Gram-negative infections at IDWeek: New FDA approvals, new treatment data

Gram-negative bacteria can quickly develop antibiotic resistance and can confer the resistance to other bacteria. The cell envelope of gram-negative bacteria, which features two membranes and sometimes an additional capsule or slime layer, can better equip them to survive immune surveillance in humans and persist in the antibiotic-laden hospital environment. Data presented at IDWeek in San Francisco bolstered the view that we might at least keep pace with gram-negative antibiotic resistance.

Plazomicin

Plazomicin is a next-generation aminoglycoside antibiotic derived from sisomicin. It resists the activity of most aminoglycoside-modifying enzymes, except methylases, and is active against the majority of carbapenem-resistant Enterobacteriaceae (CRE) isolates in the United States.

James A. McKinnell

This past June, the FDA approved plazomicin for the treatment of complicated urinary tract infection (cUTI) including acute pyelonephritis (AP) with limited or no treatment options, based on the results of the pivotal phase 3 EPIC trial.

The as-yet unpublished phase 3 CARE (NCT01970371) trial compared plazomicin with colistin in the treatment of serious CRE bloodstream or ventilator-associated infections. Plazomicin bettered colistin in terms of day 28 mortality or serious disease-related complications. In patients with bloodstream infections, all-cause mortality or significant complications were significantly less in the plazomicin arm.

Cefiderocol

Cefiderocol is a novel siderophore cephalosporin antibiotic developed as a treatment for multidrug-resistant (MDR) gram-negative infections. In the phase 2 APEKS-cUTI study, cefiderocol demonstrated noninferiority to imipenem/cilastatin in the treatment of 452 patients with cUTIs. Composite clinical and microbiological responses were 73% for cefiderocol vs. 55% for imipenem/cilastatin. The clinical response rate was similar between the two groups.

Two ongoing clinical trials are evaluating the use of cefiderocol in the treatment of severe infections caused by carbapenem-resistant organisms (CREDIBLE-CR, NCT02714595) and in gram-negative nosocomial pneumonia (APEKS-NP, NCT03032380). Final results are expected by the end of 2018 and in 2019, respectively.

Ceftazidime-avibactam

Ceftazidime-avibactam is approved by the FDA for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), and in combination with metronidazole to treat cUTI including AP and complicated intra-abdominal infection (cIAI). The drug combination is active against carbapenemase-producing Klebsiella pneumoniae (KPC), OXA-48 type KPC, and AmpC beta-lactamase producers. Metallo-beta-lactamase producing bacteria are not inhibited.

The phase 3 randomized, double-blind, noninferiority REPROVE clinical trial assigned 879 HABP/VABP patients to intravenous ceftazidime and avibactam or meropenem. The study arms were comparable for day 28 all-cause mortality and for the rates of clinical cure in several assessed categories, including the intent-to-treat population. The treatments were comparably good in subgroups, including ventilated patients, patients with HABP or VABP and patients with normal or impaired renal clearance. A notable observation was the presence of 11 Pseudomonas aeruginosa baseline isolates that developed resistance to meropenem while on therapy and one K. pneumonia baseline isolate that ultimately developed resistance to ceftazidime-avibactam.

Ceftolozane-tazobactam

Ceftolozane-tazobactam is FDA-approved for the treatment of cUTI and cIAI. The drug combination is active against P. aeruginosa (including MDR and extensively drug resistant forms), Haemophilus and Moraxella, but not against carbapenemase-producing Enterobacteriaceae. The FDA-approved dose is 1.5 g every 8 hours. Notably, the recently completed ASPECT-NP phase 3 study (NCT02070757) of IV ceftolozane-tazobactam vs. IV meropenem in the treatment of adult participants with either VABP or HABP evaluated a higher dose of 3 g every 8 hours. The 726-patient trial met the primary endpoint of day 28 all-cause mortality and clinical cure rate. Ceftolozane-tazobactam was noninferior to meropenem.

Highly beta-lactam-resistant Pseudomonas

As reported at IDWeek, a survey of 309 isolates obtained throughout Los Angeles County found that among those resistant to ceftazidime-avibactam, 36% were susceptible to ceftolozane-tazobactam. However, the collective data from this and other studies indicate that approximately one-third of P. aeruginosa isolates with resistance to cephalosporins, piperacillin-tazobactam and carbapenems are not susceptible to either ceftolozane-tazobactam or ceftazidime-avibactam. These data highlight the need for susceptibility testing if these novel agents are used to treat P. aeruginosa infections.

Development of resistance to ceftolozane-tazobactam in MDR P. aeruginosa due to modification of intrinsic (AmpC) and horizontally acquired beta-lactamases has been reported.

