The occurrence of carbapenem-resistant organisms is increasing globally. Each healthcare facility should develop a documented infection control policy and ensure its effective implementation, thus protecting patient outcomes from these serious infections in an age of advanced medical technology.

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CROs (Carbapenem-resistant organisms)

Studies show that CROs (Carbapenem-resistant organisms) are associated with four times higher mortality than Carbapenem susceptible ones. In today’s era of advanced laboratory technologies, it’s vital to identify resistance mechanisms in CRE infections for accurate antimicrobial treatments.

What is India’s suffering is that the majority of infections are by gram-negative organisms. To treat carbapenem-resistant organisms, clinicians often must resort to a highly toxic last-line group of antibiotics such as tigecycline, fosfomycin, and colistin.

The prevalence of resistance to these antibiotics is also on the rise. This further results in the spread of carbapenem-resistant organisms as these infections become difficult to manage. Variations in susceptibility to different agents depending upon location underscore the importance of using local antibiogram data for clinical decisions.

KPC enzymes are predominantly seen in Western countries. The prevalence of Class B NDM Carbapenemase in India is alarming. Class D- OXA co-production is observed in approximately 35-40% of cases of NDM-producing organisms. Given their correlation with elevated mortality rates, these strains are anticipated to pose a significant threat in the foreseeable future.

So let us dive into this highly important topic.

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Case study

A 76-year-old man was admitted to the hospital with exacerbated COPD. He was placed on Mech Ventilator. He developed a fever and raised WBC count. The patient was empirically started on Meropenem plus Vancomycin. However, the patient continues to have fever spikes. Respiratory secretions grew Klebsiella pneumoniae which was resistant to all antimicrobials tested except intermediate to Colistin (MIC of <=0.5) and Tigecycline (MIC of Resistant drugs included all Beta lactams, PIT, Cefoperazone-sulbactam, Ceftazidime-avibactum, Minocycline and Aztreonam. On PCR analysis isolate was found to be NDM positive.

Challenge question

What course of antibiotic would you opt for in treating this infection due to carbapenem-resistant Klebsiella pneumonia?

1. Colistin based regimen
2. Tigecycline-based regimen
3. Ceftazidime- avibactam with Aztreonam
4. High-dose Meropenem infusion

Answer: Deciding On The Best Armentorium, its Tigecycline-based regimen

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Understanding the different regimens

1. Tigecycline-based regimen

Tigecycline should not be preferred for bloodstream or respiratory tract infections however may be considered in combination therapy, particularly when no alternative medications are available, there’s no bacteremia, and Pseudomonas is not a concern.

Tigecycline monotherapy is effective against intra-abdominal and skin-soft tissue infections since higher drug concentration can be achieved.

2. Polymyxin-based regimen

Colistin or Polymixin should only be used when no other option is available. Colistin in nebulised form can be considered along with IV Colistin for severe pneumonia. Colistin can be combined with other susceptible agents such as carbapenem, aminoglycosides, fosfomycin or tigecycline. Combining colistin and tigecycline appears to be protective against the development of colistin resistance during the therapy when compared to colistin combination with other agents or colistin monotherapy. Renal dose adjustment should be performed for colistin therapy.

3. Newer Beta Lactamase Combination: Ceftazidime- avibactam with Aztreonam

1. Beta-lactam plus beta-lactamase combinations such as Ceftazidime- avibactam, Imipenem- relebactam and Ceftolozane- tazobactam are effective against carbapenemase-producing organisms but not useful against those producing Metallobetalactamase.
2. A combination accessible in India is Ceftazidime- avibactam but has a limited utility against NDM which is the most common and challenging mechanism of carbapenem resistance. Aztreonam is the only beta-lactamase inhibitor effective against NDM-producing organisms.
3. The addition of aztreonam to the ceftazidime- avibactam combination has shown a synergistic effect even when both agents are resistant and are often employed to treat infections caused by NDM-producing organisms. (Here ceftazidime- avibactam takes care of OXA, KPC, ESBL and AmpC enzymes while aztreonam is stable against MBL). However, the laboratory should confirm this synergistic effect in vitro by demonstrating an increase in the zone of inhibition.
4. This approach carries high efficacy for treating MBL-producing enterobacteria and minimising resistance development. This strategy is also effective against OXA co-producers. A combination of ceftazidimeavibactam with aztreonam must be given simultaneously where aztreonam infusion is to be started a few hrs after initiating CAZ-AV infusion and to be continued for three hours.
5. However variable responses may occur in infections caused by Carbapenem-resistant Pseudomonas species or Acinetobacter species since they are usually associated with the simultaneous presence of multiple resistance mechanisms along with MBL production such as overexpression of efflux pumps, porin gene-related mutation, low outer membrane permeability etc.
6. The combination of two active agents should be considered for treating carbapenem-resistant Pseudomonas or Acinetobacter species wherever possible. Monotherapy may be used for uncomplicated mild infections with CRAB. Administering cefoperazone-sulbactam or high dose Sulbactam monotherapy are effective options against CRAB infections.
7. However, these two organisms are often OXA23 coproducers in contrast to OXA48 production in the enterobacterale group. This complicates management because sulbactam, which is known to be effective against Acinetobacter species, is ineffective in the presence of the OXA23 enzyme.
8. Previous research indicated that CR-PA infections that are susceptible to cefepime or ceftazidime with slightly elevated MIC values require pharmacodynamically optimised doses to achieve sufficient concentration at the target site.
9.  Clinicians should always consider the presence of cross-resistance amongst standard β-lactam agents and thus shift to stronger alternatives when treating CR-PA infections (e.g. cefoperazone- sulbactam or ceftazidime- avibactam). Treatment with polymixins should only be started when no other option is available.
10. High-dose Meropenem infusion
11. In cases of systemic infection and lack of access to novel agents, high doses of Carbapenem could be effective, provided resistance to carbapenem is mild.
12. Thus High-dose Meropenem infusion can be given provided the MIC value is in the susceptible dose-dependent (SDD) range. However, CROs are commonly associated with high Meropenem MIC value which limits their use as an alternative regimen.

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Cefepime- zidebactam combination

1. At present there’s no targeted antimicrobial agent available against NDM-producing organisms.
2. Cefepime- zidebactam, is a novel combination with beta-lactam enhancer, presently undergoing phase 3 clinical trials.
3. A zidebactam is a beta lactam enhancer. This combination has shown efficacy against MBL-producing gram-negative organisms including Pseudomonas aeruginosa.
4. Cefidericol monotherapy has demonstrated effectiveness against Carbapenem-resistant gram-negative bacteria including MBL producers.
5. This newer agent has a superior safety profile than colistin. However, Cefidericol is not yet accessible in India.

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Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Sumit Chavan MD (Microbiology) is a practising microbiologist from Pune.