SCCM Resource Library-Bad Bugs, More Drugs: New Options for Treating Multidrug-Resistant Infections

Video Transcription

In recent years, a number of novel broad-spectrum antibiotics have become available on the U.S.  market to treat highly resistant infections that are commonly encountered in ICU patients.  Among these new agents, new beta-lactam-beta-lactamase inhibitor combinations have gained much attention as promising therapies for carbapenem-resistant gram-negative bacteria.  In addition, new tetracycline derivatives, such as aravacycline, also have shown potent in vitro activity and may expand our armamentarium.  In this session, I will describe the data surrounding these new agents, their potential role in the care of critically ill patients, and possible pitfalls with their use.  I have nothing to disclose. During this presentation, I will review the data for three new antimicrobials and describe  their role in the care of critically ill patients and identify possible limitations with their use.  In the first part of my presentation, I am going to discuss some of the most common MDR pathogens encountered in the ICU that some of these novel antibiotics will target.  The organisms we will review are carbapenem-resistant Enterobacteriales, difficult-to-treat resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii.  According to the latest CDC statistics, almost 3 million people are infected with a resistant organism each year in the U.S., with more than 35,000 of those dying.  CRE and CREB are classified by the CDC as urgent threats with approximately 10,000 infections and 1,000 deaths each year in the U.S.  MDR Pseudomonas is classified as a serious threat with three times as many infections and deaths each year.  In 2018, a new designation was coined for especially resistant Pseudomonas, difficult-to-treat resistant Pseudomonas aeruginosa.  Of note, this presentation will focus on treating carbapenem-resistant organisms, which means  I will not be reviewing the treatment of extended-spectrum beta-lactamase-producing Enterobacteriales infections.  As I go through this presentation, I will commonly refer to the Ambler classification of beta-lactamases. There are four classes of beta-lactamases. Class A includes ESBLs and KPCs.  Class B includes metallobeta-lactamases. Class C includes the AMP-C producers, and Class D are oxacillinases.  Conveniently, the Infectious Diseases Society of America has recently issued two guidance documents concerning these serious infections.  Version 1, published in 2020, reviews ESBLs, CREs, and DTR Pseudomonas. Version 2, published at the end of 2021, reviews AMP-C beta-lactamase-producing Enterobacteriales,  Crab, and Stenotrophomonas infections. In this second part of my presentation, I am going to review the data for some of the  new drugs, specifically Aravacyclin, Imipenem, Silostatin, Relobactam, and Miropenem-Vavorobactam for the treatment of CRE, difficult-to-treat resistant Pseudomonas, and Crab.  The first novel antibiotic I want to discuss is Aravacyclin. Aravacyclin is a novel tetracycline antibiotic that has activity against a wide variety of  organisms including resistant gram-positives, resistant gram-negatives, and some anaerobes. It is stable to several tetracycline-resistant mechanisms, including ribosomal protection  proteins and tet-specific efflux proteins. The two main trials that were pivotal for the approval of Aravacyclin are the IGNITE-1 and IGNITE-4 trials.  Both studies were Phase III randomized double-blind, double-dummy, multi-center, multinational, active-control, non-inferiority studies.  IGNITE-1 compared intravenous Aravacyclin to Iripenem, and IGNITE-4 compared intravenous Aravacyclin to Iripenem, both for the treatment of adults with complicated intra-abdominal  infections that required surgical or percutaneous intervention. The primary outcome of the study was the clinical response rate at the test-of-cure visit and  the micro-intent-to-treat population. The non-inferiority margin was 10% for IGNITE-1 and 12.5% for IGNITE-4.  There was no statistically significant difference in the clinical response rate between Aravacyclin  and the comparator in either of the trials, therefore non-inferiority was achieved in both studies.  Interestingly, carbapenem-based producing organisms were not well represented in either group of either study.  In addition, it's curious to find such high rates in IGNITE-1 for Pseudomonas and Acinetobacter,  two organisms where you wouldn't expect Iripenem to be effective, and you also wouldn't expect Aravacyclin to be effective against Pseudomonas.  There are several theories to explain this, including that source control was a key component  of the treatment plan in these studies, likely reducing the bacterial inoculum substantially  early in the treatment course, and also most of the infections were polymicrobial, so it's postulated that Aravacyclin and Iripenem were targeting only the infecting flora.  Aravacyclin proved to be non-inferior to Iripenem and Miripenem in two large, well-designed trials for the treatment of complicated intra-abdominal infections.  