Meropenem/vaborbactam

Meropenem and vaborbactam — the first carbapenem/beta-lactamase inhibitor combination — previously demonstrated convincing success in the phase 3 TANGO 2 trial against CRE infections compared with the best available therapy. The results were bolstered by the concurrent demonstration of the efficacy of meropenem-vaborbactam against more than 14,000 gram-negative clinical isolates. The drug is approved by the FDA for treatment of adults with cUTIs.

Imipenem/cilastatin+relebactam

The results of the phase 3 RESTORE-IMI 1 trial (NCT02452047) reported the comparable activity of the beta-lactamase inhibitor relebactam to colistin when relebactam was used in combination with imipenem/cilastatin (IMI/REL) for the treatment of HABP, VABP, cIAI and cUTI.

A supplemental analysis of the trial reported at IDWeek showed efficacy in the primary analysis population and a supplemental population based on local microbiology data. The efficacy in the trial appears to extend more broadly. A 2017 survey of 188 hospitals from 54 countries as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) trial presented at IDWeek revealed microbiologic activity of IMI/REL against global isolates of P. aeruginosa and most Enterobacteriaceae, including KPC-positive isolates.

Safety analysis of the RESTORE-IMI 1 data presented as a poster chronicled the nephrotoxicity associated with the therapy in patients with imipenem-nonsusceptible bacterial infections. The use of two different assessment criteria of acute kidney injury (KDIGO and RIFLE) revealed that a significantly smaller percentage of patients receiving IMI/REL experienced protocol-defined nephrotoxicity compared with those receiving colistin (% difference: –45.9, 95% CI –69.1 to –18.4, P = .002). Also, fewer renal adverse events, including renal-related discontinuations, were observed in the IMI/REL group.

Eravacycline

The broad-spectrum fluorocycline antibiotic was FDA approved at the end of August 2018 for the treatment of cIAI. In the phase 3 IGNITE 1 trial, twice-daily IV infusions of eravacycline met the primary endpoint of noninferiority compared with ertapenem for cIAI.

The benefit was not realized in the IGNITE 3 trial of eravacycline for cUTI. Although the drug was safe and well-tolerated, it failed to meet the coefficacy endpoints of the combination of clinical cure and microbiological eradication of the pathogen.

In closing

Gram-negative bacteria can cause cUTIs, cIAIs, HABP/VABP and other serious infections. These infections are prevalent; expensive to treat, especially for high-risk patients; and can be deadly. The continued efforts toward researching and developing innovative new therapies presented at IDWeek provide some optimism for clinical success. This optimism must be tempered with the reality that drug resistance always lurks.

Disclosure: McKinnell reports no relevant financial disclosures.

Gram-negative bacteria can quickly develop antibiotic resistance and can confer the resistance to other bacteria. The cell envelope of gram-negative bacteria, which features two membranes and sometimes an additional capsule or slime layer, can better equip them to survive immune surveillance in humans and persist in the antibiotic-laden hospital environment. Data presented at IDWeek in San Francisco bolstered the view that we might at least keep pace with gram-negative antibiotic resistance.

Plazomicin

Plazomicin is a next-generation aminoglycoside antibiotic derived from sisomicin. It resists the activity of most aminoglycoside-modifying enzymes, except methylases, and is active against the majority of carbapenem-resistant Enterobacteriaceae (CRE) isolates in the United States.

James A. McKinnell

This past June, the FDA approved plazomicin for the treatment of complicated urinary tract infection (cUTI) including acute pyelonephritis (AP) with limited or no treatment options, based on the results of the pivotal phase 3 EPIC trial.

The as-yet unpublished phase 3 CARE (NCT01970371) trial compared plazomicin with colistin in the treatment of serious CRE bloodstream or ventilator-associated infections. Plazomicin bettered colistin in terms of day 28 mortality or serious disease-related complications. In patients with bloodstream infections, all-cause mortality or significant complications were significantly less in the plazomicin arm.

Cefiderocol

Cefiderocol is a novel siderophore cephalosporin antibiotic developed as a treatment for multidrug-resistant (MDR) gram-negative infections. In the phase 2 APEKS-cUTI study, cefiderocol demonstrated noninferiority to imipenem/cilastatin in the treatment of 452 patients with cUTIs. Composite clinical and microbiological responses were 73% for cefiderocol vs. 55% for imipenem/cilastatin. The clinical response rate was similar between the two groups.

Two ongoing clinical trials are evaluating the use of cefiderocol in the treatment of severe infections caused by carbapenem-resistant organisms (CREDIBLE-CR, NCT02714595) and in gram-negative nosocomial pneumonia (APEKS-NP, NCT03032380). Final results are expected by the end of 2018 and in 2019, respectively.

Ceftazidime-avibactam

Ceftazidime-avibactam is approved by the FDA for the treatment of hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), and in combination with metronidazole to treat cUTI including AP and complicated intra-abdominal infection (cIAI). The drug combination is active against carbapenemase-producing Klebsiella pneumoniae (KPC), OXA-48 type KPC, and AmpC beta-lactamase producers. Metallo-beta-lactamase producing bacteria are not inhibited.

