Prevention and management of carbapenem-resistant Enterobacteriaceae in haematopoietic cell transplantation

Gastrointestinal screening for CRE colonisation before HCT

Prior colonisation by CRE is an important predictor for subsequent infections. Colonisation by MDR organisms adversely impacts survival in early postallogeneic HCT period.^25,54,55 An Italian multicentre study showed CRE bacteraemia rates of 26% and 39% in CRE colonised autologous and allogenic HCT. ³ Preemptive detection of CRE colonisation is helpful in identifying patients who need early initiation of anti-CRE treatment during their febrile neutropenia episodes and may possibly benefit from gut microbiome restorative strategies before their HCT.^54,56,57

As Enterobacteriaceae are one of the major gut commensals, CRE colonisation can be detected by screening for their faecal carriage. Various studies have found rectal swabs to be more sensitive for detection of CRE colonisation when compared with faecal culture.^58–60 The time points of surveillance for colonisation are also important. A regular and continuous screening strategy via faecal culture has been found to be more effective for detection for CRE carriage compared with one-time screening strategy. ²⁴ Forcina et al. ²³ reported substantial reduction in mortality due to carbapenem-resistant Klebsiella pneumoniae (CRKp) BSI at 1 year post-HCT when weekly surveillance cultures strategy was employed, with contact precautions, in carriers and early targeted therapy was initiated in febrile neutropenic carriers. The 2015 Italian multidisciplinary consensus statement on CRKp infection management in HCT recipients recommended monitoring for CRE colonisation before hospital admission for HCT, weekly post-HCT monitoring in the event of CRKp isolation from other patients in the same BMT unit and in patients who present with post-HCT intestinal complications, in particular GVHD. ⁵² The recent guidance from ASTCT recommends such screening to be restricted to patients referred from CRE endemic areas. ¹⁷ Beyond identification of CRE carriers who benefit from upfront CRE-effective therapy during their febrile neutropenia, screening can also be helpful in selecting prospective HCT patients for CRE decolonisation strategies like FMT. Hence, in HCT recipients, adopting a preemptive screening strategy leads to increased identification of CRE colonisers and a reduced progression to BSIs by timely initiation of CRE-effective antimicrobial therapy. ⁶¹

Infection control strategies and management of CRE colonisers in the BMT unit

Recommendations for CRE prevention in health care settings stress on hand hygiene compliance, healthcare personnel education, antimicrobial stewardship and screening for CRE colonisers before their HCT in centres where CRE is highly prevalent. Infected or colonised patients with CRE need isolation (single rooms where feasible), and strict contact precautions with gown and gloves are recommended.^17,52,62 Initiation of effective antimicrobial therapy based on the susceptibility pattern of the colonising isolate at the onset of febrile neutropenia in CRE colonisers is strongly recommended. Surveillance data on CRE prevalence in hospitals should be regularly updated, and coordinated control effect involving various departments to prevent intrahospital transmission of CRE is recommended. ⁵²

Antimicrobial stewardship programme in BMT unit

Prior antimicrobial use such as carbapenem and aminoglycoside is an important risk factor for CRKp infection. ⁶³ Antimicrobial stewardship policies (ASP) play an important role in curtailing unnecessary antimicrobial usage, thus potentially reducing the prevalence of CRE.^64–67

Although broad-spectrum antimicrobial therapy is often necessary in HCT recipients, transplant physicians should strive to implement the following recommended practices: early de-escalation of antimicrobial therapy and daily assessment for the need for continued antimicrobial therapy. ⁶⁸ Multidisciplinary team involving transplant physicians, infectious disease specialists, microbiologists and pharmacists should regularly review the BMT unit’s epidemiology and antibiogram and implement unit-specific antimicrobial therapy algorithms. ⁶⁹ The IDSA recommends implementation of local and institution-specific clinical guidelines to improve judicious antimicrobial use. ⁶⁴ A single-centre study on patients with haematological malignancies and HCT recipients demonstrated significant reduction in carbapenem use after implementation of revised antimicrobial policy recommending piperacillin-tazobactam with or without amikacin as the first-line treatment for febrile neutropenia. ⁷⁰

