Ceftolozane/tazobactam effective against MDR Pseudomonas aeruginosa in nosocomial pneumonia
18 Jan 2024
byJoanne G. Blanco, MD
With the emergence of new subtypes of respiratory nosocomial infection and multi-drug resistant organisms (MDROs), better surveillance and infection prevention and control are necessary to address these healthcare challenges. In the MSD-sponsored scientific event entitled “Multidrug Resistant Infections: Updates on Diagnosis and Management” held on July 27, 2023, Dr Evelina Lagamayo, Clinical Pathologist and Microbiologist, Section Chief, Microbiology Department of Clinical Pathology, University of Santo Tomas Hospital; Dr Rontgene Solante, Chair, Adult Infectious Disease, Tropical Medicine, San Lazaro Hospital, and President of the Philippine College of Physicians; and Dr Carmenchu Villavicencio, Infection Control Chair of St. Luke’s Medicla Center Global City, as moderator discussed diagnostic tests for Enterobacterales and Pseudomonas aeruginosa, and the role of ceftolozane/tazobactam (ZERBAXA) in the treatment nosocomial pneumonia.
Dr Solante discussing a case of a patient as he presented the multiple resistance mechanisms of Pseudomonas aeruginosa
Patients with ventilated HAP (vHAP) are at risk of even higher mortality rates than patients with VAP
Nosocomial infection is the most common challenge that contributes to significant morbidity, mortality, and financial burden on patients, families, and healthcare systems.1 After urinary tract infection, hospital-acquired pneumonia (HAP) is the second most common nosocomial infection, and ranks first as the most dangerous with the highest mortality.2 Moreover, pneumonia acquired in the ICU leads to a negative impact in terms of morbidity, prolonged stay and duration of a mechanical ventilator in case of VAP, and a consequent increase in healthcare cost. These challenges are even heightened in the event of an inappropriate antibiotic treatment, which directly relates to the existence of multi-drug resistant organisms (MDROs) like Pseudomonas aeruginosa.3
Respiratory infections are the most prevalent nosocomial infection observed in the intensive care unit.3 Dr Lagamayo discussed various identification and sensitivity tests for Enterobacterales and Pseudomonas aeruginosa. Multiple resistance mechanisms of P. aeruginosa were discussed, including beta-lactamase production, efflux mechanisms, and porin deficiency.
There are different types of nosocomial pneumonia: hospital-acquired pneumonia (HAP), that which appears as of 48 hours from hospital admission, in the ICU or in the hospital ward; ventilator-associated pneumonia (VAP), that of which develops in ICU patients who have been mechanically ventilated for at least 48 hours; and ventilated HAP (vHAP) or hospital-acquired pneumonia requiring mechanical ventilation.4
Patients with vHAP are at risk of even higher mortality rates than patients with VAP and acute illness severity was also highest in vHAP group compared to non-vHAP and VAP as evidenced by the prevalence of and evidence of severe sepsis or septic shock at any time during hospitalization.3,5
Timeliness and appropriateness of treatment are predictors of mortality
Zaragoza, et al discussed the shift from empiric to targeted treatment of nosocomial pneumonia. After assessment of the onset, the previous use of antimicrobials or clinical condition (vHAP or VAP), empirical antimicrobial therapy is chosen based on risk factors, previous colonization, local flora and/or use of rapid techniques.3 After isolation of the microorganism, shifting to targeted antimicrobial therapy as early as possible or ‘early switch’ should be done.
Ceftolozane/tazobactam (ZERBAXA) is recommended for the treatment of MDR P. aeruginosa
Pseudomonas aeruginosa accounts for 25% of all nosocomial Gram-negative infections globally. Of this, 38.4% are carbapenem-resistant.6 In the Philippines, the majority of the antibiotics used show resistance toward P. aeruginosa.7'
The MDROs most involved in HAP are Pseudomonas aeruginosa, extended-spectrum beta-lactamase-producing enterobacteria (ESBL-E), methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii and carbapenemase-producing Enterobacteriaceae (CPE). In evaluating critically-ill patients in the ICU who are at risk for nosocomial pneumonia, it is important to know the risk factors for these pathogens. The European guidelines for nosocomial pneumonia include risk factors for MDRO: septic shock, hospital ecology with high levels of MDROs, prior use of antibiotics, recent hospitalization (> 5 days) and prior colonization by MDROs. Knowledge of local epidemiology is also essential because there are significant differences in the local prevalence of each MDRO.3
In the optimized treatment for MDR P. aeruginosa, a dual combination regimen includes the use of ceftolozane/tazobactam (ZERBAXAâ) as the first anti-pseudomonal agent, combined with gentamycin or another aminoglycoside, colistin, or fosfomycin. Other agents that can be also used as first anti-pseudomonal agents include ceftazidime/avibactam, meropenem, meropenem/vaborbactam, and piperacillin/tazobactam. For monotherapy or combination therapy, ceftolozane/tazobactam (ZERBAXA) is recommended.8
Ceftolozane/tazobactam (ZERBAXA) is the treatment of choice for P. aeruginosa because of its greater in vitro activity against P. aeruginosa, with less resistance than the remaining current anti-pseudomonal agents. It also exhibits the lowest mutant prevention concentration (MPC) against P. aeruginosa as well as colistin and quinolones (2mg/L).3
Ceftolozane/tazobactam (ZERBAXA) is noninferior to Meropenem in 28-day all-cause mortality for nosocomial pneumonia
Dr Solante discussed that ceftolozane has resistance mechanisms against P. aeruginosa’s outer membrane mechanisms, beta-lactamase activity, and efflux pumps MexXY and MexAB. Ceftolozane provides more stability than ceftazidime because of the presence of side chains that enhance these anti-pseudomonal activities. The addition of tazobactam broadens the in-vitro coverage to include the most common ESBL-producing Enterobacteriaceae.