Of note, patients who were determined to have rapidly progressing disease and those requiring vasopressor support were excluded.  There was a low incidence of ineffective source control that may have impacted the study results.  Aravacyclin was proven to be safe, with GI side effects being the predominant intolerance, albeit likely less GI issues than what would be expected to be seen with Tigacyclin.  And finally, in my opinion, there were insufficient numbers of CRE, Pseudomonas, and CREB to make strong conclusions about its effectiveness for these organisms.  IGNITE-2 is an unpublished study that compared Aravacyclin to Levofloxacin for the treatment of complicated urinary tract infections.  Patients received three to seven days of IV therapy and then switched to oral therapy to complete the seven-day treatment course.  Approximately half of the patients had pyelonephritis, and Enterobacterioles were the most common infecting organisms. Aravacyclin was not proven to be non-inferior to Levofloxacin.  Factors that were found to contribute to failure were male gender and the receipt of less than  three days of intravenous Aravacyclin before transitioning to oral Aravacyclin to complete the seven-day treatment course.  Due to the issues observed with oral Aravacyclin therapy in the IGNITE-2 trial, the IGNITE-3 trial investigated intravenous Aravacyclin also for the treatment of complicated urinary  tract infections. Similar to the results seen in the IGNITE-2 trial, Aravacyclin also did not achieve non-inferiority  in the IGNITE-3 trial for the treatment of complicated urinary tract infections, even when used intravenously for the entire treatment course.  The full data from IGNITE-2 and IGNITE-3 have not been published by the manufacturer, and Aravacyclin is not approved for the use in urinary tract infections.  Because only select data is available, it is difficult to elucidate the true reasons for treatment failure and study limitations.  A post-hoc analysis of the IGNITE-1 and IGNITE-4 trials was conducted to assess the safety and efficacy of Aravacyclin in obese patients.  As a reminder, Acarbapenem was the comparator group in both of these studies. When dosed on actual body weight in obese patients, Aravacyclin was found to be safe  and efficacious, with similar cure rates across the entire cohort, as well as within individual classes of obesity.  Similarly, there was also a post-hoc analysis of the IGNITE-1 and IGNITE-4 trials of patients who had secondary bacteremia from complicated intra-abdominal infections.  Less than 10% of patients had secondary bacteremia, nevertheless, there appeared to be a similar  incidence of clinical response, microbiological eradication, and treatment emergent adverse effects between groups.  Another major consideration for using these new antibiotics in critically ill patients is to assess their pharmacokinetics in extracorporeal therapies such as ECMO and CRRT.  This was a single case report evaluating the pharmacokinetics in a patient receiving Aravacyclin who was also receiving VVECMO and CVVHD.  The main pharmacodynamic efficacy target for Aravacyclin is AUC to MIC ratio. While some of the measured PK parameters were significantly altered in this patient, the  main target of AUC to MIC ratio was not significantly affected. Limitations to this single case report are obviously that this was a single patient who  received VVECMO and CVVHD, so these results cannot be applied to other extracorporeal treatment modalities like VAECMO or CVVH or CVVHDF.  So to wrap up the discussion on Aravacyclin, there are a couple of key points I want to reiterate.  IGNITE-2 showed a lack of a non-inferiority with an oral formulation to treat complicated urinary tract infections.  However, when intravenous therapy was also used to treat complicated UTIs as in IGNITE-3, there was also a lack of non-inferiority to the comparator therapy.  In addition, there are some Y-psych incompatibility concerns with common ICU medications to be mindful of.  Post hoc analysis has confirmed that dosing patients based on actual body weight even in obesity is safe and efficacious.  And dose adjustments are necessary when co-administered with CYP3A4 inducers, think rifampin, and when administered to patients with significant liver dysfunction.  As with most, if not all, new antimicrobial, susceptibility testing at the individual institution level can be challenging and there are some notable holes in therapy.  Aravacyclin may be considered an alternative tetracycline treatment for CRAB or when other usually primary therapies are unavailable or intolerable.  My assessment of Aravacyclin is that it is reasonable to have it on the hospital formulary, but its prescribing should be limited to the infectious diseases services only.  The next novel antibiotic I want to discuss is imipenem xylostatin relabactam. Imipenem xylostatin is a carbapenem antibiotic that has been on the market for many years.  Xylostatin has no antimicrobial activity, rather it inhibits renal dehydropeptidases from metabolizing imipenem.  