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Digging up the roots of HAP and VAP: Tailored strategy against MDR pathogens

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Professor Mathias W. Pletz

Chair at the Institute for Infectious Diseases and Infection Control,
Jena University Hospital,
Jena, Germany

In a recent webinar co-organized by the Hong Kong Thoracic Society and the CHEST Delegation Hong Kong and Macau, Professor Mathias W. Pletz delivered a presentation on fighting hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) from its origin. Apart from discussing multidrug-resistant (MDR) pathogens associated with HAP and VAP, the empiric treatment, and the mechanism of resistance of MDR pathogens, Prof. Pletz also expounded on the strategy against MDR pathogens, using international guidelines as frameworks.

Source and burden of HAP/VAP

Pseudomonas aeruginosa (P. aeruginosa) is a typical pathogen of HAP. Prof. Pletz clarify that hospital-acquired infections could be divided into 3 sub-entities, namely HAP, ventilated HAP (vHAP) and VAP. An evidence-based study analyzed HAP/VAP dataset from a Spain prospective, observational study including 421 episodes of suspected intensive care unit (ICU)-acquired bacterial pneumonia.1 Acute physiology and chronic health evaluation (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores at onset among patients with vHAP were higher than those with HAP and VAP.1 There was also a statistically significant difference in all-cause mortality at 28 days: 21.7% for HAP vs. 39.5%for vHAP vs. 27.0% for VAP.1 Prof. Pletz concluded that patients with VAP are at risk of even higher mortality rates than patients with VAP.1

4 clinical laboratories in Hong Kong participated in the Study for MonitoringAntimicrobial Resistance Trends (SMART) global surveillance program, a total of 1,524 isolates from the patients with lower respiratory tract infection (RTI), intra-abdominal infection (IAI), urinary tract infection (UTI)or bloodstream infection (BSI) were collected in Hong Kong in 2017-2019.2 P. aeruginosa, Klebsiella pneumoniae (K. pneumoniae) and Escherichia Coli (E. coli) accounted for 74% among gram-negative isolates of all infections collected in the study (figure 1).2 An additional SMART study conducted in seven Asian countries from 2017-2019 involving 3,288 isolates from patients in ICU showed that the distribution of GN isolates collected from ICU patients with lower RTIs are as follows: K. pneumoniae (27.3%); Acinetobacter baumannii (A. Baumannii) (23.7%), P. aeruginosa (23.1%); E. coli (5.2%), accounting for approximately 79%of the total distribution of GN isolates from ICU patients.3

Empiric combination therapy for HAP/VAP

MDR pathogens are complicated to treat empirically and can lead to misuse of antimicrobial therapy.4 Prof. Pletz stated that the pathogen spectrum of patients with the MDR risk factors are methicillin-resistant Staphylococcus aureus (MRSA), ESBL-bildande Enterobacteriaceae, P. aeruginosa, A. baumannii, and Stenotrophomonas maltophilia (S. maltophilia).

The risk factors of MDR bacteria in HAP/VAP include antimicrobial therapy in the last 90 days, hospitalization ≥5 days (late onset), colonization by multi-resistant GN (MRGN) or MRSA, prior medical care in Southern and Eastern Europe, Africa, Middle East, Asia, and septic shock or sepsis-associated organ dysfunction.4 The additional risk factors of P. aeruginosa include structural lung disease [i.e., advanced chronic obstructive pulmonary disease (COPD), bronchiectasis] and known colonization of P. aeruginosa.4

De-escalation & re-evaluation of combination therapy

Prof. Pletz stated that unnecessary antibiotic combination not only cause resistance, it may also harm the patient, thus, therapy re-evaluations should be implemented.5 If an antibiotic regimen works, a de-escalation should be taken 48-72 hours after the start of therapy based on the results of the re-evaluation. In case of clinical improvement but without evidence of respiratory pathogen, de-escalation to monotherapy should be done, with β-lactam antibiotic being the first choice, followed by the second choice of fluoroquinolone (contained in the initial combination). If a respiratory pathogen is detected, then switching to a targeted narrow-spectrum monotherapy should be prescribed.An initial calculated therapy against MRSA should be terminated, if such a pathogen has not been detected.

