Rising concerns of Carbapenem resistant Enterobacteriaceae and the options available: An overview

Harish Mallapura Maheshwarappa*

Director – Institute of Critical Care Medicine. Kauvery Hospital, Bengaluru

*Correspondence: M: +918095218493; Email: https://harishcriticalcareclasses.com

Background

Carbapenem-Resistant Enterobacteriaceae (CRE) was posing a dilemma in effective healthcare delivery.

About one half of patients were from rural areas, 63.64% from sub-urban and 42.27% from urban areas who had significant E. coli and Klebsiella spp infections.

The male: female ratio of the Enterobacteriaceae infection was 1:1. CRE is quickly emerging in both community and hospital environments. Klebsiella spp was the most common CRE in hospitals especially Klebsiella oxytoca Hospitalization was a strong risk factor for CRE infections. Rapid and accurate detection is critical for their effective management and control.

Epidemiology of CRE

Among the 4 classes of β-lactamases defined by the Ambler classification system the carbapenemases that confer carbapenem resistance in Enterobacteriaceae belong to 3 of them:

  1. Class A (K. pneumoniae carbapenemases, KPC)
  2. Class B (metallo- β -lactamases,MBL including New Delhi metallo- β -lactamases, NDM)
  3. Class D (OXA-48-like carbapenemases).

Which are the organisms involved?

Carbapenem-resistant Enterobacteriaceae isolated from various clinical specimens:

  • Klebsiella
  • Escherichia coli
  • Enterobacter sp
  • Citrobacter freundii

Definition

Enterobacterales (ertapenem, meropenem or imipenem), P. aeruginosa (meropenem or imipenem) and A. baumannii (meropenem or imipenem) that shows resistance to at least one of the carbapenems are called carbapenem resistant Enterobacterales (CRE). Colonization with these bacteria can also occur and does not require treatment, though similar infection control precautions should be used for colonized persons in healthcare settings in order to prevent transmission to other patients.

Who are at risk of being infected?

  • Colonized patients are at double risk from their own endogenous colonization and indwelling devices
  • Prolonged hospitalization; patients who are chronically or critically ill
  • Invasive devices such as ventilators, urinary catheters, or central venous catheters

Symptoms of Nosocomial or Hospital-acquired infection

  • Shortness of breath
  • Stiff neck
  • Reduced consciousness
  • Septic shock
  • Sepsis
  • Fatigue
  • Fever and chills
  • Abdominal (belly) pain
  • Painful swelling of skin
  • Painful urination

Routine surveillance of CRE infections in Indian settings

  • Carbapenems are the last-line effective antibiotics, and their resistance in gram-negative bacteria (GNB) has reached an alarming number (12%–83%) in Indian intensive care units (ICUs)
  • The prevalence of gut colonization of CRE, has been reported to be 3–7% in hospital settings and much higher in ICU settings
  • The risk of CRE infections following colonization has been reported to be 16.5%

Diagnosis of Carbapenem-resistant enterobacteriaceae

 

Management of CRE

Indian Council of Medical Research – Guidelines – Standard care for CRE

Appropriate patient placement

  • Limiting transport and movement of patients.
  • Use of disposable & dedicated patient care equipment

Personal protective equipment

  • Gloves
  • Gowns

Prioritized cleaning & disinfection

  • HCW education in IPC principles, monitoring of contact precautions.
  • For high risk, pre-emptive isolation/cohorting till results available

Surveillance cultures for asymptomatic CRE colonization

  • Not yet a routine standard of care.
  • Recommended in outbreaks and situation with high risk of CRE acquisition

Treatment of Carbapenem-resistant enterobacteriaceae

Management of a variety of infections due to CRE is challenging as there are very limited number of agents:

  • Colistin(CL)
  • Tigecycline
  • Minocycline
  • Fosfomycin

Indian consensus on the management of CRE infection in critically ill patients

  • New Delhi mettalo-β-lactamase (NDM) and coproduction of NDM with oxacillinase -48 like (oxa -48-like) enzyme are the most pre dominat mechanisms of carbapenem resisitant Enterobacteriaceae (CRE) ingections of india.
  • Strict contact isolation and hand hygiene is cruscial in the prevention and treatment of CRE infections in india.
  • A point –of –care (POC) test may become a powerful tool in guiding early appropriate therapy in CRE infection.
  • Role of gentamycin and polymyxins for gut decontamination in CRE carriers is strongle discourage due to the risk of emergence of further to targeted organisms.
  • The mortality risk prediction in patients with CRE Infections using a scoring system may help to triage the available treatment options.
  • Augmented renal clearance (ARC) is frequently encountered as an early (3-4 days) phenomenon in critically ill patients, and four-hourly estimation of glomerular filtration rate (GFR) would help as a surrogate markers for identifying underlying ARC.
  • Empiric combination therapy with NDM coverage should be considers for the management of CRE infection in patients with high mortality risk
  • Polymaxins are the current cornerstone molecule for empirical therapy for CRE infections in India.