Resistance to imipenem has increased over the years and the FDA recently approved a combination of imipenem xylostatin with relabactam.  Relabactam is a novel beta-lactamase inhibitor and combining it with imipenem can restore imipenem's activity against many imipenem non-facetibulogram negative pathogens including  ESBLs, AMPC, and KPC-producing enterobacterioles. RestoreME1 and RestoreME2 were the two clinical trials that brought imipenem relabactam to the market.  Both trials were randomized, double-blind, multi-center, and multinational. RestoreME1 evaluated imipenem relabactam versus imipenem pus colistin for the treatment of  HAP and VAP, complicated intra-abdominal and complicated urinary tract infections from imipenem non-susceptible organisms.  This trial was small with only 47 patients, whereas RestoreME2 had over 500 patients. It compared imipenem relabactam to piperacillin-tazobactam for the treatment of HAP-VAP.  Imipenem relabactam was found to be no different than the comparator therapy in both trials. Of note here, the RestoreME2 study population consisted largely of patients at high risk  of adverse treatment outcomes and death, with a high proportion of participants enrolled in the ICU with APACHE2 scores of greater than or equal to 15, with either augmented  renal clearance or moderate to severe renal impairment and advanced age. The first row here describes the MDR pathogens that were present in each group in each trial.  The second row is the favorable response to each. The combination of imipenem with relabactam can overcome many gram-negative resistance  mechanisms including beta-lactamase production or overexpression, porin loss, and efflux,  and is active against many strains of KPC producers, ESBL producers, and MDR carbapenem-resistant  pseudomonas, but not metallobeta-lactamases like New Delhi and or class Z beta-lactamases like OXO48.  Imipenem generally does not improve imipenem susceptibility against Acinetobacter baumannii. Several limitations to these two trials exist, including, of course, a small sample size  in RestoreME1, albeit large non-inferiority trials including MDR infections are not feasible.  These patients also needed to be sick enough to require salvage therapy, but not so sick that they couldn't participate and contribute meaningful data.  Very few patients with CRE were enrolled, most were pseudomonas, thus limiting interpretability among this subpopulation.  However, relabactam restores in vitro imipenem susceptibility against most CRE, and this could be considered a reasonable predictor of favorable therapeutic response.  The argument could be made that colistin plus a carbapenem for HAPVAT for carbapenem-resistant pseudomonas is not a standard of care.  And while this study population was more critically ill than seen in other studies, immunocompromised patients were still not included.  A post hoc analysis of RestoreME1 evaluated the renal safety of imipenem-salicylicatin-relabactam  versus imipenem plus colistin, and it's not a surprise that imipenem-relabactam was not as nephrotoxic as imipenem plus colistin.  An ex vivo Monte Carlo simulation was conducted to assess the clearance of imipenem-relabactam during CVVH and CVVHD using an M150 and HF1400 filters.  The sieving coefficients of imipenem and relabactam with each filter and at different effluent rates are shown in the table.  As a reminder, a sieving coefficient of 1 means that the drug passes freely from pre-filter plasma water to the ultrafiltrate.  Relabactam clearance follows that of imipenem and both are readily removed by CRRT. As a reminder, the normal dose of imipenem-relabactam is 1250 mg IV every 6 hours.  The authors of this analysis suggested that it be dosed at 1500 mg IV every 6 hours in CVVH or CVVHD to achieve 4 times the MIC for at least 40% of the dosing interval.  There are a wide range of targets that can be considered. The normal target for a carbapenem is to have the concentration over the MIC for at  least 40% of the dosing interval, whereas some suggest in critically ill patients that the target should be higher with either obtaining a concentration of 4 times the MIC for 40%  of the dosing interval or even maintaining a concentration above the MIC for the entire dosing interval.  As expected, the probability of target attainment varies with the intended target. These targets may also be difficult to obtain in critically ill patients without significantly  increasing the risk of neurotoxicity. I did not find any published reports of imipenem-relabactam use in ECMO, but there are some reports of imipenem use.  Imipenem is hydrophilic and has low protein binding, meaning that it is less likely to have significant sequestration in the ECMO circuit.  In this small analysis, including 10 critically ill patients, the authors concluded that if you are aiming for the traditional goal of concentrations greater than the MIC for 40%  of the dosing interval, then normal dosing may be adequate. Higher targets would require higher doses and careful consideration of possible dose-related adverse effects.  