The optimal duration of antimicrobial therapy for VAP Is not well known.6 There has been a question of whether 8 days is as effective as 15 days of treatment.6 A multicenter, prospective, randomized, double-blind French trial with 401 ICU patients with VAP and adequate therapy showed that patients treated at 8 or 15 days had no significant difference in mortality (18.8% vs. 17.2%; 90% CI: -3.7%-6.9%), and recurrent infections (28.9% vs. 26.0%; 90% CI: -3.2%-9.1%), but had more mean [standard deviation (SD)] antibiotic-free days [13.1 (17.4) vs. 8.7 (5.2) days, p<0.001].6 Additionally, patients with VAP caused by non-fermenting GN bacilli (NFGNB), which includes P. aeruginosa, had a significantly higher infection-recurrence rate in 8 days treatment, compared with patients who received 15 days of treatment (40.6% vs. 25.4%; 90% CI: 3.9%-26.6%).6 Among those patients who developed recurrent infections, MDR pathogens appeared less frequently in patients who had received 8 days of treatment, when compared with patients received 15 days treatment (42.1% vs. 62.0%, p=0.04).6 Prof. Pletz summarized the results of the comparable clinical efficacy (figure 2).

International guidelines [European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESCIM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID)] recommend 7-8 days of treatment therapy in those who respond well to antibiotic treatments, except for the patient with empyema, abscess, cystic fibrosis (CF), immunosuppression-neutropenia, and stem cell transplant.7

Mechanism of resistance of MDR pathogens

Prof. Pletz shared that there are hundreds of different mechanisms of resistance, and they can all be grouped into 4 categories, including antibiotics degrading enzymes (e.g., beta-lactamases), porin loss, efflux pumps and alteration of target molecules, while the carbapenem-resistant (CR)-GN bacteria use the beta-lactamases, porin-loss and efflux pumps mechanisms simultaneously, to some extent.

There are 2 main mechanisms of carbapenem resistance in GN bacteria.8 The first mechanism often used by CR-P. aeruginosa is porin loss, which can be developed during treatment, plus an extended spectrum β-lactamase (ESBL)/ampC β-lactamase (AmpC βLs).8 It lowers the concentration of carbapenems in the periplasmic space.8 The second mechanism, often observed in enterobacteria, is carbapenemase which will not evolve during treatment and is usually selected by horizontal gene transfer.8 However, Prof. Pletz clarify that the 2 mechanisms are not utilized by the same extent by different GN species, Prof. Pletz also mentioned a German data, which pointed out carbapenemases are always in acinetobacter, but less frequently in enterobacteria and rare in pseudomonas.9

Old and new strategies for MDR pathogens

In the fight against CR-GN bacteria, the old standard approach is a colistin-based combination therapy. An Italian multicenter retrospective cohort study including 125 patients with bloodstream infections caused by K. pneumoniae carbapenemases- (KPC-) producing K. pneumoniae showed that combination therapy had a significantly lower mortality rate as compared with monotherapy (34% vs. 54%, respectively, p=0.02).10 A combination of tigecycline, colistin and meropenem was the best formulation evaluated.10 However, Prof. Pletz highlighted that combination therapy for patients may lead to an increase in toxicity, such as colistin, a polymyxin that associated with a higher risk of nephrotoxicity compared with non-polymyxin-based therapy.11

A more recent approach for the MDR pathogen treatment is ceftolozane/tazobactam.12 Ceftolozane is stable against AmpC, porin loss and efflux because ceftolozane is not a substrate of the overexpression of MexAB/OprM efflux pumps.12,13 And ceftolozane/tazobactam can also decrease the expression of oprD and overexpression of mexB since it does not enter the bacterial cells through OprD.14,15

However, there is “no one size fits all”. Ceftolozane/tazobactam is not effective against gram-positive bacteria.16 Tazobactam protects against hydrolysis by ESBL class A and is often effective for CR-P. aeruginosa but not for carbapenemase.16 Being granted approval for complicated intra-abdominal infections (IAIs) in combination with metronidazole and complicated urinary tract infections (UTIs) in Hong Kong in 2017, ceftolozane/tazobactam has also been approved in Europe for HAP/VAP/vHAP and launched for HAP/VAP indication in Hong Kong in 2020.2,16

The aforementioned SMART trial (Hong Kong) showed the in vitro activity of ceftolozane/tazobactam against nosocomial GN bacteria.2 Overall, >96% of clinical isolates of P. aeruginosa, K. pneumoniae, and E. coli collected in Hong Kong in 2017-2019 were susceptible to ceftolozane/tazobactam.2 As tazobactam can inhibit the Cefotaximase-Munich (CTX-M) type ESBL in CR-P. aeruginosa, ceftolozane/tazobactam is active against most isolates of P. aeruginosa resistant to other antibiotics (figure 3).2

