Dr R N CHUGH Head, Dptt. Of Medicine Safdarjung Hospital Professor UCMS New Delhi Personal Physician to late Prime Minister Shri LAL BAHADUR SHASTRI

ICU INFECTIONS Dr A P Misra Sr. Consultant Fortis Flt. Lt. Rajan Dhall Hospital, New Delhi

ICU---EPICENTRE of Infections Extremely vulnerable population Multiple procedure & Devices Drugs , sedatives, muscle relaxants etc. Highest rates of Nosocomial Infections ( 20-30% ) Prolonged stay, ↑ cost ↑ morbidity & mortality India Overcrowding , Understaffing, ↓resources, lack of data , not adhering to infection control program

PLAN of TALK GLOBAL SCENARIO INDIAN OVERVIEW COMMON PATHOGENS COMMON INFECTIONS PREVENTION & CONTROL

International Study of the Prevalence & Outcome of Infections in ICUs (EPIC II) 14414 pt., 1265 ICUs, 75 countries 1 day, prospect1ive, May 8, 2007 51% infected, 70% culture + 64% respiratory Gram – 62%, Gram + 47%, Fungi 19% Staph. aureus, Acinetobacter, Pseudomonas, Candida ICU mortality 25% vs 11%, In-hospital mortality 33% vs 15% Pts. With longer stay prior to study day- higher infection rate Vincent et al JAMA2009

ICU Infections- Indian studies Apollo Hospital Chennai, Jan-July 2009 401 pts. 100 (25%) + cultures 60% Gram- E coli commonest in blood & urine Pseudomonas in respiratory secretions CONS most common Gram + 49% E coli ESBL+, 5% carbapenem resistant 35% Pseudomonas & 92% Acinetobacter-MDR 50% Staphylococcus –MRSA 31% of culture + died in ICU Ravi et al ,Am J Inf Dis 2013 Ravi et al Am J Inf Dis 2013

679 pt. 166 pt. had 198 device associated infection UTI 10.75% 9.08/1000 Pseudomonas 35.7% CLA-BSI 13.50% 13.86/1000 Klebsiella 29.2% VAP 6.15% 6.04/1000 Acinetobacter 41.3% Mortality 48.7% vs 31.5% Datta et al, Ind J Anaesth. 2014

Important Pathogens in ICUs Acinetobacter Pseudomonas E. coli Klebsiella MRSA Enterococcus Candida Clostridium difficile

Acinetobacter in ICUs in different geographical zones N AMERICA 3.7% W EUROPE 5.6% E EUROPE 17.1% OCEANIA 4.4% S AMERICA 13.8% AFRICA 14.8% ASIA 19.2% (EPIC II), JAMA 2009

Acinetobacter Commonest Respiratory pathogens in ICU , Late VAP, BSI, Wound infection, Meningitis Wattal et al: Acinetobacter 267 (32.16%) Our data : Acinetobacter 112 (25.8%) India Carbapenem sesitivity Gopalkrishnan 30% Wattal 20% Subbalaxmi 25-30% Patwardhan et al >90% MDR, 1-4 Plasmids JAPI 2010 , Ind J Med Res 2008

Acinetobacter baumannii

Acinetobacter problems RESISTANCE to ANTIBIOTICS RESISTANCE to DESICCATION mean survival time 27 d ( 21-33 d) Bio-film formation RESISTANCE to DISINFECTANTS Propanol , Macetronium , Triclasan , Ethyl sulfate, Chlorhexidine , Polyvinylpyrrolidone –iodine CONTACT TIME 30 s , PROPER DILUTION

Acinetobacter menace Carbapenem resistance in Acinetobacter a serious threat CDC 2013 2-5 times that seen in Pseudomonas & Klebsiella ↑ risk of Inappropriate Initial Antibiotic Therapy IIAT in Sepsis & Pneumonia -- 2-4 fold ↑ in death Escalation of Tt -- fails to mitigate ↑ risk BMC Inf Dis 2014, Chest 2008, Inf Con Hosp Epidemiol. 2013

Resistance mechanisms Amp C Cephalosporinase chromosomally mediated Oxacillinases (Ambler Class D) bla OXA 23 , 58 → Carbapenems Metallo β lactamases (Class B) IMP, VIM, SIM → Carbapenems first discovered in Edinburgh 1985 Non-enzymatic change in outer membrane proteins

