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 urinary tract infections or acute pyelonephritis (ASPECT-cUTI), an intravenous (IV) infusion of ceftolozane/tazobactam was found to be non‑inferior to IV levofloxacin for the composite outcome of microbiological eradication of all baseline uropathogens and clinical cure. In 2 RCTs in people receiving ceftolozane/tazobactam for complicated urinary tract or intra-abdominal infections (ASPECT-cUTI and ASPECT-cIAI), 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 acute pyelonephritis 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. Although licensed to treat complicated lower urinary tract infection in adults, clinical efficacy data in this group are limited. The acquisition cost of ceftozolane/tazobactam is more than that of many other IV antibiotics that are commonly used for complicated urinary tract infection.
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 a non‑inferiority study of people with complicated urinary tract infection or acute pyelonephritis, ceftolozane/tazobactam, 5 to 9 days after the last dose of study treatment:
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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
Urinary tract infection is a non‑specific term that refers to infection anywhere in the urinary tract, from the urethra to the bladder and the ureters to the kidneys (Frassetto 2015). According to the European Association of Urology Guidelines on urological infections, complicated urinary tract infections are associated with certain conditions, such as a structural or functional problem with the genitourinary tract, or the presence of underlying disease, which increases the risk of persistent or relapsing infection. Pyelonephritis is an infection of the upper urinary tract and can occur in 1 or both kidneys, usually developing from an ascending infection of the lower urinary tract. Acute pyelonephritis is considered to be complicated in people with increased susceptibility, for example children or older people; people with functional or structural abnormalities of the genitourinary tract or people who are immunocompromised, so that the infection will likely be severe (Frassetto 2015).
Complicated urinary tract infections (including acute pyelonephritis) are frequently caused by gram‑negative bacteria (such as Escherichia coli). According to the European Association of Urology Guidelines on urological infections, second or third generation cephalosporins, beta‑lactam antibiotics (such as penicillins) in combination with beta‑lactamase inhibitors and quinolones are often used for treating complicated urinary tract 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 urinary tract infections and acute pyelonephritis in adults. The dosage is 1 g/0.5 g administered intravenously over 1 hour every 8 hours for 7 days. Lower doses should be used in people with moderate to severe renal impairment. See the summary of product characteristics for more information.
Ceftolozane/tazobactam is also indicated for complicated intra‑abdominal infections, which are discussed in another evidence summary.
Evidence review
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ASPECT-cUTI was a multicentre, double-blind, double dummy RCT that was conducted in people with clinical evidence of complicated urinary tract infection (82% diagnosed with acute pyelonephritis and 18% with complicated lower urinary tract infection) who received IV ceftolozane/tazobactam 1 g/0.5 g every 8 hours or IV levofloxacin 750 mg once daily (plus placebo [saline] twice daily) for 7 days. The primary objective of the study was to demonstrate non‑inferiority of ceftolozane/tazobactam compared with levofloxacin in terms of composite cure rate, defined as achievement of clinical cure and microbiological eradication of all baseline uropathogens at the test-of-cure visit (5 to 9 days after the last dose of study drug) in the microbiological modified intention to treat (mMITT) population. Clinical cure was defined as complete resolution or substantial improvement, or return to pre-infection signs and symptoms of complicated urinary tract infection or pyelonephritis without the need for additional antibiotics.
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Ceftolozane/tazobactam (n=543) was found to be non-inferior to levofloxacin (n=540) in the mMITT population for the composite cure rate (76.9% compared with 68.4% respectively; treatment difference 8.5%, 95% confidence interval [CI] 2.3% to 14.6%: primary outcome). This result was comparable in the per-protocol (PP) population (83.3% compared with 75.4% for ceftolozane/tazobactam and levofloxacin respectively; treatment difference 8.0%, 95% CI 2.0% to 14.0%: secondary outcome).
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Ceftolozane/tazobactam was also found to be statistically significantly superior to levofloxacin for composite cure in both the mMITT and PP populations (not a pre-defined outcome), although the clinical relevance of this difference between the groups is unclear.
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The clinical cure rates were also found to be not statistically significantly different between ceftolozane/tazobactam and levofloxacin (92.0% and 88.6% respectively; treatment difference 3.4%, 95% CI −0.7% to 7.6% in the mMITT population) 5 to 9 days after the last dose of study treatment.
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Ceftolozane/tazobactam was found to be statistically significantly better than levofloxacin for microbiological eradication (80.4% and 72.1% respectively, treatment difference 8.3%, 95% CI 2.4% to 14% in the mMITT population). In the PP population, the most commonly isolated pathogen was E. coli and the rate of microbiological eradication was 90.5% with ceftolozane/tazobactam and 79.6% with levofloxacin (treatment difference 10.9%, 95% CI 4.9% to 16.8%).