ASPECT-NP is a randomized, controlled, double-blind, phase 3 non-inferiority trial conducted between 2015-2018 including 726 patients who were aged ≥18 years, were undergoing mechanical ventilation, and had nosocomial pneumonia (either VAP or vHAP).17 Patients were randomly assigned to receive either 3g ceftolozane/ tazobactam or 1g meropenem intravenous (IV) every 8 hours for 8-14 days.17 Primary endpoint was 28-day all-cause mortality assessed in the intention-to-treat population.17 The overall 28-day all-cause mortality was 24% in the ceftolozane/tazobactam group and 25.3% in the meropenem group [weighted proportional difference 1.1% (95% CI: -5.1 to 7.4)], thus ceftolozane/tazobactam was non-inferior to meropenem.17 However the subgroup of previous unsuccessful antibacterial therapy for current episode of nosocomial pneumonia showed favorable response for the ceftolozane/tazobactam group.17 Prof. Pletz also highlighted that the overall cure rate of ceftolozane/tazobactam was non-inferior to meropenem (54.4% vs 53.3%) with a slight trend in favor of ceftolozane/tazobactam.17

Prof. Pletz presented another United States (US) registry study to demonstrate how ceftolozane/tazobactam works clinically for MDR P. aeruginosa.18 This multicenter, retrospective observational study in the US included 205 adult patients who were treated with ceftolozane/tazobactam for MDR P. aeruginosa infections from any source for at least 24 hours between December 2014 and February 2018.18 Primary outcome was a composite of 30-day and inpatient all-cause mortality.18 Overall 30-day or inpatient mortality occurred in 19% of patients.18 Clinical success was seen in 73.7% of patients, and microbiological cure occurred in 70.7% of patients.18 Further analysis showed that initiation of ceftolozane/tazobactam within 4 days was a significant predictor of survival, clinical, and microbiological success. It is found that the mortality rate increased by almost 6-fold when ceftolozane/tazobactam started >4 days after culture.18 In contrast, the clinical success rate and microbiological cure rate increased by 3-fold when ceftolozane/tazobactam started ≤4 days after culture.18 Prof. Pletz suggested that a switch should be as early as possible to improve patient outcomes.18 Infectious Disease Society of America (IDSA) recommended ceftolozane/ tazobactam as monotherapy for the treatment of infections caused by difficult-to-treat (DTR)-P. aeruginosa.19

In general, nosocomial pneumonia (HAP and VAP) caused by MDR pathogens is associated with a high mortality rate.17 Carbapenem-resistance can be conferred by carbapenemase, porin loss, AmpC, and efflux. Ceftolozane/tazobactam is one of the guideline recommended antibiotic for DTR-P. aeruginosa and enterobacteria without a carbapenemase. Nevertheless, appropriate treatment should be adopted as early as possible to improve the patient outcomes.

 

Selected Safety Information of ZERBAXA

Indications: Zerbaxa is indicated for the treatment of the following infections in adults: Complicated intra-abdominal infections; Complicated urinary tract infections, including pyelonephritis; Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) Consideration should be given to official guidance on the appropriate use of antibacterial agents. Contraindications: ZERBAXA is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane and tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class. Precautions: Decreased Efficacy in Patients with Baseline Creatinine Clearance of 30 to 50 mL/min: In a subgroup analysis of a Phase 3 cIAI trial, clinical cure rates were lower in patients with baseline CrCl of 30 to 50 mL/min compared to those with CrCl greater than 50 mL/min (below Table). The reduction in clinical cure rates was more marked in the ZERBAXA plus metronidazole arm compared to the

Hypersensitivity reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before initiating therapy with ZERBAXA, make careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or other beta-lactams. If this product is to be given to a patient with a cephalosporin, penicillin, or other beta-lactam allergy, exercise caution because cross sensitivity has been established. If an anaphylactic reaction to ZERBAXA occurs, discontinue the drug and institute appropriate therapy. Clostridium difficile-associated diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ZERBAXA, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is confirmed, discontinue antibacterials not directed against C. difficile, if possible. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. Development of Drug-Resistant Bacteria: Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria. Adverse Events: Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis The most common adverse reactions (5% or greater in either indication) occurring in patients receiving ZERBAXA were nausea, diarrhea, headache, and pyrexia. Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP). The most common adverse reactions (2% or greater) occurring in patients receiving ZERBAXA were hepatic transaminase increased1, renal impairment/renal failure2, diarrhea, intracranial hemorrhage3, vomiting, clostridium difficile colitis4.

1Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hypertransaminasaemia, liver function test abnormal.

2 Includes acute renal failure, anuria, azotemia, oliguria, prerenal failure, renal failure, renal impairment.

3Includes cerebellar hemorrhage, cerebral hematoma, cerebral hemorrhage, hemorrhage intracranial, hemorrhagic stroke, hemorrhagic transformation stroke, intraventricular hemorrhage, subarachnoid hemorrhage, subdural hematoma.

4Includes Clostridium difficile colitis, Clostridium difficile infection, Clostridium test positive.
Laboratory Values In clinical trials, there was no evidence of hemolysis in patients who developed a positive direct Coombs test in any treatment group.
Before prescribing, please consult the full Prescribing Information.

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