|Year : 2022 | Volume
| Issue : 2 | Page : 63-70
Beta-lactam beta-lactamase inhibitors
Department Microbiology, Manipal Hospital, New Delhi, India
|Date of Submission||14-Oct-2022|
|Date of Acceptance||19-Nov-2022|
|Date of Web Publication||13-Dec-2022|
94, Dhaula Kuan Part 1, Delhi Cantt. New Delhi - 110 010
Source of Support: None, Conflict of Interest: None
Four new β lactam-β lactamase inhibitor (BL-BLI) combinations, namely ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam and imipenem-cilastatin-relebactam are currently approved by the Food and Drug Administration for complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs) and two of them for hospital-acquired pneumonia/ventilator-associated pneumonia. The clinical trials of these antibiotics have shown them to be non-inferior to comparator antibiotics. These antibiotics have action against extended-spectrum beta-lactamase enterobacterales and Klebsiella pneumoniae carbapenemase producers. Some have action against OXA-48 producing Gram-negative bacilli. However, all the above BL-BLI antibiotics have no action against metallo-β lactamase-producing organisms. These are currently being used for the treatment of cUTI and cIAI caused by multidrug-resistant (MDR) Enterobacterales and MDR Pseudomonas aeruginosa.
Keywords: Beta-lactam beta-lactamase inhibitors, multidrug-resistant enterobacterales, multidrug-resistant Pseudomonas aeruginosa
|How to cite this article:|
Joshi S. Beta-lactam beta-lactamase inhibitors. J Acad Clin Microbiol 2022;24:63-70
| Introduction|| |
Infections caused by drug-resistant Gram-negative bacilli (GNB) are currently the important public health problem, especially in the intensive care units. Among them, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant (CR) Pseudomonas aeruginosa are listed as critical priority organisms as per the World health Organisation. Beta-lactams have been the mainstay of treating GNB. The action of β-lactams is by the inhibition of penicillin-binding proteins (PBPs) which are essential to the cell wall formation. Bacteria, in turn, produce β-lactamases which destroy the β-lactams and thus cause resistance. These beta-lactamases can be classified into four molecular classes:
- Class A (extended-spectrum beta-lactamases [ESBLs], Klebsiella pneumoniae carbapenemase (KPCs)
- Class B (metallo-beta-lactamases (MBLs), such as New Delhi Metallo-beta lactamase (NDM), Verona integron-encoded metallo-β-lactamase (VIM) and Imipenemase (IMP), which can lead to resistance to all carbapenems except monobactam)
- Class C (AmpC) (chromosomal or plasmid mediated), which confer resistance to cephalosporins)
- Class D (OXAs that confer resistance mostly to carbapenems).
The development of β-lactamase inhibitors helped in conserving the action of β-lactams. These inhibitors lack antibacterial activity at clinically relevant concentrations. However, they are coupled with a β-lactam, based on similarities in pharmacokinetics like elimination half-life, distribution in the body, metabolic pathways and activity of the inhibitor against β-lactamases capable of hydrolysing the β-lactam [Table 1].
| Ceftazidime avibactam|| |
Ceftazidime is hydrolysed by Class A ESBLs, Carbapenemases, Class B carbapenemases, Class C cephalosporinase but not most of Class D carbapenemases. Avibactam inhibits Class A, C, and some D β lactamases. Hence, ceftazidime avibactam (CAZ-AVI) is active against Enterobacterales (ESBL, Carbapenemase producers), OXA-24, 40 and 69 (in Acinetobacter baumannii) and OXA-48 in K. pneumoniae. In the INFORM (International Network for Optimal Resistance Monitoring) study, 34,062 isolates of Enterobacteriaceae were collected between 2012 and 2014, and the overall susceptibility to CAZ-AVI was 99.9 to 100% for Enterobacterales including ESBL and AmpC producing isolates. In meropenem non-susceptible isolates collected between 2015 and 2017, 73.0% was susceptible to CAZ-AVI.
Resistance rate and mechanism
The main mechanism of resistance against CAZ-AVI is the presence of class B metallo-β-lactamases and some class D β-lactamases. Other mechanisms include efflux pump activity, loss of porins and increased expression of blaKPC gene., Furthermore, single-point mutation in ceftazidime not reversible with avibactam is associated with resistance.