Major impediments to ASP implementation include lack of key personnel, limited antimicrobial options in settings with a high prevalence of MDR organisms and poor interpersonal and interdepartmental communication. These inevitably result in increased TRM rates, prolonged hospitalisation and high intensive care requirements.^71,72 Formulation of institution-specific protocols for antimicrobial use, regular training and motivation of all healthcare staff for compliance with ASP, multidisciplinary team collaboration and improving interpersonal communication can overcome these obstacles.

Escalation versus de-escalation approaches in management of neutropenic sepsis in the BMT unit

There is no clear consensus on escalation versus de-escalation strategy and treatment duration of antimicrobial therapy for neutropenic sepsis.

In escalation strategy initial empirical antimicrobial treatment provides cover for Enterobacteriaceae and Pseudomonas aeruginosa but not MDR bacteria like CRE. Coverage for the latter is provided by ‘escalating’ the initial antimicrobials to a broader spectrum combination regimen that is effective against these as well. A de-escalation strategy, on the contrary, provides upfront initial coverage for highly resistant pathogens. Therapy is ‘de-escalated’ later with subsequent focus on microbiology isolates. ⁷³ We believe that de-escalation strategy is better suited for practice settings where CRE is highly prevalent. We further posit that screening for CRE colonisation in patients before their HCT permits identification of the subset who will benefit from de-escalation strategy of antimicrobial therapy in their febrile neutropenic episode. Timely initiation of CRE-active therapy in profoundly neutropenic HCT patients is the most effective strategy in preventing CRE bacteraemia-related deaths. ²⁹

An Italian multicentre survey on HCT patients reported 26% and 39% CRKp infections in autologous and allogeneic HCT recipients, respectively, colonised by CRKp. ³ Initial empirical therapy targeted against CRKp was associated with 2.67-fold increase in survival [hazard ratio (HR) range: 1.43–4.99; p = 0.002].

Treatment duration: The 2011 IDSA guidelines on febrile neutropenia recommend continuing the antimicrobial therapy until neutrophil recovery (absolute neutrophil count >500 cells/mm³) or longer, if clinically necessary. ² However, the European Conference on Infections in Leukaemia (ECIL-4) guidelines recommend stopping antimicrobials after defervescence in patients with no identifiable cause of infection who are afebrile for more than 48 h irrespective of the neutrophil count or the expected duration of neutropenia. ⁷³ The 2021 National Comprehensive Cancer Network (NCCN) guidelines discuss both the options and suggest de-escalation to fluoroquinolone prophylaxis in patients who become afebrile. ⁷⁴

Several large retrospective studies on HCT recipients with febrile neutropenia without any identifiable infectious focus show that early cessation of antimicrobials has no adverse impact on mortality, rehospitalisation, clinical deterioration and recurrence of fever at ⩾72 h.^75–83 A multicentre, randomised controlled trial (HOW LONG study) evaluated cessation of antimicrobials before neutrophil recovery in febrile neutropenic patients without an aetiological diagnosis who are clinically recovered and apyrexic for >72 h and compared this approach with continual antimicrobials until neutrophil recovery to >500 cells/mm³. ⁸⁴ Almost a fourth of participants in this study were HCT recipients. Early cessation of empirical antimicrobial therapy was found to be associated with a significant increase in antibiotic-free days without an adverse impact on mortality and recurrence of fever.

