Dr Kate McCarthy UQCCR

Dr Kate McCarthy UQCCR

Am J Med 1958

1944 Streptmycin 1948 Chlrtetracycline 1949 Chlramphenicl 1949 Nemycin 1955 Tetracycline 1958 Clistin 1964 Gentamicin 1967 Carbenicillin 1973 Fsfmycin 1975 Tbramycin 1975 Ticarcillin 1976 Amikacin 1980 Ceftaxime 1980 Piperacillin 1983 Ceftazidime 1983 Nrflxacin 1985 Imipenem cilastin 1986 Aztrenam 1986 Ticarcillin clavulanic acid 1987 Ciprflxacin 1992 Piperacillin tazbactam 1993 Levflxacin 1994 Cefepime 2005 Dripenem

3rd leading gram negative pathgen islated frm patients with a nscmial BSI Vulnerable hst ICU admissin Haematlgical/Onclgical malignancy Hspital cntact Sepsis Pr prgnsis crude mrtality 38% - 50% Emerging categries f HCAI/CAI Increasing antimicrbial resistance wrldwide Evidence fr decreased and maintenance f virulence in MDR PA. MDR Significant risk factr fr 30 day mrtality Neutrpenia Immunsuppressin Invasive Prcedure Urinary catheter J, E et al.. Micrb Drug Resist 2011.; Jhnsn, et al. Transpl Infect Dis 2009.; Kang et al. CID 2003. Lee et al. Am J Emerg Med 2012; Mrata, et al. Antimicrb Agents Chemther 2012. Olivares et al, Envirnmental micrbilgy 2012. Tam et al, AAC 2010; Jhnsn et al. Transpl Infect Dis 2009

1. Des empirical therapy matter? 2. Shuld I be using cmbinatin empirical therapy? 3. What is the rle f antibitic infusins? 4. Is there a rle fr targeting ther virulence factrs f P. aeruginsa? 5. Are there any new drugs n the hrizn?

Gram negative bacteremia Kreger et al. American jurnal f medicine 1980 ICU patients with BSI Ibrahim et al. Chest 2000. Septic shck Kumar et al. Chest 2009. Pseudmnas aeruginsa bacteremia? Siegman-Igra et al, Int J Infect Dis 1998; Kang et al, CID 2003; Micek et al, AAC 2005; Ldise et al, AAC 2007; Osih et al, AAC 2007.

Retrspective chrt study Tertiary care university hspital Primary episde f nscmial bacteraemia, including plymicrbial infectins Apprpriate empiric antimicrbial rx WI 48 hrs f BC being taken One antibitic that is active in vitr Standard administratin Site f infectin based clinical examinatin + islatin frm the prtal f entry Lw risk sites = hepatbiliary, urinary tract and catheters High risk sites = pneumnia, nn hepatbiliary tract infectin, unknwn fcus 30 day mrtality Infectin 2011 202 patients Mean age 55, male Slid tumurs, haematlgical malignancy and liver disease Resistance rates ceftazidime 36.6%, P/T 22.3%, imipenem. 22.8%, ciprflxacin 22.8%, aminglycside 23.8% and MDR 17.8%. 39.6% received inapprpriate empirical therapy

Neutrpenic patients Chel-In Kang et al, CID 2003. Sepsis r septic shck RR1.8 (.051) Schechner et al, Diagn Micrbil Infect Dis 2011.

Ldise et al, AAC 2007.

Bdey et al. Arch Intern Med 1985

30 day mrtality OR 220.5 p=.009 CID 2008

Histrically up t the late 1960 s mst infectins were fatal. Gentamicin 1964 Carbenicillin 1967 Challenged by ceftazidime, imipenem cilastin, ciprflxacin shwn t be effective single agents even in neutrpenic patients Cmbinatin carbenicillin + gentamicin was shw t be synergistic in vitr. Higher survival rates than either drug alne in experimental infectins in animal mdels. Human studies invlving primarily cancer patients (+/- neutrpenia) favured cmbinatin therapy. Klastersky et al, Cancer 1973, Schimpff et al, NEJM 1978 Later studies - betalactam + amingycside/quinlne. Varying results Hilf et al, Am J Med1989, Vidal et al, Arch Intern Med 1996, Leibvici et al, AAC 1997, Siegman-Igra Int J Infect Dis1998, Chatziniklau et al, Arch Int Med 2000, Chamt et al, AAC 2003, Micek et al, AAC 2005, Bwers et al, AAC, 2013 Standard f care