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Generally, most of the people who were recorded as not having microbiological eradication after treatment were still found to be clinically cured and these patients were considered to have asymptomatic bacteriuria (European public assessment report).
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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 urinary tract infections (ASPECT-cUTI) and complicated intra-abdominal infections (ASPECT-cIAI) were nausea, headache, constipation, diarrhoea and pyrexia. These were generally mild or moderate in severity. A decline in renal function has been observed in people 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-cUTI 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 (75.1%), white (85.8%) and female (74.0%), with normal renal function or only mild renal impairment (92.1%). Additionally, 82.0% of participants had a diagnosis of acute pyelonephritis. Therefore, the results may not be generalisable to men and older people, particularly those with a diagnosis of complicated lower urinary tract infection or people with moderate to severe renal impairment. No data were reported evaluating infection severity or symptoms such as the presence of urosepsis. 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 pregnant or breastfeeding women or in children and is only indicated for use in adults.
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The dosage of levofloxacin (750 mg daily) used in the study was higher than the dosage recommended in the UK summary of product characteristics (500 mg daily) but is the dosage licensed in the US and is in line with European Association of Urology guideline recommendations for complicated urinary tract infections. At baseline, prior to the first-dose of study treatment, approximately 30% of gram‑negative and 57% of gram‑positive pathogens were resistant to levofloxacin. The difference in baseline antibacterial resistance had the potential to bias the results in favour of ceftolozane/tazobactam and suggests that levofloxacin was not a good choice of comparator (European public assessment report).
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In their assessment, the Committee for Medicinal Products for Human Use (CHMP) concluded that the complicated lower urinary tract infection indication is poorly supported based on ASPECT-cUTI due to the small number of participants with this diagnosis eligible for inclusion in the final analyses (60 people taking ceftolozane/tazobactam in the PP population). Nevertheless, the CHMP accepted that ceftolozane/tazobactam may be of use in people with complicated urinary tract infection due to certain beta-lactamase producing pathogens. Consequently, the summary of product characteristics reflects the limitations of the evidence. This includes the exclusion from clinical trials of people who were immunocompromised or those with severe neutropenia, or those with severe renal impairment, and the small percentage of people included with complicated lower urinary tract infections (European public assessment report).
Context
Empirical treatment of symptomatic complicated urinary tract infections should take into account a number of factors including possible pathogens causing the infection and local antibiotic resistance patterns. Antibiotic treatment options include fluoroquinolones, aminopenicillins combined with a beta-lactamase inhibitor, third generation cephalosporins, and aminoglycosides. The choice of therapy should be guided by urine culture whenever possible, and the initial empirical selection of an antimicrobial agent should be re-evaluated once culture results are available. Although many patients can be treated as outpatients, supportive care in a hospital setting may be needed (European Association of Urology Guidelines on urological infections). The clinical diagnosis and continuing need for antibiotics should be reviewed within 48–72 hours (Public Health England 'Start smart − then focus').
Public Health England makes similar recommendations for the treatment of acute pyelonephritis in their guidance for primary care on managing common infections. If hospital admission is not needed, urine should be sent for culture and susceptibility testing, and empirical antibiotic treatment with ciprofloxacin or co‑amoxiclav should be started. Some people may require hospital admission if they do not respond to treatment. Outpatient parenteral antibiotic treatment may be an option on the advice of a microbiologist.
A vial of ceftolozane/tazobactam costs £67.03 excluding VAT (MIMS, May 2016). Therefore, the cost of a course of treatment is £1,407.63 for 7 days, excluding VAT, any procurement discounts and administration costs. The acquisition cost of ceftolozane/tazobactam is more than that of many other antibiotics that are commonly used for complicated urinary tract infections. The procurement cost of a 7‑day course of these other treatments is less than £480 (see costs of alternative treatments for more detail).
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. In 1 RCT conducted in people with complicated urinary tract infections (ASPECT-cUTI), ceftolozane/tazobactam was non‑inferior to levofloxacin for the primary outcome of a composite cure rate. However, there was no statistically significant difference in clinical cure rates. It is also unclear whether the results apply to some populations; for example, those with severe renal impairment, or who are immunocompromised or have severe neutropenia. Pyelonephritis was the most common diagnosis in the study and less information is available on using ceftolozane/tazobactam in people with complicated lower urinary tract infections. Commissioners and local decision makers will need to determine the place in therapy of ceftolozane/tazobactam within local hospital antibiotic policies for managing complicated urinary tract 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. |