Ceftazidime and avibactam have several similarities in their pharmacokinetic properties. Both have short plasma half-lives (2.7 h), low plasma binding (<10%), volume of distribution around 20 litres and both are excreted unchanged by the kidney. The proportion of CAZ to AVI is 4:1 and the adult dose is 2.5 gm eight hourly over a two hour infusion. The pediatric dosage is 50 mg/kg body weight per day for patients aged 3 months to 17 years for complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI). No dosage adjustments are required for elderly, body weight, sex, or race. Dosage adjustment is recommended for patients with creatinine clearance <50 ml/min.
CAZ-AVI is approved by Food and Drug Administration (FDA) for cIAIs, cUTI in adults and children and hospital-acquired bacterial pneumonia (HABP), and ventilator-associated bacterial pneumonia (VAP) in adults.
Randomized controlled trials evaluating ceftazidime avibactam
A meta-analysis was done by Sternbach et al. included eight trials, 4093 patients and compared CAZ-AVI with or without metronidazole versus any other antibiotic regimen (mainly carbapenems) for the treatment of cUTI, cIAI and hospital-acquired pneumonia. No difference in all-cause mortality was seen at late follow-up. No significant differences in clinical cure or microbiological cure at test of cure (TOC) were demonstrated as well. Zhang et al. in his meta-analysis of cUTI and cIAI found a higher microbiological cure rate with CAZ-AVI. He also noted that the rate of serious adverse events was significantly higher with CAZ-AVI versus the comparator mainly carbapenems.
Infections by specific pathogens
Ceftazidime-resistant Enterobacterales and P. aeruginosa: In an analysis of randomised controlled trials (RCTs) in adults, clinical response was 86% in the CAZ-AVI arm versus 85% in the carbapenems based comparator arm.
Jorgensen et al. treated 63 patients who had resistant Pseudomonas spp infections with CAZ-AVI and noted a mortality of 17.5% at 30 days and clinical response of 69.8%.
CRE: A meta-analysis by Zhong et al. showed significantly lower mortality and higher cure rates with CAZ-AVI versus the comparator in CRE infections, more so for KPC producers. A meta-analysis by Onorato et al. compiled 11 retrospective studies and case series evaluating CAZ-AVI as monotherapy versus a combination for CRE and CR Pseudomonas. The mortality rates were similar in both groups.
Two phase 2 RCTs were done on 180 patients evaluating CAZ-AVI versus cefepime for cUTI and CAZ-AVI with metronidazole versus meropenem for cIAI. Clinical cure rates were similar. Microbiological cure rates were similar for cIAI. Rates of any adverse events were similar and serious adverse events were non-significantly more common with CAZ-AVI (10.1% versus 6.0%).,
Clinical cures were similar between CAZ-AVI and comparator in three RCTs.,,
Chronic renal failure
Patients with severe renal or liver impairments were excluded from RCTs evaluating CAZ-AVI. Shields et al. reported lower clinical success among patients requiring continuous renal replacement therapy (RRT). In view of fewer studies, a need to re-evaluate dose adjustment for renal impairment is required.
There is very few data available on this subset of patients.
No significant difference in adverse events between CAZ-AVI and comparators in RCT's was noted. Gastroenteritis AE (adverse events) in (~ 20% patients), increase in creatinine (~2% patients) were more with CAZ-AVI than carbapenems. Other AEs reported included pyrexia, peripheral edema, hypersensitivity reaction and neurological AE's.
Emergence of resistance to ceftazidime avibactam during treatment
There is emergence of resistance to CAZ-AVI during treatment. Wagenlehner et al. reported increase of MIC four fold from baseline in 2% of his cases. Shields et al. reported three cases of CAZ-AVI resistant K. pneumoniae following CAZ-AVI treatment for 10 to 19 days. They found new mutations in plasmid borne blakpc-3. Iannaccone et al. reported 23 cases of K. pneumoniae bacteremia treated with CAZ-AVI. Of these cases 4 had a relapse of bacteremia: two with CAZ-AVI-resistant isolate, one with MIC increase from 2 to 8 ug/ml and one with no relevant MIC variation.
| Ceftolozane – Tazobactam|| |
The combination of ceftolozane–tazobactam (TOL-TAZ) is active against ESBL producing Enterobacterales including E coli carrying CTXM-14 and CTXM-15, multidrug resistant (MDR) P. aeruginosa and some anaerobes like Bacteroides fragilis. There is limited activity against ESBL producing K. pneumoniae, CRE and anaerobic cocci. TOL-TAZ has enhanced affinity for the PBP's of P. aeruginosa. Thus it is less affected by the porin permeability or efflux pumps.
