Managing difficult-to-treat infections in immunocompromised patients

Infections by multidrug-resistant organisms (MDROs), especially Gram-negative rods, are associated with higher mortality, higher morbidity, longer hospital stay and increased public healthcare costs.1 For patients infected with carbapenemase-producing Enterobacteriaceae (CPE), few effective antibiotics are available. In practice, these patients are usually treated with old classes of drugs including colistin, fosfomycin and aminoglycosides. However, these antibiotics are highly toxic with a poor quality of evidence supporting their clinical efficacy.2

To address these unmet medical needs, “new old drugs” can be considered. Ceftolozane-tazobactam has a lower minimal inhibitory concentration (MIC) against many groups of Gram-negative rods and is stable in the presence of ESBL and AmpC β-lactamases as well as being less susceptible to porin or efflux mutations.3 With the ASPECT-cUTI and ASPECT-cIAI studies demonstrating non-inferiority to best available treatment, ceftolozane-tazobactam can be a potent alternative to meropenem and carbapenem in managing drug-resistant infections.4,5 That said, Dr. Sridhar, Siddharth noted that ceftolozane-tazobactam has reduced activity against Gram-positive and anaerobic organisms, often requiring additional metronidazole for better infection management. Notably, ceftolozane-tazobactam is also not active against the carbapenemase genes KPC, NDM and OXA-48 which are sporadically encountered in Hong Kong.6 As such, Dr. Sridhar suggested ceftazidime-avibactam to be considered for patients infected with KPC or certain OXA-48 CPEs as retrospective experience in the hematological setting showed that ceftazidime-avibactam is no worse than best available comparator.7

While not yet approved in Hong Kong, cefiderocol is a novel β-lactamase inhibitor that is stable against class A, B and D carbapenemases as well as ESBL and AmpC β-lactamases. As a siderophore that chelates ferric iron, cefiderocol can effectively enter the bacteria through the iron transport chain unaffected by the carbapenemase excretion in the extracellular space.8 Notably, cefiderocol inhibited 98.2% and 98.8% of ceftazidime-avibactam and ceftolozane tazobactam- non-susceptible Enterobacteriaceae isolates, respectively, with similar efficacy against Pseudomonas aeruginosa.9 Although being associated with a higher all-cause mortality in one real-world clinical trial that may be attributed to imbalanced patient selection, cefiderocol monotherapy is effective against carbapenem-resistant Gram-negative rods and should be considered as an alternative to the highly toxic colistin-based therapy.10

The treatment for cytomegalovirus (CMV) infection is often limited by toxicities with intravenous foscarnet, the only available option for ganciclovir-resistant CMV, which is associated with severe nephrotoxicity, electrolyte abnormalities, teratogenicity, and marrow suppression. When managing CMV, letermovir is an alternative with a unique mechanism of action that enables fewer off-target effects with no cross-resistance to ganciclovir or foscarnet. In the real-world, letermovir prophylaxis had significantly reduced the risk of CMV infection to 7.7% when compared to 39.4% with placebo and was not associated with nephrotoxicity or myelotoxicity.11 That said, case reports have also reported treatment failures during CMV reactivation with letermovir monotherapy alone.12 Therefore, Dr. Sridhar recommended additional ganciclovir or forscanet when CMV reactivates. Notably, letermovir has no activity against HSV or VZV and acyclovir is separately required as prophylaxis against these pathogens.

Recently, a large-scale retrospective study found that patients affected by both COVID-19 and hematological malignancies have worse outcomes than both the general population with COVID-19 and patients with haematological malignancies without COVID-19 (standardized mortality ratio=2.04 and 41.3, respectively).12 Importantly, Dr. Sridhar noted that there are currently no effective antivirals for COVID-19 and immunocompromised patients may select out highly infectious SARS-CoV-2 variants, given the increased time in the body to mutate. Although the efficacy of COVID-19 vaccines is yet to be established in hematological patients, Dr. Sridhar believed the safety of the vaccine to mirror that of the general population.

While guidelines are broadly supportive of vaccinating immunocompromised patients due to their higher risk of severe COVID-19, Dr. Sridhar noted that the timing of vaccination with relation to immunosuppression would be crucial. In Hong Kong, immunocompromised patients still have the luxury to defer vaccination until their B- and T-cell responses to vaccines recover as the rate of COVID-19 in the Hong Kong community remains low. “Generally speaking, the vaccines are good at keeping COVID-19 down and our patients have the luxury to delay vaccination until they can mount a response. Overall, I would encourage patients to receive vaccination at the right time,” concluded Dr. Sridhar.

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