Advice
Key points from the evidence
Key points from the evidence
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The content of this evidence summary was up-to-date in June 2016. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information. |
Summary
In a randomised controlled trial (RCT) in adults with complicated intra‑abdominal infections, intravenous ceftolozane/tazobactam plus metronidazole was found to be non‑inferior to intravenous meropenem plus saline (placebo) in terms of clinical cure rates 24–32 days after starting treatment. However, it is unclear whether the results apply to some populations; for example, people aged over 65 years, or those with renal impairment or who are at a higher risk of dying. Appendiceal perforation or abscess was the most common diagnosis in the study and less information is available on using ceftolozane/tazobactam in people with other diagnoses.
In 2 RCTs in people receiving ceftolozane/tazobactam for complicated intra‑abdominal or urinary tract infections, the most commonly reported adverse effects were nausea, headache, constipation, diarrhoea and pyrexia, which were generally mild or moderate in severity.
Ceftolozane/tazobactam may be an option for treating complicated intra‑abdominal infections in some adults, when the pathogen is resistant to first‑line empirical treatment options but susceptible to ceftolozane/tazobactam, or when first‑line options are contraindicated. The acquisition cost of ceftolozane/tazobactam is more than that of many other intravenous antibiotics that are commonly used for complicated intra‑abdominal infections.
Regulatory status: Ceftolozane/tazobactam received a marketing authorisation in September 2015 and was launched in the UK in November 2015.
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Effectiveness In the ASPECT-cIAI RCT (n=993):
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Safety According to the European public assessment report:
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Patient factors
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Resource implications
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Introduction and current guidance
Intra‑abdominal infections include a wide spectrum of conditions from uncomplicated appendicitis to faecal peritonitis. In complicated intra‑abdominal infections, the infection progresses from a single organ and affects the peritoneum, causing intra‑abdominal abscesses or diffuse peritonitis. Peritoneal contamination may result from surgery‑associated infection, trauma or spontaneous perforation (for example, appendicitis, perforated ulcer or diverticulitis) (European public assessment report).
Complicated intra-abdominal infections are frequently caused by gram‑negative bacteria (such as Escherichia coli), with or without anaerobic pathogens. Second or third generation cephalosporins in combination with metronidazole, beta‑lactam antibiotics (such as penicillins) in combination with beta‑lactamase inhibitors and carbapenems are commonly used for treating complicated intra‑abdominal infections. However, increasing resistance to commonly prescribed antimicrobial agents is a recognised serious global problem (European public assessment report). Ceftolozane/tazobactam was developed to address antimicrobial resistance in serious infections caused by gram‑negative pathogens.
Product overview
Zerbaxa powder for concentrate for solution for infusion contains ceftolozane, a new cephalosporin antibiotic, and tazobactam, an established beta‑lactamase inhibitor, which can protect ceftolozane from hydrolysis by some beta‑lactamases, broadening its spectrum of activity (European public assessment report).
Ceftolozane/tazobactam is indicated for treating complicated intra‑abdominal infections in adults. The dosage is 1 g/0.5 g administered intravenously over 1 hour every 8 hours for 4–14 days. Lower doses should be used in people with moderate to severe renal impairment. Metronidazole should be co‑administered with ceftolozane/tazobactam if anaerobic pathogens are suspected of causing the intraabdominal infection because ceftolozane/tazobactam is not reliably active against anaerobes. See the summary of product characteristics and European public assessment report for more information.
Ceftolozane/tazobactam is also indicated for complicated urinary tract infections (including acute pyelonephritis), which are discussed in another evidence summary.
Evidence review
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This evidence summary is based on the key phase III licensing study for ceftolozane/tazobactam, ASPECT-cIAI. This study was a prospective, randomised, double-blind, non-inferiority trial, which included adults with complicated intra‑abdominal infections (43% with appendiceal perforation or abscess) who received intravenous ceftolozane/tazobactam 1 g/0.5 g plus metronidazole 500 mg (n=487) every 8 hours or intravenous meropenem 1 g plus saline (placebo, n=506) every 8 hours for 4–10 days. Treatments could be continued for up to 14 days in people who had multiple abscesses, non‑appendix‑related diffuse peritonitis, failure of prior antimicrobial therapy or hospital‑acquired infection. Outcomes were tested in the following populations:
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intention-to-treat (ITT): all randomised participants regardless of receipt of study drug
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microbiological ITT (MITT): all randomised participants with at least 1 baseline pathogen identified in the abscess or peritoneal fluid, regardless of susceptibility to the study drug
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clinically evaluable per‑protocol (CE): all randomised participants who received the protocol specified amount of study drug, met the protocol specific disease definition of complicated intra‑abdominal infection, adhered to trial procedures, and had a test‑of‑cure visit within the specified window (24–32 days after starting treatment)
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microbiologically evaluable (ME) per‑protocol: the subset of CE participants who had at least 1 baseline infecting pathogen identified that was susceptible to the study drug.
The primary objective of the study was to demonstrate non-inferiority of ceftolozane/tazobactam plus metronidazole compared with meropenem in terms of clinical cure rates at the test‑of‑cure visit in the MITT population. Clinical cure was defined as complete resolution or significant improvement in signs and symptoms of the index infection, with no additional antimicrobials or interventions required.