Antimicrobial therapy for CRE

The effective antimicrobial armamentarium against CRE is still a work in progress. Monotherapy options against CRE are limited and not yet widely available. Hence, combination antimicrobial regimens incorporating high-dose extended-infusion meropenem, tigecycline, polymyxins and aminoglycosides remain in widespread use. Their use is complicated by multiple drug interactions, add-on organ toxicities and possibility of reduced effectiveness due to accrual of resistance.^85,86 There are promising data on newer CRE-effective β -lactam/ β -lactamase inhibitors (BL-BLIs): ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam.^87–91 However, these agents are not uniformly active against all carbapenemases. For instance, ceftazidime-avibactam does not have activity against metallo- β -lactamase (MBL)-producing Enterobacteriaceae. Hence, for treatment of MBLs, either cefiederocol monotherapy or a combination of ceftazidime-avibactam with aztreonam is recommended, as the latter is not hydrolysed by MBLs and MBL-producing Enterobacteriaceae frequently coproduce other enzymes; KPC and OXA-48 against which aztreonam has no activity.^53,92,93 Table 4 summarises the available antimicrobials and their activity against various CRE. Management algorithm of CRE in HCT patients is illustrated in Figure 2.

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Table 4.

Available antimicrobial agents with activity against CRE.^29,47,94,95

Older antimicrobials
Drugs	Dose	Comments
Polymyxins• Colistin• Polymyxin B	9 million units loading followed by 4.5 million units i.v every 12 h2.5 mg/kg loading dose, then 1.5 mg/kg i.v every 12 h	• Disadvantages: nephrotoxicity and neurotoxicity
Rifampin	600–900 mg i.v every 24 h	• Rifampicin addition may be considered to exploit synergism in colistin resistance• Disadvantage: drug interactions with conditioning regimes
Tigecycline	100 mg i.v loading f/b every 12 hDoses up to 100 mg every 12 h can be used	• Must be used in combination regimen with colistin and fosfomycin or aminoglycosides or rifampicin or carbapenams• Low bloodstream and urinary tract concentration.• Bacteriostatic drug.• Disadvantages: not good for BSI due to high lipophilic nature and gastrointestinal side effects
Aminoglycosides• Gentamycin• Amikacin	3–5 mg/kg/day i.v every 24 h15 mg/kg every 12 h	• Variable CRE activity• Used in combination regimen• Nephrotoxicity and otovestibular toxicity
Fosfomycin	4 g i.v every 4 h	• Used as adjunctive therapy for CRE• Active against all classes of CRE• Low barrier to development of resistance
Carbapenems• Meropenem (high-dose prolonged infusion)Double carbapenems• Ertapenem + doripenem/meropenem	2 g i.v every 8 h1 g i.v every 24 h (Ertapenem)500 mg i.v every 8 h (Doripenem)2 g i.v every 8 h (Meropenem)	• Can be used in CRKp infections with meropenem MIC ⩽8–16 mg/l• Must be used in combination regimen• Can be used in CRKp infections with meropenem MIC >8–16 mg/l
New antimicrobials
Drugs	Dose	Activity
		Class A (e.g. KPC)	Class B (e.g. NDM)	Class D (e.g. OXA-48)
Ceftazidime-avibactam	2.5 g i.v q8h	Yes	No	Yes
Aztreonam	2 g i.v q8h	No	Yes	No
Meropenem-vaborbactam	2 g i.v q8h	Yes	No	No
Imipenem-cilastatin-relebactam	1.25 g i.v q6h	Yes	No	No
Cefiderocol	2 g i.v q8h	Yes	Yes	Yes
Plazomicin	10–15 mg/kg i.v q24h	Yes	Variable a	Yes
Eravacycline	1 mg/kg i.v q12h or 1.5 mg/kg i.v q24h	Yes	Yes	Yes

BSI, bloodstream infections; CRE, carbapenem-resistant Enterobacteriaceae; CRKp, carbapenem-resistant Klebsiella pneumoniae; i.v, intravenous; KPC, Klebsiella pneumoniae carbapenemase; MIC, minimum inhibitory concentration; NDM, New Delhi metallo- β -lactamase; OXA, oxacillinase.

a

Frequently inactive against strains that produce NDM-type metallo- β -lactamases.

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Figure 2.

