1605
type: MedicalGuidelineRecommendation
type: EssentialMedicineRecommendation
recognizing authority: World Health Organization
guideline date: 2021-07-02
guideline subject: TherapeuticProcedure
  code: MedicalCode
    code value: J01DI04
    coding system: ATC
  drug: cefiderocol
  indication: Carbapenem resistant Escherichia coli
evidence origin: The Expert Committee noted that antimicrobial resistance is a global public health threat and that effective antibiotics against multidrug-resistant Gram-negative organisms, such as carbapenem-resistant Enterobacterales (a critical priority pathogen on WHO’s priority pathogens list), are urgently needed. The Committee further noted that very few options are currently available to treat Gram-negative organisms that produce metallo-beta-lactamases, which are highly endemic in some WHO regions. Cefiderocol offers activity against some of the critical and high-priority multidrug-resistant, Gram-negative pathogens, including those producing metallo-beta-lactamases, against which other antibiotics listed on the EML have no or only limited activity. The Committee also accepted that cefiderocol has a safety profile consistent with other beta-lactams. The Expert Committee noted that the two double-blinded studies (APEKS-cUTI and APEKS-NP) on which regulatory authority approval of cefiderocol is based applied a non-inferiority design, a common practice in antibiotic trials. Both trials demonstrated that cefiderocol was non-inferior to carbapenems with regard to microbiological and clinical response and mortality, despite large non-inferiority margins being applied. Of note, the presence of an infection caused by multidrug-resistant organisms was not an inclusion criterion in these trials. In addition, the pathogen-focused phase III CREDIBLE-CR trial comparing cefiderocol with best available therapy showed similar clinical cure for treatment of infections caused by carbapenem-resistant Gram-negative bacteria. However, there was a higher mortality at the end of the study in the subset of patients infected with Acinetobacter spp. The Committee therefore recommended the inclusion of cefiderocol in the complementary list of the EML as a Reserve group antibiotic, based on an acceptable benefit-to-risk profile and high public health need. The increased mortality observed in the CRED…
evidence origin: The applicant conducted a comprehensive and systematic literature review for cefiderocol, including in vitro and in vivo studies and any comparative or non-comparative studies and randomized clinical trials. In vitro studies The SIDERO-WT analysis investigated the activity of cefiderocol and relevant comparators against carbapenem-susceptible and carbapenem-resistant pathogens (9–11). To date, 30 459 samples have been tested, with 9205 Gram-negative clinical isolates tested in 2014–2015, 8954 in 2015–2016 and 10 470 in 2016–2017. Cefiderocol was effective at low minimum inhibitory concentrations (MICs) for more than 99% of isolates in each testing period. The latest surveillance SIDERO-WT study (2016–2017) showed that cefiderocol demonstrated activity against 99.4% of Gram-negative pathogens at a MIC of 4 microgram/mL compared with 90.2% for ceftazidime + avibactam, 84.3% for ceftolozane + tazobactam and 95.5% for colistin. In an analysis of difficult-to-treat resistant pathogens, cefiderocol demonstrated activity against 94.5% of difficult-to-treat resistant A. baumannii, 99.8% of P. aeruginosa and 98.3% of Enterobacterales; these pathogens were less susceptible to other available treatments. In addition, 98.7% of carbapenem-non-susceptible Enterobacteriaceae, and 96.4% of carbapenem-non-susceptible non-fermenters were sensitive cefiderocol at a MIC of ≤ 4 microgram/mL (12). The SIDERO-CR study collected carbapenem-resistant isolates and multidrug-resistant non-fermenter isolates from Europe, North America, South America and the Asia Pacific region (9,13). Cefiderocol showed potent in vitro activity against all of these pathogens, as well as activity against isolates with previously characterized resistance factors (13). In vivo studies APEKS-cUTI was a phase II, multicentre (multinational), double-blind, randomized, active-controlled, parallel-group non-inferiority study conducted in 452 hospitalized adults with complicated urinary tract infections, with or withou…