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In the MITT population, ceftolozane/tazobactam plus metronidazole was found to be non‑inferior to meropenem plus saline in terms of clinical cure rates at the test‑of‑cure visit. The clinical cure rate was 83.0% in the ceftolozane/tazobactam group compared with 87.3% in the meropenem group (weighted difference −4.2%, 95% confidence interval [CI] −8.91% to 0.54%). The lower limit of the 95% CI for the difference between the study treatments was more than −10% and, therefore, met the statistical requirement for non‑inferiority. This result was confirmed in the ME per‑protocol population, as is required to prove non‑inferiority. In the ME population, the clinical cure rates were 94.2% and 94.7% respectively (weighted difference −1.0%, 95% CI −4.52 to 2.59). The results were also consistent in the ITT and CE populations, and in analyses at other time points.
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Clinical failure was defined as death due to complicated intra‑abdominal infection before the test‑of‑cure visit, persistent or recurrent infection requiring additional intervention, and treatment with additional antimicrobials for ongoing symptoms of intra‑abdominal or surgical site infection. In both treatment groups, in the MITT population, 8.2% of patients failed treatment at the test‑of‑cure visit. The most common reasons for treatment failure were persisting or recurrent abdominal infection requiring an additional intervention (2.8% of failures in the ceftolozane/tazobactam plus metronidazole group and 3.6% of failures in the meropenem plus saline group: statistical analysis not reported) and the requirement for additional antibiotics for ongoing complicated intra‑abdominal infection (3.3% and 2.6% respectively: statistical analysis not reported).
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The frequency of treatment‑emergent adverse events was similar in both treatment groups (44.0% with ceftolozane/tazobactam plus metronidazole compared with 42.7% with meropenem plus saline). The most common adverse events in either group were nausea (7.9% and 5.8% respectively) and diarrhoea (6.2% and 5.0% respectively). Statistical analyses were not reported.
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According to the summary of product characteristics, in 2 phase III studies (total n=2,047: 1,015 taking ceftolozane/tazobactam and 1,032 taking meropenem or levofloxacin), the most common adverse effects reported in 3 in 100 people or more receiving ceftolozane/tazobactam for complicated intra‑abdominal infections (ASPECT-cIAI) and complicated urinary tract infections (ASPECT-cUTI) were nausea, headache, constipation, diarrhoea and pyrexia. These were generally mild or moderate in severity. A decline in renal function has been seen in patients receiving ceftolozane/tazobactam. As with many other antibiotics, ceftolozane/tazobactam carries a risk of Clostridium difficile infection. (See the NICE evidence summary medicines and prescribing briefing on the risk of Clostridium difficile infection with broad-spectrum antibiotics.)
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The ASPECT-cIAI study has various limitations that should be taken into account when considering its application to practice. For example, the majority of participants were aged 18–64 years (77%), with no renal impairment (70%) and an Acute Physiology and Chronic Health Evaluation (APACHE) II score (used to predict mortality in intensive care units on a scale of 0–71) of 0–10 (87%), suggesting a low risk of mortality. Therefore, the results may not be generalisable to older people, particularly those with severe renal impairment or a high risk of mortality. People who were immunocompromised or had severe neutropenia were excluded from the study, as were those with severe or rapidly progressing disease such as septic shock, and those not expected to survive for 4–5 weeks. Therefore, the results may not apply to these patients. Ceftolozane/tazobactam has not been studied in children and is only indicated for use in adults.
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The Committee for Medicinal Products for Human Use (CHMP) concluded that, although ASPECT-cIAI met its pre‑defined primary end point, with supportive sensitivity analyses, the broad indication of complicated intra‑abdominal infection is poorly supported based on this single pivotal study. The CHMP noted that about half of people had a primary focus of infection in the appendix compared with a maximum of 30% recommended in CHMP guidance. Also, cure rates were very high for infections of appendiceal origin (for example, 89% with ceftolozane/tazobactam and 92% with meropenem in the ITT population) and much lower for infections originating from the colon (for example, 66% and 71% respectively in the ITT population) (European public assessment report).
Context
Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America and the World Society of Emergency Surgery recommend empirical antibiotic treatment with single or combination antimicrobial regimens depending on the severity of infection, the pathogens presumed to be involved (taking into account whether the infection is community- or healthcare‑associated) and local antibiotic resistance patterns. Treatment regimens commonly include beta‑lactam/beta‑lactamase inhibitor combinations, carbapenems, cephalosporins, metronidazole, fluoroquinolones and aminoglycosides.
A vial of ceftolozane/tazobactam costs £67.03 excluding VAT (MIMS April 2016). Therefore, the cost of a course of treatment ranges from £804.36 for 4 days to £2,815.26 for 14 days, excluding VAT and any procurement discounts and administration costs. The acquisition cost of ceftolozane/tazobactam is more than that of many other intravenous antibiotics that are commonly used for complicated intra‑abdominal infections.
Estimated impact for the NHS
Appropriate use of antibiotics is important to reduce the serious threat of antibiotic resistance and the risk of healthcare-associated infections such as C. difficile. Commissioners and local decision makers will need to determine where ceftolozane/tazobactam fits within local hospital antibiotic policies and guidelines for managing complicated intra‑abdominal infections, taking the principles of antimicrobial stewardship into account.
The manufacturer of ceftolozane/tazobactam, Merck Sharp & Dohme Limited, anticipates that the antibiotic will be used in line with good antimicrobial stewardship, on the advice of a microbiologist, to treat gram‑negative infections, when the pathogen is resistant to first‑line empirical treatment options but susceptible to ceftolozane/tazobactam.
Public Health England's Start smart − then focus toolkit outlines best practice in antimicrobial stewardship in the secondary care setting. NICE has issued guidance on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use.
Full text of estimated impact for the NHS.
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About this evidence summary 'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance. |