Resistance mechanisms (contd.) - Multi-drug Efflux Pumps AdeABC - Alteration in Affinity/ Expression of PBP Aminoglycoside modifying enzymes ↓ binding to Lipopolysaccharide ( LPS) target site Polymyxins Other ESBLs VEB 1 , PER 1, PER 2 , TEM 92, 116 SHV 16, CTX M2 , 43 MDR / XDR / PDR

Acinetobacter & Carbapenems 4 yr. surveillance of A. baumannii resistance pattern in China 2008-2011 Imipenem 14.8% → 90.8% Meropenem 23.3% → 91% J Thor. Dis. 2013, Aug Total Carbapenem consumption is significantly correlated with resistance to IMP, MRP, β lactam, Fluoroquinolones, Aminoglycosides J Clin Pharmacol. 2013 Doripenem Oxa 58 Discordance Infusion time 3 hr

POLYMYXINS Discovered in 1947 Target lipopolysaccharide of outer membrane of gram – bacte. Nebulized colistin Kwa et al 86 % favourable, 5% bronchospasm Berlana et al 71 pt. Favourable, microbiological eradication in all pt. receiving nebulized colistin 1 death after premixed CMS , not FDA approved USE CMS IMMEDIATELY AFTER PREPARATION Predose bronchodilation 1-3 million units in divided doses / d ( max. 6 mu/d)

SULBACTAM etc. Intrinsic activity against Acinetobacter Wood et al A. baumannii VAP, Retrospective Imipenem+ cilastin vs. Ampicillin –Sulbctam 83 % vs 93% Equivalent efficacy in BSI Meningitis mixed results CSF penetration 2-32% of serum conc. Peak levels after 1 gm. IV Dose 6 gm/ d in divided doses , Max. 12 gm/d RIFAMPIN , COMBINATION CHEMOTHERAPY

Klebsiella Global prevalence N. America 9%, W. Europe 9.7%, Oceania 11.8% S. America 16.1%, Africa 18.5%, Asia 20.7%, E. Europe 21.3% JAMA 2009 K P C growing threat INDIA Wattal et al 80.6% Amp C Carbapenem resistance 51% Tigecycline resistance 61% Gopalkrishnan et al Cefperazone-sulbactam sensitive 70% Piperacillin-tazobactam 60% Carbapenem resistance ↑ 0% in 2005 to 34% in 2008 Subbalaxmi et al CPZ-SB & Piperacillin-tazobactam sensitive 61%

E coli Global prevalence W. Europe 17.1%, E. Europe 14.8%, S. America 14.3%, N. America 14.2%, Oceania 13.2%, Africa 11.1%, Asia 16.7% INDIA SMART study- 79% ESBL producer Gopalkrishnan et al 65% CPZ-SB 80% & PP-TZ 70% sensitivity 5-25% combined resistance to Cephalosporins, Quinolones & Aminoglycosides in Europe Some CTX-M ESBL may have Carbapenem resistance

Pseudomonas Global prevalence W.Europe 17.1%, E.Europe28.0%, S.America 26.3%, N. America 12.9%, Oceania 14.7%, Africa 14.8%, Asia 28.7% INDIA Wattal et al 20% in respiratory isolates Gopalkrishnan et al Carbapenem sensitive 50-70% Subbalaxmi et al Carbapenem sensitivity ↓ 64% in 2007 to 35% in 2008 Patel et al Carbapenem sensitivity < 70%

Staphylococcus aureus & MRSA Global prevalence W.Europe 19.6% (8.7%), E.Europe 21.6% (10.4%), S.America 19.2% (11.0%), N.America 26.9% (17.5%), Oceania 27.5% (9.3%), Africa 29.6% (20.4%), Asia 16.1% (10.0%) INDIA- INSAR Isolation Rate of MRSA OPD IPD ICU Year 28 42 43 2008 27 49 47 2009 26310 isolates MRSA 41% Ind J Med Res 2013 Feb

Staph. aureus & MRSA, Enterococcus Glycopeptide remain mainstay of Treatment Vancomycin intermediate strains in US Report of VRSA in India LINEZOLID , TIGECYCLINE & DAPTOMYCIN Coagulase negative Staph. aureus ( CONS) - most common CLA-BSI -high resistance to oxacillin & Clindamycin - colonizers / contaminants Enterococcus -- E. fecalis , E. fecium VRE

