Case Example
A 45-year-old man with childhood agammaglobulinemia was admitted with fevers, fatigue, and transient rash. Laboratory data on admission revealed leukopenia, normal renal function, and an elevated lactate dehydrogenase (LDH) and he was diagnosed with hemophagocytic lymphohistiocytosis (HLH) early in his hospital course. HLH is a disease of excess immune activation which can lead to severe inflammation resulting in multiorgan failure and be life-threatening [
16]. He clinically decompensated and was admitted to the intensive care unit with respiratory failure requiring intubation, septic shock requiring vasopressors, and acute renal failure requiring hemodialysis. During his hospital course, he initially received piperacillin–tazobactam from hospital days 1 to 9 which was then changed to meropenem from hospital days 10 to 18. Cultures performed on tracheal secretions on hospital days 5 and 10 grew a carbapenem-resistant
K. pneumoniae (piperacillin–tazobactam minimum inhibitory concentration [MIC] > 64/4 µg/ml, meropenem MIC 4 µg/ml, ceftazidime–avibactam MIC 0.75 µg/ml by E-test, M-V disc diffusion zone diameter of 22 mm) which was believed to be a colonizer. He subsequently developed bacteremia with positive blood cultures on hospital day 17 with this same organism. His hospital course was complicated by disseminated intravascular coagulation, severe hepatitis, encephalopathy, acute punctate infarct in the left cerebellum, aspergillosis of the scrotum, and necrotizing pancreatitis associated with fluid collections of which cultures also grew the same carbapenem-resistant
K. pneumoniae, now resistant to M-V. He was treated with multiple antibiotics and eventually changed to ceftazidime–avibactam for completion of therapy. He received dexamethasone, etoposide, and intrathecally administered methotrexate for HLH with repeat BM biopsy showing no disease. He was discharged after a 5-month hospital stay to a rehabilitation center.
This case demonstrates the complexity of patients who develop CRE infections. Some have an underlying immunocompromising condition such as cancer, organ transplant, or receipt of immunosuppressants and then clinically deteriorate with sepsis due to an infection by a CRE resulting in organ dysfunction or organ failure.
Subgroup analyses of patients without prior antibiotic therapy, immunocompromised state, and renal insufficiency in the TANGO II study suggest that at both the end of therapy (EOT) and test of cure (TOC = EOT + 7 days) time points, M-V had higher clinical cure rates in addition to decreased 28-day all-cause mortality when compared to BAT.
This is the only report to our knowledge to evaluate subgroups of patients with carbapenem-resistant organisms.
Prior Antibiotic Therapy
Most patients who develop infections with CRE have been exposed to multiple previous antibiotics as in the previously described case. Some have failed therapy, by either developing resistance to the treatment administered or lack of clinical response despite antibiotic administration, may have an empiric change of antibiotic agents. The patient case described earlier had improved with empiric treatment with a less broad-spectrum antibiotic agent; however, he subsequently developed septic shock for which a change in antibiotics was warranted.
BAT was chosen at the discretion of the study investigator and consisted of antibiotic therapy either alone or in combination of carbapenems, aminoglycosides, colistin, polymixin B, tigecycline or monotherapy with ceftazidime–avibactam (C-A). Prior antibiotic failure was determined by the study investigator at the time of enrollment. Of the 38 patients who were analyzed, 23 received M-V and 15 received BAT.
Of the patients who were not categorized as prior antibiotic failure in the TANGO II trial, those who received primary therapy with M-V had better outcomes compared with those who received BAT within the microbiologic-CRE modified intent-to-treat (mCRE-MITT) group [
17]. The mCRE-MITT was defined as patients who received at least one dose of study drug and had culture confirmation of a baseline isolate that was CRE (Table
2) [
17].