The phase 3 randomized, double-blind, noninferiority REPROVE clinical trial assigned 879 HABP/VABP patients to intravenous ceftazidime and avibactam or meropenem. The study arms were comparable for day 28 all-cause mortality and for the rates of clinical cure in several assessed categories, including the intent-to-treat population. The treatments were comparably good in subgroups, including ventilated patients, patients with HABP or VABP and patients with normal or impaired renal clearance. A notable observation was the presence of 11 Pseudomonas aeruginosa baseline isolates that developed resistance to meropenem while on therapy and one K. pneumonia baseline isolate that ultimately developed resistance to ceftazidime-avibactam.

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Ceftolozane-tazobactam

Ceftolozane-tazobactam is FDA-approved for the treatment of cUTI and cIAI. The drug combination is active against P. aeruginosa (including MDR and extensively drug resistant forms), Haemophilus and Moraxella, but not against carbapenemase-producing Enterobacteriaceae. The FDA-approved dose is 1.5 g every 8 hours. Notably, the recently completed ASPECT-NP phase 3 study (NCT02070757) of IV ceftolozane-tazobactam vs. IV meropenem in the treatment of adult participants with either VABP or HABP evaluated a higher dose of 3 g every 8 hours. The 726-patient trial met the primary endpoint of day 28 all-cause mortality and clinical cure rate. Ceftolozane-tazobactam was noninferior to meropenem.

Highly beta-lactam-resistant Pseudomonas

As reported at IDWeek, a survey of 309 isolates obtained throughout Los Angeles County found that among those resistant to ceftazidime-avibactam, 36% were susceptible to ceftolozane-tazobactam. However, the collective data from this and other studies indicate that approximately one-third of P. aeruginosa isolates with resistance to cephalosporins, piperacillin-tazobactam and carbapenems are not susceptible to either ceftolozane-tazobactam or ceftazidime-avibactam. These data highlight the need for susceptibility testing if these novel agents are used to treat P. aeruginosa infections.

Development of resistance to ceftolozane-tazobactam in MDR P. aeruginosa due to modification of intrinsic (AmpC) and horizontally acquired beta-lactamases has been reported.

Meropenem/vaborbactam

Meropenem and vaborbactam — the first carbapenem/beta-lactamase inhibitor combination — previously demonstrated convincing success in the phase 3 TANGO 2 trial against CRE infections compared with the best available therapy. The results were bolstered by the concurrent demonstration of the efficacy of meropenem-vaborbactam against more than 14,000 gram-negative clinical isolates. The drug is approved by the FDA for treatment of adults with cUTIs.

Imipenem/cilastatin+relebactam

The results of the phase 3 RESTORE-IMI 1 trial (NCT02452047) reported the comparable activity of the beta-lactamase inhibitor relebactam to colistin when relebactam was used in combination with imipenem/cilastatin (IMI/REL) for the treatment of HABP, VABP, cIAI and cUTI.

A supplemental analysis of the trial reported at IDWeek showed efficacy in the primary analysis population and a supplemental population based on local microbiology data. The efficacy in the trial appears to extend more broadly. A 2017 survey of 188 hospitals from 54 countries as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART) trial presented at IDWeek revealed microbiologic activity of IMI/REL against global isolates of P. aeruginosa and most Enterobacteriaceae, including KPC-positive isolates.

Safety analysis of the RESTORE-IMI 1 data presented as a poster chronicled the nephrotoxicity associated with the therapy in patients with imipenem-nonsusceptible bacterial infections. The use of two different assessment criteria of acute kidney injury (KDIGO and RIFLE) revealed that a significantly smaller percentage of patients receiving IMI/REL experienced protocol-defined nephrotoxicity compared with those receiving colistin (% difference: –45.9, 95% CI –69.1 to –18.4, P = .002). Also, fewer renal adverse events, including renal-related discontinuations, were observed in the IMI/REL group.

PAGE BREAK

Eravacycline

The broad-spectrum fluorocycline antibiotic was FDA approved at the end of August 2018 for the treatment of cIAI. In the phase 3 IGNITE 1 trial, twice-daily IV infusions of eravacycline met the primary endpoint of noninferiority compared with ertapenem for cIAI.

The benefit was not realized in the IGNITE 3 trial of eravacycline for cUTI. Although the drug was safe and well-tolerated, it failed to meet the coefficacy endpoints of the combination of clinical cure and microbiological eradication of the pathogen.

In closing

Gram-negative bacteria can cause cUTIs, cIAIs, HABP/VABP and other serious infections. These infections are prevalent; expensive to treat, especially for high-risk patients; and can be deadly. The continued efforts toward researching and developing innovative new therapies presented at IDWeek provide some optimism for clinical success. This optimism must be tempered with the reality that drug resistance always lurks.

Disclosure: McKinnell reports no relevant financial disclosures.