Data from the United States between 2015 and 2017 showed an overall susceptibility of 97.5% in P. aeruginosa; of which MDR P. aeruginosa showed 82.8% susceptibility and XDR P. aeruginosa showed 82.9% susceptible isolates. In a study on 6000 Gram-negative isolates from paediatric patients in Europe and US, susceptibility to TOL-TAZ was 94.6% and 97.4% in Enterobacterales and P. aeruginosa, respectively. Tato et al. showed that TOL-TAZ was highly active against MDR P. aeruginosa and against E coli including AmpC and ESBL producers. In a study by Pazzini et al., TOL-TAZ was active against 85% ESBL producing E. coli, 57.5% ESBL producing K. pneumoniae and the majority of carbapenemase producing GNB (99%) were non susceptible.
Resistance rates and mechanism
P. aeruginosa produces a chromosomally encoded Class C cephalosporinase (Pseudomonas-derived cephalosporinase-PDC). PDCs can hydrolyse ceftolozane and cause resistance. Sader et al. reported that TOL-TAZ resistant isolates carried a VIM type metallo-beta lactamase gene. Emerging resistance following exposure to TOL-TAZ was reported by Haidar et al. Resistance developed in 14% cases due to de novo mutations, AmpC overexpression and amino acid substitutions affecting the Beta lactamase Ω loop. This resistance emerged on days 8 and 19 of treatment and 2 weeks after the completion of a 30-day treatment course. Jorgensen et al. detected resistance in 9.7% of MDR P. aeruginosa after 3, 7 and 8 days after the initiation of monotherapy with TOL-TAZ.
Ceftolozane and tazobactam share similar protein binding values – 16 to 21% and 30% respectively. However, they differ in the metabolic disposition. Ceftolozane is excreted unchanged and less than 20% tazobactam is metabolised to an inactive M1 metabolite. Ceftolozane, unmetabolised tazobactam and M1 metabolite are all excreted renally.
The duration of time above a threshold value (%T > threshold) is the best pharmacokinetic-pharmacodynamic (PK-PD) index for the activity of tazobactam when combined with ceftolozane. % T > MIC was identified as the index that best correlated with antimicrobial activity of ceftolozane against non-β lactamase-producing Enterobacterales and P. aeruginosa. For cUTI and cIAI, the approved dosing regimen is 1 gm ceftolozane and 0.5 gm tazobactam every eight hours as a one hour, i.v., infusion. For HABP/VAP, a higher dose of 2 gm ceftolozane and 1 gm tazobactam is indicated.
For patients with renal impairment, dosage adjustments are required.
For pediatric patients less than 12 years, 20 mg/kg body weight ceftolozane and 10 mg/kg body weight tazobactam administered as a one hour infusion every eight hours is proposed.
TOL-TAZ is FDA approved for adult cUTI, cIAI and HABP/VABP. It is not yet approved for use in paediatric patients. Cheng et al. published a meta-analysis of three RCT's involving 2198 patients evaluating TOL-TAZ for cUTI and cIAI and other comparators including meropenem. Clinical cures at TOC and microbiological response rates were similar between study arms. No significant difference between SAEs and AEs was noted. In a randomised control trial involving 726 patients of nosocomial pneumonia, TOL-TAZ versus meropenem was evaluated. No significant difference in the study arm for efficacy and safety outcomes was noted.
For XDR P. aeruginosa, two studies, compared TOL-TAZ with polymixin or aminoglycosides. Clinical and microbiological success rates were 76.6% and 75.6% for any Pseudomonas and 73.4% and 74.2% for MDR- and XDR-infected patients. One RCT comparing TOL-TAZ with meropenem did not report a difference in clinical cure in both trial arms for patients with ESBL Enterobacterales infection.
Paediatric population: One phase 1 study included 37 children showed no mortality, serious clinical adverse effects and no clinically significant laboratory abnormalities.
Chronic renal failure patients: Moderate renal impairment patients had lower clinical response rates with TOL-TAZ.
- Diabetes mellitus: Patients with diabetes mellitus had lower clinical response.
- Elderly:,, Three RCTs reported no significant difference in clinical cure rates between TOL-TAZ and comparator
- Safety data: Rates of AEs in RCTs were similar between TOL-TAZ and comparator. Most common AEs included gastrointestinal AE's, C difficile infection, headache, pyrexia and abnormal LFT's.