Table 2
Efficacy results in patients without prior antimicrobial failure in the mCRE-MITT population [
17]
Clinical cure at TOC | 16 (69.6) | 4 (26.7) | + 42.9 (+ 13.7 to + 72.1) |
Clinical cure at EOT | 19 (82.6) | 5 (33.3) | + 49.3 (+ 20.8 to + 77.7) |
Microbiologic curea at EOT | 19 (82.6) | 6 (40.0) | + 42.6 (+ 13.4 to + 71.8) |
Microbiologic curea at TOC | 16 (69.6) | 5 (33.3) | + 36.2 (+ 5.9 to + 66.6) |
Day-28 mortality | 1 (4.3) | 5 (33.3) | − 29.0 (− 54.3 to − 3.7) |
The baseline pathogen was K. pneumoniae in approximately 90% of these patients, the same pathogen isolated in our patient case. Clinical cure at TOC was higher (69.6% vs. 26.7%, absolute difference + 42.9) in the M-V group compared to BAT. This difference continued through the evaluation of clinical cure at EOT (82.6% vs. 33.3%). Similarly, M-V showed better efficacy than BAT when evaluated for microbiologic cure at EOT (82.6% vs. 40%), microbiologic cure at TOC (69.9% vs. 33.3%), and 28-day mortality (4.3% vs. 33.3%). This analysis supports the clinical application of M-V over BAT in patients who have not failed prior antibiotic therapy.
Immunocompromised
Among patients with solid tumors or hematologic malignancy and CRE infections, mortality rates are extremely high—up to 60% [
18,
19]. The patient described in our case did not have a malignancy; however, it is evident that his immune system was compromised as demonstrated by the development of disseminated aspergillus infection, which is rarely seen in the immunocompetent host [
20]. Unlike most phase 3 studies of new antimicrobials, TANGO II included immunocompromised patients.
Immunocompromised status was defined as underlying active leukemia, lymphoma, prior transplant or splenectomy on medical history, any active receipt of immunosuppressive drugs including selective immunosuppressants, calcineurin inhibitors, or high-dose systemic steroids (equivalent to more than 20 mg/day of prednisone for more than 2 weeks) or neutropenia (absolute neutrophil count [ANC] less than 1000 cells/mm3) at any point during the study period.
Of the 50 subjects who had a baseline pathogen (m-MITT population), 19 (38.0%) were immunocompromised: four leukemia/lymphoma, five medication, and 10 transplant cases. Forty-three of these 50 patients had an identified baseline pathogen which was CRE (mCRE-MITT); 18 (41.9%) were categorized as immunocompromised. The most common infection types among immunocompromised subjects (mCRE-MITT) were bacteremia (11/18, 61.1%), cUTI/AP (3/18, 16.7%), HABP/VABP (2/18, 11.1%), and cIAI (2/18, 11.1%).
Clinical cure rates for mCRE-MITT immunocompromised subjects were higher for those in the M-V arm compared to the BAT arm with an absolute increase of 47.5% at EOT and 70% at TOC. On ad hoc analysis, the increase in cure rate at TOC achieved statistical significance (95% CI 41.6–98.4,
p < 0.0001). Rates of microbial cure (defined as either microbial eradication or presumed eradication) for the 18 immunocompromised subjects were higher for those in the M-V arm vs. BAT arm (absolute increase of 47.5% at EOT and 70% at TOC). The all-cause mortality at day 28 was lower for those patients who received M-V compared to those who received BAT (20% vs. 37.5%). This was associated with an absolute risk reduction (mortality) of 17.5% and relative risk reduction of 46.7%. Table
3 shows the efficacy endpoints of the mCRE-MITT patient population, including those with immunocompromised and renal insufficiency [
14].
