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Factors for decision making

Factors for decision making

Effectiveness

Tango I was a randomised, double-blind, double-dummy trial that compared meropenem with vaborbactam (2 g/2 g IV [intravenous] over 3 hours, every 8 hours) with piperacillin with tazobactam (4 g/0.5 g IV over 30 minutes, every 8 hours) in adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. The primary outcomes were overall success, a composite outcome of clinical cure (complete resolution or significant improvement of baseline signs and symptoms) and microbial eradication (baseline pathogens reduced to below 103–104 colony-forming units/ml urine) at the end of IV treatment or microbial eradication at the test of cure visit (7 days after the end of treatment).

Tango II was an open-label, randomised trial that compared meropenem with vaborbactam (2 g/2 g IV over 3 hours, every 8 hours) with best available antibiotic treatment (polymyxin, carbapenem, aminoglycoside or tigecycline antibiotics alone or in combination; or ceftazidime with avibactam alone) in adults with cUTI or acute pyelonephritis, complicated intra-abdominal infection (cIAI), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), or bacteraemia suspected or documented to be caused by carbapenem-resistant Enterobacterales. Tango II was a descriptive study only and no formal power or sample size calculations were performed.

Overall success

At the end of treatment in Tango I (mean 8 days, n=374), the overall success rate was 98.4% (189/192) with meropenem with vaborbactam, compared with 94.0% (171/182) with piperacillin with tazobactam (difference 4.5%, 95% confidence interval [CI] 0.7% to 9.1%; p<0.001 for non‑inferiority), in adults with cUTI or acute pyelonephritis. The lower limit of the 95% CI was greater than the prespecified non‑inferiority margin of −15%, showing that meropenem with vaborbactam was statistically non‑inferior to piperacillin with tazobactam.

A pre‑specified statistical analysis showed that meropenem with vaborbactam was also statistically significantly better than piperacillin with tazobactam (the lower limit of the 95% CI exceeded 0, p=0.01).

Microbial eradication

Meropenem with vaborbactam was statistically non‑inferior to piperacillin with tazobactam for microbial eradication at the test of cure visit in Tango I in adults with cUTI or acute pyelonephritis (66.7% [128/192] compared with 57.7% [105/182] respectively; difference 9.0%, 95% CI −0.9% to 18.7; p<0.001 for non‑inferiority).

In adults with cUTI or acute pyelonephritis (n=16), cIAI (n=4), HAP or VAP (n=5), or bacteraemia (n=22) caused by carbapenem-resistant Enterobacterales in Tango II, there was no difference in rates of microbial eradication between meropenem with vaborbactam and best available antibiotic treatment at the:

  • end of treatment visit (65.6% [21/32] compared with 40.0% [6/15] respectively; difference 25.6%, 95% CI −4.1% to 55.4%; p=0.09) or

  • test of cure visit (53.1% [17/32] compared with 33.3% [5/15]; difference 19.8%, 95% CI −9.7% to 49.3%; p=0.19).

However, the design of Tango II means the statistical analyses performed are not robust and no firm conclusions can be drawn based on this trial.

Clinical cure

In Tango I, in adults with cUTI or acute pyelonephritis, there was no statistically significant difference between meropenem with vaborbactam, and piperacillin with tazobactam, in the rate of clinical cure at the:

  • end of treatment visit (98.4% [189/192] compared with 95.6% [174/182] respectively; difference 2.8%, 95% CI −0.7% to 7.1%) or

  • test of cure visit (90.6% [174/192] compared with 86.3% [157/182] respectively; difference 4.4%, 95% CI −2.2% to 11.1%).

In Tango II, meropenem with vaborbactam was associated with higher rates of clinical cure than best available antibiotic treatment at both the:

  • end of treatment visit (65.6% [21/32] compared with 33.3% [5/15] respectively; difference 32.3%, 95% CI 3.3% to 61.3%; p=0.03) and

  • the test of cure visit (59.4% [19/32] compared with 26.7% [4/15]; difference 32.7%, 95% CI 4.6% to 60.8%; p=0.02).

