Plazomicin does not display improved activity over traditional aminoglycosides against other problematic resistant Gram-negative bacteria, namely Pseudomonas aeruginosa and Acinetobacter baumannii. Plazomicin has been assessed in two phase III randomized controlled trials. The EPIC trial compared plazomicin and meropenem for the management of cUTI. In this trial, plazomicin demonstrated superiority in composite cure (81.7% vs 70.1%; difference 11.6%; 95% confidence interval [CI] 2.7-25.7) at the test-of-cure visit, which was driven by enhanced sustained microbiological eradication. The CARE trial compared plazomicin-based and colistin-based combinations in patients with serious infections due to carbapenem-resistant Enterobacteriaceae (CRE). In this analysis, plazomicin-based combinations were associated with numerically decreased mortality or serious disease-related complications when compared with colistin-based combinations (23.5% vs 50%, respectively; 90% CI -0.7 to 51.2). Furthermore, plazomicin was also associated with a lower incidence of nephrotoxicity than colistin. However, small sample sizes limit the interpretation of the findings in the CARE trial. Plazomicin is a novel aminoglycoside that offers clinicians an additional option for the management of CRE infections, with superior activity compared with traditional aminoglycosides and potentially improved efficacy and decreased toxicity compared with colistin.

Topics: Animals; Anti-Bacterial Agents; Carbapenems; Clinical Trials as Topic; Colistin; Dose-Response Relationship, Drug; Drug Approval; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Meropenem; Randomized Controlled Trials as Topic; Sisomicin; United States; United States Food and Drug Administration; Urinary Tract Infections

The challenge posed by increasing levels of drug-resistant bacteria world-wide is manifest, and must be dealt with both by new approaches to the use of existing antibiotics and by the introduction of novel drugs. ACHN-490 is the first neoglycoside, or next-generation aminoglycoside, to begin clinical development. ACHN-490 was designed to target key pathogens, particularly gram-negative organisms and those resistant to older antibiotics. ACHN-490 demonstrates promising in vitro activity against wild-type and resistant bacteria while retaining the favorable bactericidal and synergistic properties of the aminoglycoside class. These attributes, along with the results of Phase 1 studies of ACHN-490 injection, suggest that ACHN-490 may help to fill the growing unmet need for new antibacterial agents.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Microbial Sensitivity Tests; Molecular Structure; Sisomicin