Antimicrobial prescribing: ceftolozane with tazobactam for treating hospital-acquired pneumonia, including ventilator-associated pneumonia

Effectiveness

ASPECT-NP was a multicentre randomised controlled, double-blind, non-inferiority trial. It included 726 adults (mean age 60 years) with hospital-acquired pneumonia (HAP) caused by Gram-negative pathogens, who were undergoing mechanical ventilation. Of these, 71% had ventilator-associated pneumonia (VAP) and 29% had HAP that had worsened and needed mechanical ventilation (ventilated HAP). Participants were randomised to receive ceftolozane with tazobactam 2 g/1 g or meropenem 1 g intravenously every 8 hours for 8 to 14 days. The primary outcome reported was 28-day all-cause mortality (the FDA primary outcome) and the key secondary outcome was clinical cure at the test-of-cure visit (7 to 14 days after the end of treatment: the EMA primary outcome). Clinical cure was defined as resolution of baseline signs and symptoms of HAP, with no new signs or symptoms and no need for additional antibiotic treatment.

Safety

In the ASPECT-NP trial, treatment-related adverse events were reported by 11% (38/361) of participants using ceftolozane with tazobactam and 8% (27/359) of participants using meropenem (no statistical analysis). Serious adverse events were also more common with ceftolozane with tazobactam than with meropenem (2% [8/361] compared with 1% [2/359] respectively; no statistical analysis).

Study treatment was discontinued because of treatment-related adverse events in 1% of participants in both groups (4/361 using ceftolozane with tazobactam and 5/359 using meropenem). Study treatment was discontinued because of insufficient therapeutic effects in 6% (23/361) of participants in the ceftolozane with tazobactam group and 4% (15/359) of participants in the meropenem group (no statistical analyses). No deaths in either group were considered related to study treatment.

The summary of product characteristics states that the most common adverse effects (at least 3 in 100) seen in phase 3 trials assessing ceftolozane with tazobactam for all licensed indications were nausea, headache, constipation, diarrhoea, pyrexia and raised liver enzymes. These were generally considered mild or moderate in severity.

Limitations of the evidence

ASPECT-NP was a relatively large, well-designed and reported study, which was undertaken in accordance with regulatory requirements. All study participants were mechanically ventilated and critically ill; therefore, it is unclear whether the study results are applicable to people with less severe HAP without intubation. The study excluded people with immunosuppression and cystic fibrosis, and people receiving dialysis. Adults only were included and ceftolozane with tazobactam is not currently licensed for treating children and young people.

To ensure a high concentration in the lungs of the seriously ill people in the study, the dose of ceftolozane with tazobactam used (and subsequently licensed for HAP and VAP) was double that recommended for other indications (2 g/1 g compared with 1 g/0.5 g for complicated urinary tract infections and complicated intra-abdominal infections; summary of product characteristics). According to some reports, higher doses of meropenem may have been preferable as the comparator (2 g 8 hourly over 3 hours for equivalent antibacterial activity to high-dose ceftolozane with tazobactam; Kalil and Zavascki 2019 and Frippiat et al. 2014). This suggests that the study may have underestimated the efficacy of meropenem. However, although specialists advised that high doses of meropenem are sometimes used for HAP and VAP in the UK, standard doses (as used in the study) are generally preferred.

Ceftolozane with tazobactam is a relatively new antibiotic, which is generally not used first line. Therefore, data on resistance and the impact in clinical practice in the UK are limited. The English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) Report 2018 to 2019 states that monitoring the use of new antibiotics and detecting emerging resistance to these medicines is a crucial component of antimicrobial usage surveillance to inform antimicrobial stewardship activities and preserve treatment effectiveness. Although susceptibility testing for ceftolozane with tazobactam is currently uncommon and selective (following resistance to first- and second-line antibiotics), resistance has nonetheless been recorded.

Person-related factors

Ceftolozane with tazobactam is administered by intravenous (IV) infusion over 1 hour, every 8 hours. In practice, it is highly likely it will be prescribed and administered in a hospital setting.

Resource implications

The acquisition cost of ceftolozane with tazobactam is £67.03 (excluding VAT) per vial, meaning the cost of 1 day's treatment at the usual dosage for HAP and VAP (2 g/1 g [2 vials] every 8 hours) is £402.18 (BNF, November 2019).

The acquisition costs (excluding VAT) of many other IV antibiotics that are used for HAP and VAP (caused or suspected to be caused by Gram-negative pathogens) are lower than that of ceftolozane with tazobactam. The acquisition cost of meropenem alone is £17.78 (excluding VAT) for 1 vial containing 1 g of powder for solution for injection (Drug Tariff, November 2019). The cost of 1 day's treatment with 2 g (2 vials) every 8 hours is £106.68.

The manufacturer estimates that usage of ceftolozane with tazobactam will be low, reflecting its anticipated positioning following confirmed susceptibility testing. Usage should be under the guidance of an appropriately experienced infection specialist (such as a clinical microbiologist or infectious diseases consultant), following the principles of good antimicrobial stewardship.

Depending on the proven pathogens contributing to the infection, ceftolozane with tazobactam may need to be given in combination with other antimicrobials for which additional treatment costs would need to be considered.

See the full evidence review for more information.

ISBN: 978-1-4731-3639-7