All-cause mortality

All-cause mortality was not assessed in Tango I. In Tango II, there was no significant difference between meropenem with vaborbactam and best available antibiotic treatment in all-cause mortality at 28 days (15.6% [5/32] compared with 33.3% [5/15]; difference −17.7%, 95% CI −44.7% to 9.3%; p=0.20). However, the design of the trial means that analyses are not robust and firm conclusions cannot be made.

Safety

In people with cUTI or acute pyelonephritis in Tango I who took at least 1 dose of study treatment (n=545), the proportions of people who experienced adverse events were broadly similar between the groups:

  • Treatment-related adverse events were reported by 15.1% (41/272) of people receiving meropenem with vaborbactam, and 12.8% (35/273) of people receiving piperacillin with tazobactam.

  • Adverse events leading to study treatment discontinuation occurred in 2.6% (7/272) and 5.1% (14/273) of people respectively.

In people with suspected or documented carbapenem-resistant Enterobacterales in Tango II who took at least 1 dose of study treatment (n=75):

  • Treatment-related adverse events were reported by 24.0% (12/50) of people receiving meropenem with vaborbactam, and 44.0% (11/25) of people receiving best available antibiotic treatment.

  • Adverse events leading to study treatment discontinuation occurred in 10.0% (5/50) and 12.0% (3/25) of people respectively.

Statistical analyses were not reported for safety outcomes in either trial.

The summary of product characteristics for meropenem with vaborbactam reports that the most common adverse reactions among 322 participants in pooled phase 3 trials were headache (8.1%), diarrhoea (4.7%), infusion site phlebitis (2.2%) and nausea (2.2%). Severe adverse reactions were observed in 2 participants (0.6%; an infusion-related reaction and an increase in blood alkaline phosphatase). A serious infusion-related reaction was reported in an additional participant (0.3%).

The Vaborem European public assessment report (EPAR) concludes that the safety database for meropenem with vaborbactam is relatively small but does not indicate any major concerns resulting from addition of vaborbactam to meropenem.

Limitations of the evidence

Tango I was a relatively large, well-designed and reported trial, which was undertaken in accordance with regulatory requirements. However, it was not designed to evaluate meropenem with vaborbactam for treating carbapenem-resistant pathogens, and very few organisms that were resistant to meropenem but susceptible to meropenem with vaborbactam were detected at baseline. Therefore, this trial cannot determine whether the vaborbactam dose was adequate to protect meropenem against class A and class C beta-lactamases. Pharmacokinetic and pharmacodynamic data were used to support the marketing authorisation in this regard.

Tango II was a supportive, open-label descriptive study with several other limitations. It included a small number of participants, with outcomes assessed in only 47 people with confirmed carbapenem-resistant Enterobacterales.

Both trials included adults only and there is no evidence to support the use of meropenem with vaborbactam in children and young people. No randomised controlled trials have compared meropenem alone and meropenem with vaborbactam.

Meropenem with vaborbactam is a new antimicrobial and therefore data on resistance and the impact in clinical practice in the UK are limited.

Person-related factors

Meropenem with vaborbactam is administered by IV infusion over 3 hours, every 8 hours and, in practice, it is highly likely that it will be prescribed and administered in a hospital setting.

Resource implications

The acquisition cost of meropenem with vaborbactam is £55.67 (excluding VAT) per vial, meaning the cost of 1 day's treatment at the usual dosage (2 g/2 g [2 vials] every 8 hours) is £334.02 (personal communication Menarini, October 2019).

The acquisition costs of other IV antibiotics that are used for cUTI, acute pyelonephritis, cIAI, HAP and VAP are generally lower than that of meropenem with vaborbactam. 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, October 2019). The cost of 1 day's treatment with 2 g (2 vials) every 8 hours is £106.68.

The manufacturer of meropenem with vaborbactam (Menarini) anticipates that usage will be low, following the principles of good antimicrobial stewardship, and will be under the guidance of a microbiologist. A wide range of antibiotics, alone or in combination, are used for treating cUTI, acute pyelonephritis, cIAI, HAP and VAP, and regimens may be changed based on response to treatment or results from microbiological susceptibility testing.

Depending on the proven pathogens contributing to the infection, meropenem with vaborbactam 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: 978-1-4731-3594-9