ICMR – Guidelines – Treatment strategy for CRE

  • CRE Rx depends heavily on susceptibility profile, preferably MIC based.
  • Options include: Meropenem high-dose extended-infusion (if MIC 2-8 mg/L); or meropenem + amikacin; meropenem/imipenem + colistin
  • Tigecycline high dose with loading dose (not indicated in septicaemia); minocycline alternative
  • Aztreonam for MBL producers
  • Ceftazidime-avibactam for KPC and OXA-48 producers
  • Colistin or polymyxin B

Ceftazidime-avibactam therapy for treatment of CRE

  • Complicated intra-abdominal and urinary tract infections (UTIs) including pyelonephritis
  • Hospital-acquired pneumonia (HAP)
  • Broad-spectrum antibacterial activity and is effective against class-A and class-C beta-lactamases (as well as KPC)
  • Some class D carbapenemases
  • Only agent active against OXA-48-like producers.

Mechanism of Action

Avibactam does not inhibit class B enzymes (metallo-β-lactamases) and is not able to inhibit many class D enzymes.

CeftazidimeAvibactam
Inhibits bacterial peptidoglycan cell wall synthesis following binding to penicillin binding proteins (PBPs)Non β-lactam, β-lactamase inhibitor

Acts by forming a covalent adduct with the enzyme that is stable to
hydrolysis
Leads to bacterial cell lysis and deathInhibits both Ambler class A and class C β-lactamases and some class D enzymes,
including extended-spectrum β-lactamases (ESBLs), KPC and OXA-48 carbapenemases, and AmpC
enzymes

Ceftazidime-avibactam therapy Vs all other Molecules

109 patients with CR-Kp bacteraemia

Other regimens included aminoglycoside (n 11), carbapenem (n 8), colistin (n 4), tigecycline (n 4), and ciprofloxacin (n 2) monotherapy, as well as combination regimens of colistin plus tigecycline (n 3), aminoglycoside plus tigecycline (n 2), and 1 each of aminoglycoside plus cefepime, aminoglycoside plus colistin plus tigecycline, colistin plus aztreonam, colistin plus cefepime, colistin plus ciprofloxacin, carbapenem plus doxycycline, and carbapenem plus tigecycline. Ceftazidime-avibactam therapy

Ceftazidime-avibactam therapy – For the Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections in Patients with Liver Cirrhosis

  1. In hospital survival according to the presence of CAZ AVI (Ceftazidime-Avibactam) in the antibiotic treatment of cirrhotic patients with CRKP infection.
  2. Ceftazidime-avibactam therapy was associated with lower rates of treatment failure (7% vs. 38%, P = 0.032) independent of severity of liver disease (Child Class) and mono or combination antibiotic therapy.
  3. Treatment including ceftazidime-avibactam was associated with a lower rate of treatment failure in cirrhotic patients with CRKP infections.
  4. Considering the favorable efficacy and outcomes of ceftazidime-avibactam, this drug should be considered for the treatment of these severe infections in patients with liver cirrhosis, though further investigation is required.

Ceftazidime-avibactam therapy – In complicated urinary tract infections

A 51 (31%) of 164 patients in the ceftazidime-avibactam group and 66 (39%) of 168 in the best available therapy group had an adverse event

Ceftazidime-avibactam therapy – In complicated intra-abdominal infections

  1. A total of 204 patients were randomized in a 1:1 ratio to receive either 2 g ceftazidime plus 500 mg avibactam plus a separate infusion of 500 mg metronidazole or 1 g meropenem plus 0.9% saline (as placebo for metronidazole) every 8 h for a minimum of 5 days and a maximum of 14 days.
  2. Favorable clinical response rates were seen in 91.2% (62/ 68) ceftazidime-avibactam plus metronidazole
  3. Favorable clinical response rates were seen in 93.4% (71/76) of patients in the ceftazidime-avibactam plus meropenem