Healthcare Associated Pneumonia (HAP) & Ventilator Associated Pneumonia (VAP) Prevalence HAP 10-65%, VAP 25% Mehta et al VAP 10.46/1000 ventilated days Chawla et al HAP 53.9% , VAP 8.95/1000 ventilator days Joseph et al H influenzae, S pneumoniae, S aureus, Enterobacteriaceae---EARLY VAP Acinetobacter, Pseudomonas ---LATE VAP Clinical criteria to diagnose VAP Sensitivity 69% , Specificity 75% J Hosp. Inf. 2007 Oct, Thorax 1999

Clinical Pulmonary Infection Score System

PROMPT, APPROPRIATE ANTIBIOTIC ↓ MORTALITY INITIAL Choice of COMBINATION ANTIBIOTICS for HAP/ VAP MDR Pathogens Antibiotics Pseudomonas Acinetobacter Klebsiella 3rd/4th generation Cephalosporins + β lactam inhibitors Or Piperacillin + Tazobactum +Ciprofloxacin / Levofloxacin Imipenem / Meropenem Amikacin / Tobramycin / Gentamycin plus MRSA Linezolid / Vancomycin

HAP & VAP (contd.) Diagnosis-quantitative culture BAL/pBAL/PSB/TBA Biomarkers- CRP, PCT, Strem-1 Margarita R Carbrera-Cancio ↓ VAP rates from 6.18/1000 in 1998 to 0.44/1000 in 2010 Protocol- ↑ of head by 30⁰, twice weekly body bath with chlorhexidine, mupirocine on nares, hand washing, tracheostomy by day 7, staff adherence, infection control campaign Respiratory Care 2012 June

Blood Stream Infection 41000 Central Line Associated Blood Stream Infections (CLABSI) in US every year Mehta et al 7.92/1000 catheter days→ 4% excess mortality in ICUs in India Chopdekar et al 9.26/1000 c.d. ( 27.02/1000 c.d .in NICU) Incidence of BSI ↑ duration of catheterization, no. of ports, no. of manipulations Prevention Training , Avoid femoral vein for CVC, Use of CVC with minimum no. of ports, Maximal sterile barrier precautions J Hosp. Inf. 2007 Oct, Ind J Med Microbiology 2011

Catheter Associated Urinary Tract Infection (CAUTI) Most common HAI NNIS 3.38/1000 patient days in ICU Mehta et al 1.21/1000 ↑ mortality of 11.6% Rosenthal et al 8.9/1000 in 55 ICUs in 8 developing countries Pathogens – E coli, Candida most common Prevention - Use only when necessary, Sterile techniques, Closed drainage, Remove as soon as possible, Silicone catheters Publ. Health Rep. 2007, J Hosp. Inf. 2007

Surgical Site Infection (SSI) NNIS 0.95/1000 patient days in 2002 accounted to 11% deaths Suchitra et al – 1125 surgeries, prospective - 12% SSI S. aureus (33%) & Enterococcus (33%) commonest MRSA & Gram – bacteria Elderly, Diabetics, Malnourished, obese, Immuno-compromised Prevention – Adequately treating pre-existent infections, Good anti-septic practices, Good diabetic control, Antibiotics before surgery Afr. J Microbiol. R. 2009 Pub Health Report 2007 Public Health Report 2007

Clostridium difficile Associated Diarrhea Diarrhea, pain in abdomen Complications- ileus, toxic megacolon Risk factors- previous exposure to various antibiotics, length of hospital stay, Age >64 yr Diagnosis –CD antigen A & B enzyme immunoassay –rapid, less sensitive PCR- more sensitive & specific Treatment – i/v Metronidazole , oral Vancomycin Fidoxamicin , Fecal transplant

Fungal infections Considerable increase Candida most common Wattal et al- 84.8% non-albicans Candida in ICU C tropicalis 18.3%, C albicans 13.2%, C haemulonii 9.5%, C glabrata 6.2%, C krusei 3.1% C albicans- sensitive to Fluconazole & Voriconazole C haemulonii sensitive to Capsofungin, resistant to Amphotericin B & Flucytosine C tropicalis & C glabrata resistant to Fluconazole JAPI 2010 Dec