evidence origin: In total, across the APEKS-cUTI, APEKS-NP and CREDIBLE studies, 386 serious adverse events were reported: 226 in patients treated with cefiderocol, 103 in patients treated with meropenem, 17 in patients treated with imipenem + cilastatin and 40 in patients treated with best available therapy. In the total sample, 56/549 (10.2%) patients treated with cefiderocol experienced treatment-related adverse events and 45/347 (13.0%) patients using comparator treatments experienced treatment-related adverse events. Overall, there were fewer treatment-emergent adverse events with cefiderocol (344/549; 62.7%) than with comparator treatments (252/347; 72.6%). The most common adverse reactions for cefiderocol were diarrhoea (8.2%), constipation (4.6%), pyrexia (4.0%) and urinary tract infection (4.7%). In total, 22 serious adverse reactions were reported: eight in patients treated with cefiderocol, six in patients treated with meropenem, one in a patient treated with imipenem + cilastatin and seven in patients treated with best available therapy. The clinical safety for cefiderocol has been investigated in three randomized clinical trials, two specific to different infection sites and one specific to carbapenem-resistant pathogens. In total, 549 patients were treated with cefiderocol in these trails (14–16). In the APEKS-cUTI study, the proportion of patients who experienced at least one adverse event was lower in the cefiderocol group than in the imipenem + cilastatin group (41% versus 51%). The most common adverse events were diarrhoea (4% versus 6%), hypertension (4% versus 5%) and constipation (3% versus 4%), and there was an increased incidence of C. difficile colitis in the imipenem + cilastatin group compared with the cefiderocol group. Serious adverse events occurred in a smaller proportion of patients treated with cefiderocol than patients treated with imipenem + cilastatin (5% versus 8%) (14). In the APEX-NP study, overall, treatment-emergent adverse events and treatmen…
evidence origin: Cefiderocol is appropriate for treating infections caused by aerobic Gram-negative organisms in adults who have limited treatment options. Treatment options may be limited because of multidrug-resistant or carbapenem-resistant pathogens, which are associated with higher mortality rates and increased clinical and economic burden. Without definitive evidence that an infection is resistant to first-line treatment, empiric therapy may be used, and appropriate treatment may be delayed. A recent systematic review examined the effect of delayed antibiotic therapy in patients with severe bacterial infections. It concluded that mortality was significantly lower in patients who did not experience a delay in receiving the appropriate therapy (38). Several systematic reviews have examined the effect of antimicrobial resistance and multidrug-resistant infections on health care costs, and all found an association between increased costs and resistance (39–41). As a result, antibiotics that can effectively treat multidrug-resistant infections can potentially provide health benefits and health care savings. The wholesale acquisition of cefiderocol (10 vials) in the United Kingdom and the USA was reported in the application as £ 1319.00 and US$ 1833.33, respectively. Length of treatment varies from patient to patient, depending on infection site and underlying patient conditions. The dose of cefiderocol varies with renal function, but for a normal renal function, the standard dose is 2 g by infusion every 8 hours. This represents a daily dose of six vials a day, at a cost of £ 791.40 a day in the United Kingdom and US$ 1100 a day in the USA. A cost–effectiveness analysis compared cefiderocol with colistin-based regimens to treat complicated urinary tract infections and hospital-acquired and ventilator-associated pneumonia caused by confirmed carbapenem-resistant pathogens (42). It concluded that cefiderocol was a cost-effective option compared with the colistin-based treatment, with…
section: 6.2.3. Reserve group antibiotics
  type: Section
  parent item: 6.2. Antibacterials
    type: Section
    parent item: 6. Anti-infective medicines
drug unit: Parenteral > General injections > IV: 1 g in vial (as sulfate tosylate) powder for injection
patent information: Main patent is active in several jurisdictions. For more information on specific patents and license status for developing countries visit www.MedsPaL.org
list: ComplementaryList
population: Population
  age: AdolescentAndAdult
  sex: Female
  sex: Male
  condition: Carbapenem resistant Escherichia coli
included in emlc: false
status for indication: AddedToEml
history: DecisionToAdd
  guideline date: 2021-07-02
  list: ComplementaryList
history: DecisionToAdd
  guideline date: 2021-07-02
  list: ComplementaryList
history: DecisionToAdd
  guideline date: 2021-07-02
  list: ComplementaryList
therapeutic equivalence in class: false

cefiderocol
type: Drug
type: Medicine
non proprietary name: cefiderocol
active ingredient: cefiderocol
ingredient: cefiderocol
drug unit: Parenteral > General injections > IV: 1 g in vial (as sulfate tosylate) powder for injection
guideline: 1226
guideline: 1227
guideline: 1605
guideline: 1606
status: AddedToEml
antibiotic stewardship group: KeyAccessGroup
antibiotic stewardship group: ReserveGroup

Carbapenem resistant Escherichia coli
type: MedicalIndication
code: MedicalCode
  code value: MG50.24
  coding system: ICD-11