Ceftolozane-tazobactam

Class: 5th generation cephalosporin.
Available as ceftolozane-tazobactam, a beta lactam-beta lactamase inhibitor (BLBLI) combination.

Mechanism of Action:

Similar to other beta-lactam antibiotics. It binds to the penicillin-binding protein (PBP) to inhibit the biosynthesis of the cell wall.
It binds with the PBP3 of E coli and PBP3, PBP1a, and PBP1b of Pseudomonas aeruginosa.

Mechanism of resistance:

• Beta-lactamases,
• Modification of PBP binding sites by gene acquisition or target alteration,
• Up-regulation of efflux pumps, and
• Loss of outer membrane porin channels.

It is active against ESBL-producing Enterobacterales but not carbapenemase.
It also has some activity against Pseudomonas with chromosomal ampC, upregulated efflux pump or porin loss [Shotridge 2021].

PK/PD:

• Important parameter – Time over MIC (T/MIC). The concentration needs to be at least 60-70% of the dosing interval for bactericidal activity.
• Route – IV
• Plasma protein binding – 20% (approx)
• Vd – 13.5L
• T1/2 – 3 to 4hrs
• Excretion – renal, (not metabolised) by glomerular filtration.
• Hepatic impairment – No hepatic metabolism
• Renal impairment – dose adjustment needed in renal impairment
• Paediatric population – not enough data
• Augmented renal function (ITU) – no adjustment needed.

Use:

• Complicated intraabdominal infections
• Complicated urinary tract infection
• Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP)
• Sepsis
• Maraolo (2020) reviewed the off-label indications like skin-soft tissue, bone-joint infection and bacteremia and found the overall clinical success rate was 76.2%.

Adverse effect:

• GI adverse effects, C difficile associated diarrhoea, Increase in AST/ALT,
• Headache,
• Renal impairment,
• Candidiasis,
• Allergy/hypersensitivity reaction,
• Leucopenia, thrombocytopenia
• Hypoprothrominaemia (esp in renal/hepatic impairment, poor nutrition or long antibiotic course),
• Haemolytic anaemia (+ve Coomb’s test), hypokalemia.

Interaction:

Oral contraceptive, loop diuretics, Warfarin.

Contraindication/caution:

• Penicillin hypersensitivity
• Pregnancy and breastfeeding – limited data
• C difficile associated diarrhoea/Pseudomembranous colitis

[Ref: NICE Evidence summary]

Spectrum:

Activity is similar to ceftazidime but increased activity against Pseudomonas.
It has limited activity against gram-positive bacteria.

Cefotolozane-tazobactam is active against –

• Enterobacterales – Including ESBL, but not carbapenemase) –
  E coli, Klebsiella spp, Enterobacter cloacae, Serratia spp. Citrobacter spp. (KESC)
  Proteus spp, Providencia spp, Morganella morganii (PPM).
• Pseudomonas aeruginosa – including ampC producers, those with oprD porin loss or upregulated efflux pump.
• Haemophilus influenzae (including if beta-lactamase positive strains).
• Gram-positive bacteria: Group B Streptococcus, Streptococcus anginosus group, Streptococcus salivarius.
• Anaerobes: B fragilis, Propinibacterium, Fusobacterim, Prevotella. 

Trials

ASPECT-NP – multicentre randomised controlled, double-blind, non-inferiority trial. A high dose of ceftolozane with tazobactam was non-inferior to meropenem for treating seriously ill people with VAP or ventilated HAP caused by Gram-negative pathogens such as Pseudomonas aeruginosa (including multidrug-resistant strains) and Enterobacterales including ESBL producers.

This study did not include less severe HAP patients, immunosuppressed patients, cystic fibrosis patients, dialysis patients, and children.

ASPECT-cUTI: RCT  in adults with complicated urinary tract infections or acute pyelonephritis IV ceftolozane/ tazobactam was non‑inferior to IV levofloxacin clinical cure and statistically superior for microbiological eradication. This trial did not have enough data on men, older people, children, pregnant patients/breastfeeding women, immunocompromised, septic shock, complicated lower urinary tract infections or people with moderate to severe renal impairment.

ASPECT-cIAI: RCT in adults with complicated intra‑abdominal infections, intravenous ceftolozane/tazobactam plus metronidazole, was non‑inferior to intravenous meropenem plus saline (placebo) in terms of clinical cure rates 24–32 days after starting treatment. This result may not be generalisable to older people, those with severe renal failure, rapidly progressing disease (septic shock), children, and immunocompromised patients.