Bacteria---Fungal Interactions ↑ incidence of Gram — infection after Anti-fungal Prophylaxis BMC Anesthesiology 2015 FARNESOL a Sesquiterpene molecule from C. albicans inhibits production of virulence factors in P. aeruginosa inhibits viability of A. baumannii in Bio-films can ↑ susceptibility of E. coli & S. aureus to common antibiotics Mol Microbiology 2007 Aspergillosmine A , natural fungal product can restore sensitivity of Carbapenens to NDM-1 & VIM-2 ( Metallo-betalactamases) Nature 2014

5 essential steps for Cross Transmission Organisms from patients→ inanimate objects Transfer to hands of Health Care Worker Surviving on HCW’s hands Inadequate hand washing or hand antisepsis Contact with another patient

Bacterial Survival time on Hands Acinetobacter 60 min E. coli 6 min ( mean) Klebsiella 2 min (mean) VRE 60 min Pseudomonas 30 min; 180 min in sputum Rotavirus 16% survive 20 min, 2% survive 60 min

Ignaz Semmelweiss 1847, Oliver Holmes, John Snow Discovered that healthcare provider s could transmit disease ↑ maternal mortality Obstetricians & Medical students vs. Midwives A Pathologist die of SEPSIS after getting a scalpel wound while performing Autopsy in a patient with PUERPERIAL SEPSIS, Pathologist’s clinical illness mimicked that of woman with Puerperial sepsis introduced CHLORINATED LIME Hand washing in clinics --- ↓ Maternal mortality rates from 9.92 % to 1.27% in 2 yr. HIS THEORIES WERE DISMISSED BY MOST OF MEDICAL ESTABLISHMENT till 1890 – Koch gave Germ Theory

Hand washing compliance rates Nurse 52% Physician 30% Nursing assistant 47% Other 38% Pittet et al Ann Int Med 1999

HAND WASHING with Soap & Water and not with Alcohol based cleaners Clostridium difficile - Spores resistant to Alcohol Nora & other related viruses

Prevention & Control of ICU Infections Hospital Infection Control Committee Surveillance of Infecting Organisms & Drug Resistance Antibiotic Policy Prescription Auditing Infection Control Measures Proper Use of Devices

THANK YOU

Respiratory samples- Fortis Jessa Ram data, 1-1-2011 to 31-12-2013 Total no. of samples—961 Culture + samples--- 434 No. % Acinetobacter 112 25.8 Klebsiella sp. 100 23.0 Pseudomonas sp. 90 20.7 E coli 52 11.9 Candida 80 18.4

Urine samples 1-1-2013 to 30-12-2013 Fortis Jessa Ram Hospital, New Delhi Total no. 108 Culture + 36 No. of organisms isolated 36 E coli 7 Klebsiella 7 Pseudomonas 2 Candida 18 Proteus 1 Enterococcus 1

Blood samples 1-1-2013 to 30-12-2013 Fortis Jessa Ram Hospital, New Delhi Total no. 101 Culture + 33 No. of organisms isolated 33 Staphylococcus aureus 4 Staphylococcus hemolyticus 4 Staphylococcus epidermidis 4 Staphylococcus hominis 4 E coli 4 Klebsiella 8 Acinetobacter baumanii 3 Providencia stuartae 1 Acinobacillus ureae 1

ICU Infections—Indian studies Eastern India, 242 Pt., 2012 NI 16.71/1000 Pt. d. Pneumonia 10.37/1000 VAP 26.6/1000 Vent. d. UTI 7.44/1000 Cath. d. BSI 2.46/1000 CVC d. IJCCM, 2015 Western India, 487 pt. 2011-2012 72.3% recovered, 13.9% died, 13.8% palliative care ↑ mortality – A. baumannii K pneumoniae, P aeruginosa Recovery- direct admission, lower APACHE 2 score, shorter ICU stay Lung India, 2015

Prospective,multicentric,observational 27 Indian ICUs, Apr. 2011-Aug 1400 Candidemia (6.51 / 1000 ICU admissions) 65.2% adults Acquisition early (median 8 d., range 4-15 d.) 31 Candida sp., C. tropicalis 41.6% Azole & Multi-drug resistance in 11.8% & 1.9% PSU hospitals more resistant strains 30 d. Crude & attributable mortality rates 44.7 % and 19.6% A. Chakrabarti et al , Int. Care Medicine, 2014 Prophylaxis & Pre-emptive therapy