Ceftazidime/avibactam in against carbapenem-resistant Gram-negative bacteria: Efficacy

Monotherapy and combination therapy

  1. In patients infected with carbapenem-resistant Pseudomonas aeruginosa (CRPa)
  2. No difference between patients treated with ceftazidime/avibactam monotherapy or combination therapy was observed in overall mortality
  3. Microbiological outcome among 247 patients was included
  4. Microbiological cure was achieved in 63.4% of patients treated with ceftazidime/avibactam alone
  5. Microbiological cure was achieved in in 64.9% of those treated with combination therapy

Ceftazidime-Avibactam Therapy – For Treatment of Renal Function (RECLAIM)

  1. In Reclaim, patients with cIAI (n 1,066) were randomized 1:1 to receive either ceftazidime-avibactam (2.5 g q8h for patients with CLCR of 50 ml/min) plus metronidazole (0.5 g q8h) or meropenem (1 g q8h) for 5 to 14 days;
  2. Patients with CLCR of 50 ml/min received the original ceftazidime-avibactam dosage adjustments.

Ceftazidime-Avibactam versus Meropenem – In Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia (REPROVE)

  1. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible.
  2. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group
  3. In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group

Ceftazidime-avibactam therapy – For treatment of Complicated Urinary Tract Infections (RECAPTURE)

  1. Noninferiority of ceftazidime-avibactam vs doripenem was demonstrated for following endpoints:
  2. Patient-reported symptomatic resolution at day 5: 276 of 393 (70.2%) vs 276 of 417 (66.2%) patients
  3. Combined symptomatic resolution/microbiological eradication at test of cure (TOC): 280 of 393 (71.2%) vs 269 of 417 (64.5%) patients
  4. Microbiological eradication at TOC occurred in (77.4%) ceftazidime-avibactam vs (71.0%) doripenem patients

Ceftazidime-avibactam therapy Indian study

Ceftazidime-avibactam therapy Retrospective Study 2021 by Nagvekar et al. For treatment of CRE

Summary

The experience was recorded and analyzed at two tertiary care centers including only adult patients with CRE infection who had received CZA alone or in combination with other antibiotics (February 2019 and January 2020)

Results

  1. OXA-48 was detected in 17 patients (15 Klebsiella pneumoniae, 2 nxf)
  2. NDM was detected in 7 patients (7 E. coli)
  3. Combination of NDM and OXA-48 was detected in 33 patients (33 Klebsiella pneumoniae) who had received CZA treatment
  4. CZA in the combination of polymyxin in 4 patients, with tigecycline in 7 patients and polymyxin and Fosfomycin combination along with CZA in 2 patients
  5. Patients who were on monotherapy were less sick patients, it was the beginning of using CZA.

For treatment of CRE based on Infection type

  • The intra-abdominal infection (31.57%)
  • Nosocomial pneumonia (26.31%)
  • Bloodstream infection (8.77%)
  • UTI (8.77%)
  • Wound infection (7.01%)
  • Skin and soft tissue infection (7.01%)
  • Six patients had an established solid organ transplant
  • pneumonia was the predominant pathogen
  • Most of the patients showed synergy (zone of hope)

CZA is a viable option for the treatment of infections due to CRE, as well as for acutely ill or post-transplant patients.

Case Presentation

Case 1: Bloodstream Infection

Developed central Line-associated Bloodstream Infection with carbapenem-resistant K. pneumoniae (OXA48 gene detected). The same organism was isolated from urine and respiratory cultures. Despite removing the central line and being on meropenem, colistin, tigecycline and gentamicin, repeated blood cultures revealed carbapenem-resistant K. pneumonia

Management

  • Started on ceftazidime–avibactam 2.5 g IV every 8 hr as he was on continuous renal replacement therapy (CRRT)
  • Received the treatment regimen in combination with tigecycline for 14 days
  • Repeated blood, urine and respiratory cultures at days 1, 14 and 21 from the start of ceftazidime–avibactam.
  • Test results were negative for carbapenem-resistant K. pneumonia

Case 2: Hospital acquired Pneumonia

Persistent fever and leucocytosis were present on day 23 and a bronchial alveolar lavage (BAL) culture grew K. pneumonia.