Emergence of resistance to TOL-TAZ during treatment: In a study by Bassetti et al., TOL-TAZ resistance was detected in 3 out of 101 patients being treated with TOL-TAZ for P. aeruginosa infections. Xipell et al. demonstrated 1 in 23 patients developing a resistant strain.
| Meropenem-Vaborbactam|| |
Meropenem-vaborbactam (MER-VAB) has documented the activity against class C β lactamases, class A β lactamases including CTX-M, SHV, TEM, SME and NMC, KPC producing isolates and BKC-1 carbapenemases found in K. pneumoniae and Enterobacter cloacae., In case of K. pneumoniae, strains with reduced permeability due to porin mutations, vaborbactam restored the activity of meropenem against class A and class C β lactamase producing K. pneumoniae. In a study on 11,559 Enterobacterales collected during 2015, MER-VAB inhibited 99.3% of all strains and 99.5% of KPC producers at FDA susceptible breakpoints of ≤4/8 mg/L. The combination had limited activity against MBL and carbapenem hydrolysing class D enzymes. Kinn et al. reported that vaborbactam significantly decreased meropenem MIC in both non-KPC producing and KPC producing CREs. Athans et al. in 2019 reported the resolution of infection in a liver transplant recipient with KPC producing K. pneumoniae after treatment with MER-VAB.
Resistance rates and mechanism
Castanheira et al. noted that MER-VAB-resistant isolates produced MBL or had decreased expression of porin and/or hyper-expression of efflux system.
Both vaborbactam and meropenem have low plasma binding (approx. 33% and 2%, respectively). Approximately 28% of meropenem is hepatically hydrolysed to an inactive metabolite. Both parent and metabolite and vaborbactam are excreted renally.
The approved dose for MER-VAB combination is 2 gm each of meropenem and vaborbactam infused over three hours every eight hours. Renal impairment warranted dosage adjustment is based on the estimated glomerular filtration rate.
MER-VAB is FDA approved for adults with cUTI. In a TANGO phase 1 trail, of the 374 patients were included in the microbiological intention-to-treat group, 85% had Enterobacterales as the causative pathogen. This trial compared MER-VAB with piperacillin-tazobactam (PIP-TAZ). Clinical cure or improvement and microbiological eradication was seen in 98.4% in MER-VAB arm versus 94% in PIP-TAZ arm. No difference in adverse events or severe adverse events was seen in both groups.
Paediatric population: currently MER-VAB is not approved for paediatric patients by FDA.
Cancer patients: In a subgroup analysis by Viale in 15 cancer patients with CRE, who were part of the TANGO 2 trial (MER-VAB versus best available therapy-BAT) for suspected CRE infection, 8 patients who were treated with MER-VAB had lower mortality, fewer AEs and higher cure rates.
The TANGO II phase3 RCT included 77 adult patients with CRE randomised into MER-VAB treating arm or other drugs treating arm (carbapenem, polymyxin, aminoglycoside and/or tigecycline). Bassetti et al. performed a post hoc analysis of the above RCT, analysing 22 MER-VAB patients and 15 BAT patients without prior antimicrobial treatment failure. He found significantly lower mortality and higher rates of clinical and microbiological cure with MER-VAB.
MER-VAB has good in vitro activity against Burkholderia species including B cepacia and B gladioli and Achromobacter sps.
Emergence of resistance to MER-VAB during treatment
Sun et al. reported development of resistance during exposure to low drug concentrations of MER-VAB. Resistance was due to an increase in blaKPC copy number and ompK36 inactivation. In another study by Shields et al., 20 patients were treated with MER-VAB for more than 48 h. Within 90 days, 35% of cases had microbiological failure (isolation of the same bacterial species with more than 7 days of treatment with MER-VAB). Half of these recurrent isolates showed a >=8 fold increase in MIC to MER-VAB. Whole genome sequencing identified IS5 insertion in ompK36 promotor gene.
| Imipenem-Cilastatin-Relebactam|| |
Imipenem-cilastatin is combined with relebactam mainly to restore the activity against CRE and P. aeruginosa. P. aeruginosa may be resistant to imipenem due to the decreased expression of OprD and overproduction of AmpC βlactamases. Relebactam inhibits AmpC and improves imipenem activity. Imipenem-cilastatin-relebactam (IMI-REL) is effective against bacteria-carrying class A and class C β lactamases and has limited activity against blaOXA-48 expressing Enterobacterales and no activity against MBL.