In the ASPECT-NP trial, hospitalized patients with HAP or VAP received either ceftolozane/tazobactam (ZERBAXA) 3g IV every 8 hours or meropenem 1g IV every 8 hours for 8-14 days. At day 28, ceftolozane/tazobactam (ZERBAXA) was found to be non-inferior to meropenem for vHAP and VAP. Ceftolozane/tazobactam (ZERBAXA) also has a potential advantage over meropenem in vHAP as mortality rates begin to diverge on day 2 of therapy. Ceftolozane/tazobactam (ZERBAXA) also showed lower mortality in patients with failing initial therapy and lower resource utilization versus meropenem in terms of hospital length of stay, ICU length of stay, and days on mechanical ventilation.
In the same trial, adverse events for both treatment arms were the same and no safety signals specific to ceftolozane/tazobactam (ZERBAXAâ) were elicited.
Timely and appropriate antibiotic therapy is the key to better outcomes in nosocomial pneumonia. With the evidence presented, including the findings from the ASPECT-NP trial, supports the conclusion that Ceftolozane/tazobactam (ZERBAXA) is noninferior to meropenem, demonstrating not only its efficacy but also its potential advantages in terms of mortality rates and resource utilization. When addressing challenging infections such as MDR Pseudomonas aeruginosa, Ceftolozane/tazobactam (ZERBAXA) is a recommended treatment.3
References:1. Sikora A, Zahra F. National Center for Biotechnology Information. Nosocomial infections. Available at: https://pubmed.ncbi.nlm.nih.gov/32644738/. Accessed February 27, 2023.2. Taušan Ð, et al. Front Med 2022;9:1040654.3. Zaragoza R, et al. Critical Care 2020;24:383.4. Torres A, et al. Eur Respir J 2017;50:1700582.5. Zilberberg MD, et al. Crit Care Med 2022;50:460–468.6. Moise PA, Gonzalez M, Alekseeva I, et al. JAC Antimicrob Resist 2021;3.7. Antimicrobial Resistance Surveillance Program (ASP). Data Summary Report 2021. Available at: https://www.arsp.com.ph. Accessed February 27, 2023.8. Karaiskos I, et al. Front Public Health 2019;7:151.
PH-ZER-00234 Nov/2023
Dr Solante discussing a case of a patient as he presented the multiple resistance mechanisms of Pseudomonas aeruginosaPatients with ventilated HAP (vHAP) are at risk of even higher mortality rates than patients with VAP
Nosocomial infection is the most common challenge that contributes to significant morbidity, mortality, and financial burden on patients, families, and healthcare systems.1 After urinary tract infection, hospital-acquired pneumonia (HAP) is the second most common nosocomial infection, and ranks first as the most dangerous with the highest mortality.2 Moreover, pneumonia acquired in the ICU leads to a negative impact in terms of morbidity, prolonged stay and duration of a mechanical ventilator in case of VAP, and a consequent increase in healthcare cost. These challenges are even heightened in the event of an inappropriate antibiotic treatment, which directly relates to the existence of multi-drug resistant organisms (MDROs) like Pseudomonas aeruginosa.3
Respiratory infections are the most prevalent nosocomial infection observed in the intensive care unit.3 Dr Lagamayo discussed various identification and sensitivity tests for Enterobacterales and Pseudomonas aeruginosa. Multiple resistance mechanisms of P. aeruginosa were discussed, including beta-lactamase production, efflux mechanisms, and porin deficiency.
There are different types of nosocomial pneumonia: hospital-acquired pneumonia (HAP), that which appears as of 48 hours from hospital admission, in the ICU or in the hospital ward; ventilator-associated pneumonia (VAP), that of which develops in ICU patients who have been mechanically ventilated for at least 48 hours; and ventilated HAP (vHAP) or hospital-acquired pneumonia requiring mechanical ventilation.4
Patients with vHAP are at risk of even higher mortality rates than patients with VAP and acute illness severity was also highest in vHAP group compared to non-vHAP and VAP as evidenced by the prevalence of and evidence of severe sepsis or septic shock at any time during hospitalization.3,5
Timeliness and appropriateness of treatment are predictors of mortality
Zaragoza, et al discussed the shift from empiric to targeted treatment of nosocomial pneumonia. After assessment of the onset, the previous use of antimicrobials or clinical condition (vHAP or VAP), empirical antimicrobial therapy is chosen based on risk factors, previous colonization, local flora and/or use of rapid techniques.3 After isolation of the microorganism, shifting to targeted antimicrobial therapy as early as possible or ‘early switch’ should be done.
