Pharmacokinetics and safety of panobacumab: specific adjunctive immunotherapy in critical patients with nosocomial Pseudomonas aeruginosa O11 pneumonia

Lü, Qin; Rouby, Jean‐Jacques; Laterre, Pierre‐François; Eggimann, Philippe; Dugard, Anthony; Giamarellos‐Bourboulis, Evangelos J.; Mercier, Emanuelle; Garbino, Jorge; Luyt, Charles‐Édouard; Chastre, Jean; Georgescu-Kyburz, Violetta; Rudolf, Michael P.; Gafner, Verena; Lazar, Hedvika; Koch, H; Perez, Antonio; Krämer, Stefanie-Dorothea; Tamm, Michael

doi:10.1093/jac/dkr046

Cited by 58 publications

(42 citation statements)

References 22 publications

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“…Among the drug-resistant bacterial ESKAPE pathogens, P. aeruginosa may present the greatest challenge because of its large genome coding capacity and complex regulatory networks, allowing the bacterium to phenotypically adapt to environmental pressures and to form persistent biofilm communities. Multiple P. aeruginosa proteins and carbohydrates have been explored individually as antibody targets in the laboratory, few of which are currently under clinical evaluation (9,38).…”

Section: Discussionmentioning

confidence: 99%

A multifunctional bispecific antibody protects against Pseudomonas aeruginosa

DiGiandomenico¹,

Keller²,

Gao³

et al. 2014

Sci. Transl. Med.

227

233

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Widespread drug resistance due to empiric use of broad-spectrum antibiotics has stimulated development of bacteria-specific strategies for prophylaxis and therapy based on modern monoclonal antibody (mAb) technologies. However, single-mechanism mAb approaches have not provided adequate protective activity in the clinic. We constructed multifunctional bispecific antibodies, each conferring three mechanisms of action against the bacterial pathogen Pseudomonas aeruginosa by targeting the serotype-independent type III secretion system (injectisome) virulence factor PcrV and persistence factor Psl exopolysaccharide. A new bispecific antibody platform, BiS4, exhibited superior synergistic protection against P. aeruginosa-induced murine pneumonia compared to parent mAb combinations or other available bispecific antibody structures. BiS4αPa was protective in several mouse infection models against disparate P. aeruginosa strains and unexpectedly further synergized with multiple antibiotic classes even against drug-resistant clinical isolates. In addition to resulting in a multimechanistic clinical candidate (MEDI3902) for the prevention or treatment of P. aeruginosa infections, these antibody studies suggest that multifunctional antibody approaches may be a promising platform for targeting other antibiotic-resistant bacterial pathogens.

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Section: Discussionmentioning

confidence: 99%

A multifunctional bispecific antibody protects against Pseudomonas aeruginosa

DiGiandomenico¹,

Keller²,

Gao³

et al. 2014

Sci. Transl. Med.

227

233

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show abstract

“…Because it was a retrospective epidemiological study, no informed consent was needed. Written informed consent was obtained in only 14 patients with serotype O11 HAP or VAP when they were included in a phase IIa study [19]. …”

Section: Methodsmentioning

confidence: 99%

Pseudomonas aeruginosa serotypes in nosocomial pneumonia: prevalence and clinical outcomes

et al. 2014

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IntroductionPseudomonas aeruginosa frequently causes nosocomial pneumonia and is associated with poor outcome. The purpose of this study was to assess the prevalence and clinical outcome of nosocomial pneumonia caused by serotype-specific P. aeruginosa in critically ill patients under appropriate antimicrobial therapy management.MethodsA retrospective, non-interventional epidemiological multicenter cohort study involving 143 patients with confirmed nosocomial pneumonia caused by P. aeruginosa. Patients were analyzed for a period of 30 days from time of nosocomial pneumonia onset. Fourteen patients fulfilling the same criteria from a phase IIa studyconducted at the same time/centers were included in the prevalence calculations but not in the clinical outcome analysis.ResultsThe prevalence of serotypes was: O6 (29%), O11 (23%), O10 (10%), O2 (9%), and O1 (8%). Serotypes with a prevalence of less than 5% were found in 13% of patients, 8% were classified as not typeable. Across all serotypes, 19% mortality, 70% clinical resolution, 11% clinical continuation, and 5% clinical recurrence were recorded. Age and higher APACHE II (Acute Physiology and Chronic Health Evaluation II) were predictive risk factors associated with probability of death and lower clinical resolution for P. aeruginosa nosocomial pneumonia. Mortality tends to be higher with O1 (40%) and lower with O2 (0%); clinical resolution tends to be better with O2 (82%) compared to other serotypes. Persisting pneumonia with O6 and O11 was, respectively, 8% and 21%; clinical resolution with O6 and O11 was, respectively, 75% and 57%.ConclusionsIn P. aeruginosa nosocomial pneumonia, the most prevalent serotypes were O6 and O11. Further studies including larger group sizes are needed to correlate clinical outcome with virulence factors of P. aeruginosa in patients with nosocomial pneumonia caused by various serotypes; and to compare O6 and O11, the two serotypes most frequently encountered in critically ill patients.

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“…More recently [139], a multicenter, open-label Phase 2a study of this vaccine was performed (clinicaltrials.gov NCT00851435). Three doses of KBPA101 were given every 72 hours to a total of 18 patients with confirmed nosocomial pneumonia (15 with VAP and 3 with hospital-acquired pneumonia) due to serotype O11 P. aeruginosa .…”

Section: Anti-o11 Mabmentioning

confidence: 99%

“…Among the 13 patients treated per protocol, 11 resolved the infection and 2 had a recurrence. The authors of this small study declared the safety of this approach and the potential clinical efficacy [139]. While P. aeruginosa serotype O11 is prominent in infection, there are a total of ~10 serotypes associated with disease [87].…”

Section: Anti-o11 Mabmentioning

confidence: 99%

Vaccines forPseudomonas aeruginosa: a long and winding road

Priebe¹,

Goldberg²

2014

Expert Review of Vaccines

121

106

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Summary Despite the recognition of Pseudomonas aeruginosa is an opportunistic pathogen, no vaccine against this bacteria have come to market. This review describes the current state-of-the-art in vaccinology for this bacterium. This includes a discussion of those at risk for infection, the types of vaccines and the approaches for empirical and targeted antigen selection under development, as well as a perspective on where the field should go. In addition, the challenges in developing a vaccine for those individuals at risk are discussed.

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Pharmacokinetics and safety of panobacumab: specific adjunctive immunotherapy in critical patients with nosocomial Pseudomonas aeruginosa O11 pneumonia

Cited by 58 publications

References 22 publications

A multifunctional bispecific antibody protects against Pseudomonas aeruginosa

A multifunctional bispecific antibody protects against Pseudomonas aeruginosa

Pseudomonas aeruginosa serotypes in nosocomial pneumonia: prevalence and clinical outcomes

Vaccines forPseudomonas aeruginosa: a long and winding road

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