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Highlights from

The European Congress of Clinical Microbiology & Infectious Diseases

29th Annual Meeting

Amsterdam 13-16 April 2019

An update on antibiotic pipeline developments

Take-home messages
  • Ceftolozane/ tazobactam is comparable to meropenem in critically ill patients with gram-negative, ventilator-associated nosocomial pneumonia
  • Omadacycline is effective and safe in CABP and ABSSSI patients with mild-to-moderate renal insufficiency
  • Iclaprim showed similar efficacy to vancomycin across a broad range of baseline lesion sizes in ABSSSI

Many exciting developments were presented at the 29th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) on 13-16 April 2019, including new data for antibiotics in various indications, such as pneumonia and acute bacterial skin or skin structure infections (ABSSSI). The following phase III datasets focused on ceftolozane/ tazobactam, on omadacycline, and on iclaprim, in different settings.

Ceftolozane/ tazobactam in ventilator-associated nosocomial pneumonia

This therapy combines the anti-pseudomonal cephalosporin activity of ceftolozane with the extended spectrum beta-lactamase (ESBL) inhibition of tazobactam. The treatment is currently approved for use in complicated urinary tract and intra-abdominal infections, as well as acute pyelonephritis.

New data for ceftolozane/ tazobactam were released at ECCMID 2019, showing clinical and microbiological outcomes in critically ill patients with nosocomial pneumonia, all of whom were mechanically ventilated (modified intention to treat population: n=511). In this phase III, double-blind, multicentre trial, ASPECT-NP, patients were randomised 1:1 to receive 3 g ceftolozane/ tazobactam or 1 g meropenem, both intravenously, every 8 hours for 8-14 days.

The investigators reported that ceftolozane/ tazobactam provided clinical and microbiological response rates that were comparable to meropenem, regardless of the causative lower respiratory tract pathogen. In the microbiologically evaluable population (n=233), eradication rates were 79.3% with ceftolozane/ tazobactam versus 55.3% with meropenem in patients with P. aeruginosa (95% CI 1.11 to 43.01) and 66.7% ceftolozane/ tazobactam versus 69.2% with meropenem in patients with ESBL-producing Enterobacteriaceae (95% CI -21.59 to 17.14).

Considering that 30% of P. aeruginosa-caused ventilator-associated pneumonia cases are multidrug resistant, ceftolozane/ tazobactam could be a valued addition to field.

Omadacycline in CABP and ABSSSI in patients with mild-to-moderate renal insufficiency

Omadacycline, an oral/IV broad-spectrum tetracycline antibiotic, was recently approved in the US for community-acquired bacterial pneumonia (CABP) and ABSSSI. The decision was based on phase III data that demonstrated its non-inferiority to standard-of-care treatments for the respective conditions (vs moxifloxacin in CABP and vs linezolid in ABSSSI). The European Medicines Agency’s decision is due in the second half of 2019.

As renal insufficiency could impact the pharmacokinetics of omadacycline, the team decided to look further into data from the phase III trials in CABP and ABSSSI (pooled dataset: N=2,142). A total of 517 patients (24%) had mild or moderate renal insufficiency at baseline, which showed that clinical success was similar, regardless of patient’s renal function status. Clinical success with omadacycline was comparable with the standards of care for the respective indications.

In patients with CABP, treatment-related adverse events were more common in patients with renal insufficiency versus those of normal renal function, however, this was not the case for patients with ABSSSI.

From these data, the investigators concluded that omadacycline is effective and safe in patients with renal insufficiency.

Iclaprim in ABSSSI: efficacy by lesion size

Iclaprim is a selective bacterial dihydrofolate reductase inhibitor, which demonstrated non-inferiority to vancomycin in patients with ABSSSI in the phase III, double-blind trials REVIVE-1 and -2. In these parallel trials, a combined total of 1,198 patients were randomised (1:1) to receive either a fixed dose of iclaprim 80 mg twice daily, or vancomycin 15 mg/kg twice daily (adjusted based on renal function).

As larger ABSSSI lesions may be more difficult to treat than smaller lesions, the investigators decided to carry out a post hoc analysis evaluating whether efficacy was affected by baseline lesion size. Median baseline lesion size was 258 cm2 (interquartile range (IQR): 171-404 cm2) and 261 cm2 (IQR: 172-386 cm2) in the iclaprim and vancomycin arms, respectively.

While there was a trend towards decreasing efficacy as baseline lesion size increased, early clinical response rates were similar in both arms. From this, the team deduced that iclaprim provides similar efficacy compared with vancomycin across a broad range of lesion sizes in patients with ABSSSI. This does suggest, however, that even larger lesions may affect iclaprim efficacy, in which case, further analyses would be warranted.

Based on:

Martin-Loeches I, Kivistik Ü et al. Clinical and microbiologic outcomes by causative pathogen in the ASPECT-NP randomised, controlled, phase III trial evaluating ceftolozane/ tazobactam for treatment of ventilator-associated pneumonia (abstract O0302). Presented on Saturday 13 April 2019.

Cornely O A, Garrity-Ryan L et al. Safety and efficacy of omadacycline for treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections in patients with mild to moderate renal insufficiency (abstract O0304). Presented on Saturday 13 April 2019.

Noviello S, Wilcox M et al. An efficacy analysis by lesion size of iclaprim versus vancomycin in patients with acute bacterial skin and skin structure infections: pooled phase III REVIVE trials (abstract O0303). Presented on Saturday 13 April 2019.

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The content and interpretation of these conference highlights are the views and comments of the speakers/ authors.

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