Ceftolozane/tazobactam (ZERBAXA) is recommended for the treatment of MDR P. aeruginosa
Pseudomonas aeruginosa accounts for 25% of all nosocomial Gram-negative infections globally. Of this, 38.4% are carbapenem-resistant.6 In the Philippines, the majority of the antibiotics used show resistance toward P. aeruginosa.7'
The MDROs most involved in HAP are Pseudomonas aeruginosa, extended-spectrum beta-lactamase-producing enterobacteria (ESBL-E), methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii and carbapenemase-producing Enterobacteriaceae (CPE). In evaluating critically-ill patients in the ICU who are at risk for nosocomial pneumonia, it is important to know the risk factors for these pathogens. The European guidelines for nosocomial pneumonia include risk factors for MDRO: septic shock, hospital ecology with high levels of MDROs, prior use of antibiotics, recent hospitalization (> 5 days) and prior colonization by MDROs. Knowledge of local epidemiology is also essential because there are significant differences in the local prevalence of each MDRO.3
In the optimized treatment for MDR P. aeruginosa, a dual combination regimen includes the use of ceftolozane/tazobactam (ZERBAXAâ) as the first anti-pseudomonal agent, combined with gentamycin or another aminoglycoside, colistin, or fosfomycin. Other agents that can be also used as first anti-pseudomonal agents include ceftazidime/avibactam, meropenem, meropenem/vaborbactam, and piperacillin/tazobactam. For monotherapy or combination therapy, ceftolozane/tazobactam (ZERBAXA) is recommended.8
Ceftolozane/tazobactam (ZERBAXA) is the treatment of choice for P. aeruginosa because of its greater in vitro activity against P. aeruginosa, with less resistance than the remaining current anti-pseudomonal agents. It also exhibits the lowest mutant prevention concentration (MPC) against P. aeruginosa as well as colistin and quinolones (2mg/L).3
Ceftolozane/tazobactam (ZERBAXA) is noninferior to Meropenem in 28-day all-cause mortality for nosocomial pneumonia
Dr Solante discussed that ceftolozane has resistance mechanisms against P. aeruginosa’s outer membrane mechanisms, beta-lactamase activity, and efflux pumps MexXY and MexAB. Ceftolozane provides more stability than ceftazidime because of the presence of side chains that enhance these anti-pseudomonal activities. The addition of tazobactam broadens the in-vitro coverage to include the most common ESBL-producing Enterobacteriaceae.
In the ASPECT-NP trial, hospitalized patients with HAP or VAP received either ceftolozane/tazobactam (ZERBAXA) 3g IV every 8 hours or meropenem 1g IV every 8 hours for 8-14 days. At day 28, ceftolozane/tazobactam (ZERBAXA) was found to be non-inferior to meropenem for vHAP and VAP. Ceftolozane/tazobactam (ZERBAXA) also has a potential advantage over meropenem in vHAP as mortality rates begin to diverge on day 2 of therapy. Ceftolozane/tazobactam (ZERBAXA) also showed lower mortality in patients with failing initial therapy and lower resource utilization versus meropenem in terms of hospital length of stay, ICU length of stay, and days on mechanical ventilation.
In the same trial, adverse events for both treatment arms were the same and no safety signals specific to ceftolozane/tazobactam (ZERBAXAâ) were elicited.
Timely and appropriate antibiotic therapy is the key to better outcomes in nosocomial pneumonia. With the evidence presented, including the findings from the ASPECT-NP trial, supports the conclusion that Ceftolozane/tazobactam (ZERBAXA) is noninferior to meropenem, demonstrating not only its efficacy but also its potential advantages in terms of mortality rates and resource utilization. When addressing challenging infections such as MDR Pseudomonas aeruginosa, Ceftolozane/tazobactam (ZERBAXA) is a recommended treatment.3
References:1. Sikora A, Zahra F. National Center for Biotechnology Information. Nosocomial infections. Available at: https://pubmed.ncbi.nlm.nih.gov/32644738/. Accessed February 27, 2023.2. Taušan Ð, et al. Front Med 2022;9:1040654.3. Zaragoza R, et al. Critical Care 2020;24:383.4. Torres A, et al. Eur Respir J 2017;50:1700582.5. Zilberberg MD, et al. Crit Care Med 2022;50:460–468.6. Moise PA, Gonzalez M, Alekseeva I, et al. JAC Antimicrob Resist 2021;3.7. Antimicrobial Resistance Surveillance Program (ASP). Data Summary Report 2021. Available at: https://www.arsp.com.ph. Accessed February 27, 2023.8. Karaiskos I, et al. Front Public Health 2019;7:151.
PH-ZER-00234 Nov/2023