Some in vitro data suggest that imipenem-relabactam may be effective for organisms that are resistant  to ceftazidime avibactam and ceftolazine tazobactam, so there may be a niche for imipenem-relabactam  in hep-vap, complicated intra-abdominal infections, or complicated urinary tract infections caused by CRE or carbapenem-resistant pseudomonas.  Remember, relabactam does not restore imipenem activity against acinetobacter. And imipenem-relabactam appeared well-tolerated in the two trials, but extracorporeal therapies  may necessitate higher than normal doses that will likely increase the incidence of adverse effects. The last novel antibiotic that will be reviewed here is miripenem-vabrabactam.  The TANGO I and TANGO II trials were both Phase III, double-blind, double-dummy, multi-center, multinational, non-inferiority, randomized controlled trials.  TANGO I included 550 patients and compared miripenem-vabrabactam to piperacillin-tazobactam for the treatment of hospitalized patients with complicated urinary tract infections,  whereas TANGO II included 77 patients and compared miripenem-vabrabactam to best available  therapy for the treatment of HAP-VAP, bacteremia, complicated intra-abdominal infections, or complicated urinary tract infection caused by CRE.  The majority of pathogens in both studies were Klebsiella pneumonia and E. coli. In TANGO I, there were three confirmed CRE infections, whereas the entire cohort in TANGO  II had a CRE infection. In TANGO I, non-inferiority between the groups was demonstrated regarding overall success  at the end of treatment, and treatment-related adverse events were rare. In TANGO II, higher cure rates and lower mortality were seen with miripenem-vabrabactam  compared to best available therapy, and treatment-related adverse events were less frequent, mainly driven by a difference in nephrotoxicity between the two groups.  This prompted the Data Safety Monitoring Board to recommend ending the study early at one of the interim analyses.  Most patients in TANGO I were from the U.S., with less than one-third of those meeting CERS criteria, bringing into question, did this cohort even really need hospitalization?  This line of critical illness was attempted to be overcome with the enrollment criteria in TANGO II, where sicker patients were included.  It is increasingly considered standard of care to use extended infusion dosing with piperacillin-tazobactam.  However, regulatory agencies prohibited this dosing strategy in TANGO I, and of course, it would have been unethical to include and randomize patients to a piperacillin-tazobactam  treatment arm when allowing patients with carbapenem-resistant organisms to be included. TANGO II is the largest trial to date for CRE organisms, but the sample size is still  very small. Overall, miripenem-vabrabactam was well-tolerated and was found to be non-inferior to piperacillin-tazobactam  for the treatment of complicated urinary tract infections, and may be superior to best available therapy for the treatment of serious CRE infections.  A PubMed search of miripenem-vabrabactam in ECMO yielded one result. This was an ex vivo analysis of a blood-primed circuit after one dose of miripenem-vabrabactam.  The researchers found about 70% loss of miripenem at 24 hours and no significant loss of vabrabactam.  This is in alignment with previous studies of miripenem in ECMO that indicate that standard dosing is sufficient to attain non-aggressive PD targets.  This study reviewed miripenem-vabrabactam use during CVVHD using standard settings and concluded that a dose of 2,000 mg IV every 8 hours via a 3-hour infusion achieved and  maintained drug concentrations well above the MIC for the entire dosing interval. Miripenem-vabrabactam may be a good alternative for CRE infections, particularly for KPCs,  though it has poor activity against Ambler class B and D beta-lactamases. It can also be considered an alternative for ESBL and AMPC-producing infections, though  that was not the focus of this presentation. Similarly to how adding rilabactam to imipenem does not enhance its activity against acinetobacter,  adding vabrabactam to miripenem does not significantly increase its activity against pseudomonas, acinetobacter, or stenotrophomonas. Next we'll wrap up this presentation.  This summary table describes in general the activity of new antimicrobials and I've highlighted in the middle the ones reviewed today in this presentation.  Regarding the ones reviewed today, think of the ravacyclin as an additional antibiotic  in our arsenal for MDR-acinetobacter, miripenem-vabrabactam for KPCs, and imipenem-rilabactam for MDR-pseudomonas.  All three agents are active against ESBLs and AMPC beta-lactamase producers as well. So in conclusion, as with any infection, source control is key and remember many of these  trials were performed in best-case scenario situations. In addition, consultation with an infectious disease physician and pharmacist specialist  is recommended when encountering antibiotic-resistant gram-negative infections. Thank you all for listening to this presentation and I look forward to answering any questions  you have at a later date to be announced.