Greater likelihd f achieving apprpriate empirical therapy in the setting f drug resistance Peleg et al, NEJM. 2010 Antimicrbial resistance als results in delayed apprpriate therapy thus ptentially suggesting a benefit fr carefully chsen cmbinatin therapy. Ldise et al, AAC 2007;Tam et al, AAC 2010. Initial antimicrbial treatment was administered statistically mre ften amng patients receiving empirical cmbinatin antimicrbial treatment than empirical mntherapy Micek et al, AAC 2005

Drug synergy Published testing mdels d nt replicate well in viv (Traugtt et al, Pharmactherapy 2011) Recent studies utilising E tests Dripenem + amikacin r clistin r levflxacin. (He et al, Diagn Micrbil Infect Dis 2012) Merpenem and levflxacin in a PD mdel (Luie et al, AAC 2010) Clinical data lacking. Survival benefit in septic shck Early cmbinatin therapy is assciated with decreased mrtality in septic shck. (Kumar et al, Crit Care Med 2010) Preventin f the develpment f resistance In the muse mdel preventin f the develpment f resistance has been shwn with a cmbinatin f tbramycin and cefepime, and merpenem and levflxacin (Luie et al, AAC 2010) The theretical advantage f minimising emergence f resistant islates has nt been cnfirmed cnclusively in clinical studies

Ptential drug txicity ttxicity, renal impairment Increased csts Drug Resistance Expsure t any anti pseudmnal antibitic as mntherapy assciated with an increased risk f subsequent resistance t itself (Bffi EL Amari,Chamt et al 2001) Several studies have suggested that the use f flurquinlnes may select fr islates t becme resistant t all r almst all beta lactam antibitics, aminglycsides and quinlnes. (J, E et al.. Micrb Drug Resist 2011. Paramythitu et al, CID 2004. Taccnelli et al, Emerg Infect Dis 2002.) Superinfectin

Cmparisn f studies same inherent prblems as with empirical therapy Mrtality benefit f definitive treatment with effective antimicrbial therapy has been shwn mre cnsistently Siegman Igra et al. J Infect Dis 1988. Vidal et al, Arch Intern Med 1996. Chatziniklau et al. Arch Intern Med 2000. Chamt et al. AAC 2003. Adequate definitive cmbinatin therapy did nt imprve the survival rate (30days) cmpared t the prvisin f adequate definitive mntherapy Chamt et al, AAC 2003. Treatment success was higher with cmbinatin therapy as ppsed t beta lactam mntherapy but this was nt statistically significant. Blizits et al PLOSne,2011.

Cntinuus infusin r intermittent dsing f antibitics with extended infusin extensively studied fr 15 years. Clinical data appears t supprt this cncept in that aggressive dsing f piperacillin tazbactam imprves utcmes fr critically ill patients with P. aeruginsa BSI Ldise et al, CID 2007. Extended infusin cefepime reduces mrtality in patients with a P. aeruginsa bacteremia r pneumnia (MIC range f islates majrity 0.7 t 8, 16,32mg/L) (Bauer et al, AAC, 2013) Length f stay Csts Overall mrtality Higher dses and lnger infusin times better resistance suppressin f bacteria. Hwever cntrl ultimately lst. Luie et al,aac 2010.

(2013)

MC-1 (siderphre cnjugated mncarbam) Manse based LecB inhibitrs Niclsamide Nitrxline Antipseudmnal phage trials Flagella vaccine (phase 2 trial) Fthergill et al, Expert rev anti infect ther, 2012 Sbke et al, AAC 2010 Imperi et al, AAC, 2013 Hauck et al, ACS chemical bilgy, 2013 Tmaras et al, AAC 2013 Mnclnal antibdies against PcrV prtein (phase 2 trial)

Retrspective chrt study, tertiary hspital 149 patients with either mnmicrbial P. aeruginsa r A. baumannii bacteraemia Carbapenem resistance 43% f islates Adequate antimicrbial therapy Identified rganism being susceptible t at least ne f the antimicrbial agents administered within 3 days after nset f bacteremia Infect Chemther, 2013

Ceftlzane (CXA-101) Craif et al, AAC 2013 Ceftazidime-Avibactam (NXL104) Crandn et al, AAC 2012 Imipenem + MK7655 Nvel gyrase inhibitrs Tessire et al, AAC 2013

P. aeruginsa BSI is an infectin with a high mrbidity and mrtality Adequate empirical therapy is mre critical in defined patient grups High risk grups f infectin, febrile neutrpenia, sepsis r septic shck Adequate definitive therapy imprves utcmes Cmbinatin empirical therapy has nt cnsistently shwn a benefit apart frm the setting f septic shck Adjunctive therapy targeting virulence may becme a clinical reality Prspective studies are needed