Table 3
Efficacy endpoints among all patients with confirmed CRE infections (mCRE-MITT) in TANGO II study [
14]
Efficacy endpoints |
Clinical cure at EOT | 21 (65.6) | 5 (33.3) | 32.3 (3.3 to 61.3) | 0.03 | 97.0 |
Clinical cure at TOC | 19 (59.4) | 4 (26.7) | 32.7 (4.6 to 60.8) | 0.02 | 122.5 |
Microbiologic curec at EOT | 21 (65.6) | 6 (40.0) | 25.6 (− 4.1 to 55.4) | 0.09 | 64.0 |
Microbiologic curec at TOC | 17 (53.1) | 5 (33.3) | 19.8 (− 9.7 to 49.3) | 0.19 | 59.5 |
Day-28 mortality | 5 (15.6) | 5 (33.3) | − 17.7 (− 44.7 to 9.3) | 0.20 | − 53.2 |
Exploratory analysis of risk–benefit profile of M-V compared to BAT |
Day-28 all-cause mortality or nephrotoxicitye | 8 (25.0) | 6 (40.0) | − 15.0 (− 44.0 to 14.0) | 0.31 | − 37.5 |
Clinical failure or nephrotoxicityf | 10 (31.3) | 12 (80.0) | − 48.7 (− 74.6 to − 22.9) | < 0.001 | − 60.9 |
Day-28 all-cause mortality or renal AEsg | 6 (18.8) | 9 (60.0) | − 41.2 (− 69.5 to − 13.0) | 0.004 | − 68.7 |
Clinical failure or renal AEsh | 9 (28.1) | 12 (80.0) | − 51.9 (− 77.4 to − 26.3) | < 0.001 | − 64.9 |
Sensitivity analysis of clinical cure at TOC and all-cause mortality at day 28 across all infection types (mCRE-MITT) excluding prior antibiotic failured |
Clinical cure at TOC | 16 (69.6) | 4 (26.7) | 42.9 (13.7 to 72.1) | 0.004 | 160.7 |
Day-28 all-cause mortality | 1 (4.3) | 5 (33.3) | − 29.0 (− 54.3 to − 3.7) | 0.02 | − 87.1 |
In addition, there were no marked treatment adverse events (AE) noted. Among immunocompromised subjects, M-V was associated with fewer adverse events compared to BAT (84.6% vs. 100%), drug-related AEs (30.8% vs. 40.0%), serious AEs (38.5% vs. 50.0%), discontinuations of study drug or study due to AEs (15.4% vs. 30.0%), and renal-related AEs (7.7% vs. 40.0%).
Renal Insufficiency
Most patients with sepsis have some degree of acute kidney injury sometimes requiring hemodialysis as exemplified in the case previously described. Patients with decreased kidney function have an increased risk for hospital-related infection in a linear distribution [
21]. In addition, renal insufficiency impacts accurate dosing of medications and limits use of agents such as colistimethate and polymixin B which have adverse side effects of renal failure [
22,
23]. Among the 43 subjects who had a baseline CRE organism and were included in the mCRE-MITT population, nine (20.9%) subjects had a baseline creatinine clearance (CrCl) less than 50 ml/min. Dose reduction of M-V was given on the basis of CrCl. If the CrCl was less than 50 ml/min, a standard dose of 2 g–2 g was administered every 8 h. If the CrCl was between 30 and 49 ml/min, the dose was reduced by half to 1 g–1 g every 8 h. The dose was reduced to one-third of the standard dose with CrCl between 20 and 29 ml/min, to one-sixth of the dose for CrCL between 10 and 19, and finally to one-twelfth of the dose to 500 mg–500 mg every 24 h. Although hemodialysis patients could be enrolled in the study, those patients who required continuous renal replacement therapy (CRRT) were not eligible for study participation. Since CRRT is more physiologic compared to hemodialysis, we do not see this as a negative to the study exclusion.
Subjects with renal impairment with a CrCl less than 50 ml/min had lower clinical cure rates across all infection types at EOT compared with subjects with normal renal function, though there were only nine patients with impaired renal function in the mCRE-MITT cohort. Two of the five patients in the M-V group and one of the four in the BAT group achieved both clinical cure at the end of therapy and microbiologic eradication.
Patients with renal insufficiency had lower clinical cure rates across all infection times at the end of IV therapy compared to those with normal renal function regardless of treatment type (M-V 40% vs. 68.2%; BAT 25% vs. 44.4%). In terms of AEs, M-V had similar rates of treatment emergent adverse events (TEAE) compared to BAT in the 19 patients who had renal insufficiency (8/10 vs. 8/9).
There is no increased safety signal associated with M-V in patients with renal impairment.
M-V is a safe and effective treatment for serious gram-negative infections in renally impaired patients when the dose is adjusted on the basis of creatinine clearance.