Management algorithm for CRE in HCT patients. ⁵³

Combination versus monotherapy regimens in CRE sepsis

The important clinical question of whether combination antimicrobial therapy is more or less efficacious against CRE compared with novel single CRE-active agents remains to be addressed in a prospective head-to-head comparative trial. While combination antimicrobial therapy has shown increased bactericidal activity in vitro compared with monotherapy, clinical studies assessing comparative efficacy of various CRE-effective therapies show conflicting results as majority of them were conducted before the novel BL-BLIs era. ⁹⁶ Conclusions from the various studies are summarised below.

Based on existing evidence, combination therapy can no longer be recommended for treatment of CRE infections in HCT patients. Effective treatment against CRE is based on the mechanism of carbapenem resistance (Table 4). New CRE-effective antimicrobials like meropenem-vaborbactam and ceftazidime-avibactam assume a frontline role in modern recommendations. ⁵³ Hence, it is prudent to prioritise the use of these novel CRE-effective agents when adopting a de-escalation strategy in HCT patients colonised with CRE and/or those getting treated in a centre with high CRE prevalence.

Important considerations for CRE antimicrobial therapy are as follows:^53,94,106

Faecal microbiota transplant

Gut microbiota are a complex microbial ecosystem of bacteria, fungi, archaea, viruses and protozoa existing in a symbiotic or pathogenic relationship within the human gastrointestinal tract.^107,108 Recent studies have provided compelling evidence on adverse impact of reduced gut microbial diversity or dysbiosis on HCT outcomes viz. bacterial BSIs and acute GVHD.^109–111 Contributing factors to gut microbiota dysbiosis in HCT recipients include use of intensive conditioning radiation and chemotherapy, and frequent exposure to broad-spectrum antimicrobials. ¹¹² Gut colonisation by MDR bacteria is a significant risk factor for MDR BSIs in HCT recipients.^16,18 Various studies have explored the safety and efficacy of healthy donor FMT as a gut microbiota restorative strategy.^56,113,114 Bilinski et al. ¹¹³ assessed the effectiveness of FMT in eradication of MDR bacteria gut colonisation in 20 patients with blood cancers. Of these, 75% overall achieved complete MDR bacteria decolonisation after their FMT procedure. Battipaglia et al. ⁵⁶ reported a retrospective case series of 10 participants with haematological malignancies who underwent FMT for MDR decolonisation pre- and post-HCT. At a median of 13 months post-FMT, 6 out of 10 participants (60%) achieved sustained decolonisation of MDR bacteria. Concerns have been raised about the risk of transmission of infections through FMT when the procedure is performed close to HCT. It is logistically challenging to sequence FMT and HCT together keeping the safety concerns in mind. ¹¹⁵ It is unsafe to perform FMT in neutropenic patients or patients that are at risk of neutropenia within 2 weeks. It is possibly safer to sequence FMT at least 4 weeks before HCT procedure. However, this raises logistical challenges for HCT procedure as not all HCT indications permit delays. Other challenges that need to be addressed are HCT donor availability vis-à-vis FMT and exposure to new or ongoing antimicrobials. ¹¹⁴

Phage therapy

Recent biotechnological advances have enabled the use of bioengineered bacteriophages against MDR bacteria. In contrast to antibiotics, phages tend to be species and strain specific. Given their narrow spectrum of activity, microbiota dysbiosis and emergence of resistant organisms are not of primary concern. ¹¹⁶

Theoretically, this advantage makes phage therapy a potentially attractive alternative to healthy donor FMT for eradication of MDR bacteria from the gut in HCT patients. Lengthy development process and necessity for tailored phage cocktails in most patients restricts their use to treatment of chronic infections and precludes their use against CRE infections in neutropenic patients. ¹¹⁷ Another limitation is lack of understanding of phages’ interaction with resident gut flora, and human host. At present, phage therapy is not an approved therapy and data on its effectiveness against MDR bacterial infections in humans remain restricted to case reports.^118–124