Video Summary

The transcript discusses the use of novel broad-spectrum antibiotics to treat highly resistant infections commonly encountered in ICU patients. Specifically, it focuses on new beta-lactam-beta-lactamase inhibitor combinations and tetracycline derivatives such as aravacycline. These antibiotics have shown promising activity against carbapenem-resistant gram-negative bacteria and may expand treatment options. The speaker discusses the data surrounding these new agents and their potential role in critically ill patients, as well as possible limitations with their use. The presentation reviews the common MDR pathogens encountered in the ICU, including carbapenem-resistant Enterobacteriales, Pseudomonas aeruginosa, and Acinetobacter baumannii. The speaker emphasizes the need for source control and further highlights the importance of consulting with infectious disease specialists when dealing with antibiotic-resistant gram-negative infections.

Asset Subtitle

Infection, Pharmacology, Quality and Patient Safety, 2022

Asset Caption

Increasing rates of antimicrobial drug resistance in the community and in the ICU imperil our ability to care for patients with sepsis and septic shock. In this session, we will review the clinical features that clinicians can use to guide rational antimicrobial drug use, new and emerging diagnostic tests that help us make the right choice of drugs more rapidly, and the data for novel antimicrobial agents, including beta-lactam/beta-lactamase inhibitors and tetracycline derivates, that may support the care of infected patients in the ICU.

Meta Tag

Content Type Presentation

Knowledge Area Infection

Knowledge Area Pharmacology

Knowledge Area Quality and Patient Safety

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Antibiotics

Tag Pharmacokinetics Pharmacodynamics

Tag Evidence Based Medicine

Year 2022

Keywords

novel broad-spectrum antibiotics

highly resistant infections

ICU patients

beta-lactam-beta-lactamase inhibitor combinations

tetracycline derivatives

carbapenem-resistant gram-negative bacteria

	Society of Critical Care Medicine 500 Midway Drive Mount Prospect, IL 60056 USA Phone: +1 847 827-6888 Fax: +1 847 439-7226 Email: support@sccm.org	Contact Us About SCCM Newsroom Advertising & Sponsorship DONATE	MySCCM LearnICU Patients & Families Surviving Sepsis Campaign Critical Care Societies Collaborative	GET OUR NEWSLETTER
© Society of Critical Care Medicine. All rights reserved. \| Privacy Statement \| Terms & Conditions The Society of Critical Care Medicine, SCCM, and Critical Care Congress are registered trademarks of the Society of Critical Care Medicine.