Data from SMART surveillance between 2015 and 2017 showed that 92.2% P. aeruginosa were susceptible to IMI-REL. Of the imipenem non-susceptible P. aeruginosa and MDR P. aeruginosa, 85.0% and 87.3% showed susceptibility to IMI-REL. Livermore et al. found that IMI-REL was active against AmpC and ESBL producing Enterobacterales with impermeability phenotypes. In the case of Opr-D-deficient P. aeruginosa strains, there was a MIC drop of imipenem of approximately four fold dilution. Papp-Wallace et al. found in 101 KPC producing isolates of Enterobacterales, all the isolates were susceptible to IMI-REL with MIC's ≤2 mg/l. In a study published in 2019 including P. aeruginosa isolates, IMI-REL susceptibility rates were 83.7% and MIC's were ≤2 mg/l.
The organisms resistant to IMI-REL are mainly those producing MBL and some OXA class βlactamases. Other mechanisms include decreased expression of porin proteins.
Imipenem and relebactam exhibit very similar plasma protein binding, half-lives and routes of elimination. Both drugs are predominantly excreted unchanged in urine. The dosage is 1.25 gm (500 mg imipenem, 500 mg cilastatin and 250 mg relebactam) infused over 30 minutes every six hours. It has not yet been approved for pediatric patients.
IMI-REL is FDA approved for cUTI and cIAI.
RCT's evaluating IMI-REL
In a phase 2 RCT for UTI, Sims et al. compared two different doses of IMI-REL with imipenem alone (500 mg imipenem cilastatin with 250 mg relebactam versus imipenem/cilastatin 500 mg with 125 mg relebactam). Of the 302 patients, 230 had a baseline pathogen and 11% of all pathogens were imipenem non susceptible at baseline. No cases of mortality were documented and no difference between the study arms was demonstrated for clinical or microbiological response at end of therapy (EOT). There were AE's – commonly gastro-intestinal side effects, headache, hypertension etc., which were seen in the investigative arm. No significant difference in SAE's was noted.
In a phase 2 RCT for cIAI, Lucasti et al., 351 patients were enrolled including 21% elderly and 250 patients had a baseline pathogen and 13% had imipenem non susceptible pathogen at baseline. No difference between study arms for clinical or microbiological response at EOT was observed. No significant difference in SAE's and AE's requiring discontinuation of drug and mortality was seen.
A phase 3 RCT comparing IMI-REL alone versus imipenem combined with colistin for imipenem non susceptible infection was carried out the RESTORE-IMI trial. The infections included were HABP/VABP, cIAI and cUTI. Overall 31 patients had a baseline pathogen of the total 47 patients. There were no significant difference between study arms for primary outcome (71.4% versus 70%). Clinical response at 28 days was significantly higher with IMI-REL (71% versus 40%). AE's included pyrexia, nausea, decreased creatinine renal clearance and abnormal liver function tests, more in the comparator arm. Nephrotoxicity was 56% in the comparator arm as compared to 10% in IMI-REL arm. SAE's and AE's requiring drug discontinuation were more common in comparator arm.
There are β lactam-β lactamase inhibitors (BL-BLI's) in development process: cefepime-tazobactam, cefepime-enmetazobactam, cefepime-zidebactam, Aztreonam-avibactam, meropenem-nacubactam and others. To be able to use newer BL-BLI's appropriately for CRE's and MDR P. aeruginosa, it is imperative to identify the type of carbapenemase being produced by the organism. Phenotypic tests such as modified carbapenem inactivation method and eCIM (EDTA modified Carbapenem inactivation method) and Carba NP test can differentiate carbapenemase and non carbapenemase producing CRE. Molecular testing can identify specific carbapenemase families (KPC, MBL, Oxa-48 etc). The appropriate drugs for pathogens having various enzymes are shown in [Table 2].
|Table 2: Beta-lactam beta-lactamase inhibitors and carbapenemase enzymes|
Click here to view
| Summary|| |
The four new BL-BLI combinations viz. ceftazidime-avibactam, ceftolozane-tazobactam, MER-VAB and imipenem-cilastatin-relebactam are useful for treating MDR Enterobacterales and MDR P. aeruginosa causing cUTIs, cIAIs. CAZ-AVI and TOL-TAZ have been approved for hospital acquired pneumonia/ventilator-associated pneumonia. These are the latest drugs in our arsenal for combating MDR infections. However, the prudent use of these agents is essential to preserve their action. Antibiotic stewardship plays an important role with the aim of preventing resistance to these antibiotics.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]