Management

  • Piperacillin/tazobactam was changed to 2.5 g of ceftazidime/avibactam intravenously every 8 h and nebulized polymyxin E.
  • On hospital day 26, susceptibility testing established MDR K. pneumoniae and ceftazidime/avibactam was changed to doxycycline
  • Recurrence of fever, EVD cultures were obtained on day 31, revealing MDR K. pneumoniae with susceptibilities matching the BAL isolate.
  • Both isolates were carbapenemase producers
  • Ceftazidime/avibactam was restarted, 8 mg of daily intraventricular gentamicin was initiated and the patient underwent an EVD exchange the following day
  • Throughout the hospital stay, the patient remained largely unchanged neurologically.
  • On day 74, the patient was discharged to a long-term care facility, moving spontaneously and responding to voice commands.

Case 3: cUTI

Prior to admission, the patient experienced decreased appetite, abdominal pain, generalized weakness, and maintained a low-grade fever. The patient’s sputum culture from previous admission revealed ESBL K pneumoniae, and his urine culture grew carbapenem-resistant K pneumoniae (determined to be a colonizer in the previous admission) and Candida tropicalis

Management

  • The team discontinued tigecycline and decided to use a novel antibiotic regimen that consisted of ceftazidime/avibactam 0.94 gm IV every 12 hours and aztreonam 1 gm IV every 8 hours, while colistin was continued.
  • The combination of aztreonam, ceftazidime/avibactam, and colistin was well tolerated with no bone marrow suppression or seizures
  • Patient was discharged on day 24 of hospital stay with home hospice

Case 4: Hospital acquired Pneumonia

He developed ventilator associated pneumonia and was admitted to the intensive care unit requiring high ventilatory and circulatory support. Respiratory cultures persistently revealed carbapenem-resistant P. aeruginosa.

Management

  • He was treated initially with prolonged courses of multiple combinations of anti-pseudomonal agents; however he failed to exhibit a favorable response.
  • Started on ceftazidime–avibactam, 2.5 g IV every 8 h.
  • On day 2, he started to show clinical improvement and the ICU team was able to stop the circulatory support and decrease the ventilation requirement.
  • Repeated respiratory culture obtained at day 28 was negative for carbapenem-resistant P. aeruginosa.

Aztreonam with Ceftazidime –Avibactam – For treatment of Bloodstream Infections (BSI)

A 102 patients with BSI; 82 had infections caused by NDM-producing (79 Klebsiella pneumoniae and 3 Escherichia coli) and 20 by VIM-producing (14 K. pneumoniae, 5 Enterobacter species, 1 Morganella morganii) strains.

Outcomes

  • The 30-day mortality rate was 19.2% in the CAZ-AVI + ATM group
  • The 30-day mortality rate was 19.2% in the 44% in the other active antibiotics (OAA) group
  • (P = 007).
  • The CAZ-AVI + ATM combination offers a therapeutic advantage compared to other active antibiotics for patients with BSI due to MBL-producing Enterobacterales.

Evaluation of the Synergy of Ceftazidime-Avibactam

For Meropenem, Amikacin, Aztreonam, Colistin, or Fosfomycin

  1. Compared to CZA alone, we observed a 4-fold decrease in CZA MICs for a majority of K. pneumoniae strains and at least a 2-fold decrease for most P. aeruginosa isolates in the majority of combinations tested.
  2. In both P. aeruginosa and K. pneumoniae strains, CZA in combination with AMK or AZT was synergistic (≥2.15-log10 CFU/ml decrease). CZA-MEM was effective against P. aeruginosa and CZA-FOS was effective against K. pneumoniae.
  3. Synergy of CZA with MEM or AZT may be due to the restoration of MEM or AZT activity against these organisms.
  4. CZA in combination with these antibiotics has potential for therapeutic options in difficult to treat pathogens.

Conclusion

The burden of antimicrobial resistance among Gram-negative pathogens, particularly carbapenem-resistant Enterobacteriaceae, is increasing rapidly worldwide. Treatment options for serious CRE infections remain extremely limited at this time. Optimization of dosing of currently available agents and combination therapy may be the most appropriate treatment strategies at this time. However, continued research is desperately needed, in particular randomized controlled trials, to determine the most appropriate treatment for serious CRE infections.

Dr. Harish Mallapura Maheshwarappa
Director – Institute of Critical Care Medicine