Acinetobacter Infections in a Hospital Setting

University Medical Center-Medical Grand Rounds

Las Vegas, Nevada

February 17, 2006

Gonzalo Bearman MD, MPH Assistant Professor of Medicine, Epidemiology and Community Health Associate Hospital Epidemiologist Virginia Commonwealth University

Epidemiology & Prevention of Acinetobacter Infections

Microbiology Infections: Scope of the problem Impact Outbreaks

Reservoirs of Acinetobacter in the hospital

Colonization
HCWs, patients, environment

Cross transmission Treatment of Acinetobacter infections Limiting cross transmission of Acinetobacter

Infection control

Summary

Acinetobacter
Akinetos, Greek adjective, unable to move Bakterion, Greek noun, rod Nonmotile rod

Brisou and Prvot, 1954

Microbiology
Oxidase negative Nitrate negative Catalase positive Nonfermentative Nonmotile Strictly aerobic Gram negative coccobacillus
Sometimes difficult to decolorize

Frequently arranged in pairs

Bergogne-Brzin E, Towner KJ. Clin Microbiol Rev 1996;9:148-165.

Microbiology
Ubiquitous:
Widely distributed in nature (soil, water, food, sewage) & the hospital environment

Survive on moist & dry surfaces 32 species

>2/3 of Acinetobacter infections are due to A. baumanii

Highly antibiotic resistant

Numerous mechanisms of resistance to -lactams described in A. baumanii 15 aminoglycoside-modifying enzymes described Quinolone resistance due to mutations in DNA gyrase

Hospital acquired Acinetobacter infections

Major infections due to Acinetobacter

Ventilator-associated pneumonia Urinary tract Bloodstream infection infection Secondary meningitis Skin/wound infections Endocarditis CAPD-associated peritonitis Ventriculitis

Acinetobacter VentilatorAssociated Pneumonia

Acinetobacter accounts for 5-25% of all cases of VAP Risk factors:
Advanced age Chronic lung disease Immunosuppression Surgery Use of antimicrobial agents Invasive devices Prolonged ICU stay

Acinetobacter Bloodstream Infection

Most common source is respiratory tract infection Predisposing factors:
Malignancy Trauma Burns Surgical wound infections Neonates
Low birth weight Need for mechanical ventilation

Nosocomial Bloodstream Infections

Rank Pathogen 1 2 3 Coagulase-negative Staph S. aureus Enterococci BSI/10,000 admissions 15.8 10.3 4.8 Percent 31% 17% 12%

4
5 6
49 US centers

Candida spp
E. coli Klebsiella Ps. aeruginosa Enterobacter Serratia Acinetobacter baumanii

4.6
2.8 2.4 2.1 1.9 1.7 0.6

8%
6% 5% 4% 4% 2% 1%

7 7 8 9

1995-2002
N= 24,179

Wisplinghoff H, Edmond MB et al. Clin Infect Dis. 2004 Aug 1;39(3):309-17

SCOPE

Acinetobacter Nosocomial BSI

Incidence = 0.6/10,000 admissions Accounts for 1.3% of all nosocomial BSI Accounts for 1.6% of all nosocomial BSI in the ICU setting Crude mortality:
Overall 34% ICU 43% Despite the low incidence, the mortality is high

Wisplinghoff H, Edmond MB et al. Clin Infect Dis. 2004 Aug 1;39(3):309-17

Time to Nosocomial BSI

Acinetobacter BSI tends to be a late onset, hospital acquired phenomenon

Wisplinghoff H, Edmond MB et al. Clin Infect Dis. 2004 Aug 1;39(3):309-17

Source of A. baumanii Nosocomial Bloodstream Infection

The respiratory tract is an important reservoir for Acinetobacter bloodstream infections Abdominal infection 19% Central venous line 8%

Respiratory tract 71%

N=37 Garcia-Garmendia J-L et al. Clin Infect Dis 2001;33:939-946.

Inflammatory Response to A. baumanii Nosocomial Bloodstream Infection

Severe sepsis 21% Septic shock 24%

Sepsis 55%

N=42 Garcia-Garmendia J-L et al. Clin Infect Dis 2001;33:939-946.

Independent Predictors of A. baumanii Nosocomial Bloodstream Infection

Risk factors Immunosuppression Unscheduled admission Respiratory failure at admission Previous antibiotic therapy Previous sepsis in ICU Invasive procedure index* (mean value) A. baumaniil Other gram (n=42) negative (n=35) 24% 86% 3% 51% Odds Ratio (CI95) 3.0 (1.3-7.1) 3.3 (1.3-8.5)

60%
64% 79% 3.7

14%
13% 17% 2.5

2.9 (1.4-5.8)
2.3 (1.1-5.0) 4.4 (1.8-10.3) 1.8 (1.4-2.4)

No. of invasive procedure-days/number of days in ICU prior to BSI

Garcia-Garmendia J-L et al. Clin Infect Dis 2001;33:939-946.

Acinetobacter Meningitis
Most cases are hospital-acquired Often associated with neurosurgical procedures Risk factors:
Ventriculostomy Heavy use of antibiotics in the neurosurgical ICU

Impact of Acinetobacter Infection in the ICU

Impact of Acinetobacter Infection in the ICU: historical cohort study

Outcome Mortality Attributable mortality Group Cases Controls Any infection 58% 15% 43% Pneumonia 70% 17% 53%

Risk ratio for death

Cases Controls

4.0 (CI951.9-8.3) 4.0 (CI951.6-10.2)

23 days 10 days 13 days 23 days 10 days 13 days

Length of stay (median) Excess LOS

48 patients with Acinetobacter infection matched 1:1 to patients without infection Controls were matched to cases on: age (+6yrs), APACHE II (+ 4 points), admission date, principal diagnosis at ICU admission, LOS at least as long as case until isolation of AB, requirement for mechanical ventilation Garcia-Garmendia JL et al. Crit Care Med 1999;27:1794-1799.

Impact of Acinetobacter Bloodstream Infection in the ICU

Outcome Mortality Attributable mortality Risk ratio for death Cases Controls Group Cases Controls Bloodstream infection 42% 34% 8% 1.0 (CI95 0.7-1.4) 25 days 20 days 5 days

Length of ICU stay (median) Excess ICU LOS

Historical cohort study of 45 patients with Acinetobacter bloodstream infection matched 1:2 to patients without infection Controls were matched to cases on: APACHE II (+ 2 points), principal diagnosis at ICU admission, LOS at least as long as case until bacteremia

Blot S. Intensive Care Med 2003;29:471-475.

Impact of A. baumanii VentilatorAssociated Pneumonia in the ICU

Outcome Mortality Attributable mortality Cases Controls Group Cases Controls All 40% 28% 12%
P=NS

Imipenem (R) 44% 24% 20%

P=NS

Length of ICU stay (median) Excess ICU LOS

35 days 37 days -2 days

P=NS

Historical cohort study of 60 patients with A. baumanii VAP matched 1:1 to patients without A. baumanii infection Controls were matched to cases on: age, APACHE II score, admission date, principal diagnosis, LOS at least as long as case until onset of pneumonia, chronic health status

Garnacho J et al. Crit Care Med 2003;10:2478-2482.

Acinetobacter outbreaks
Detection of Acinetobacter Infections

Consider: organ site, genetic typing, hospital location

Common source outbreak with respiratory site predominance

Common source outbreak without respiratory site predominance

Respiratory site outbreaks without an identified common source

Non- respiratory site outbreaks without an identified common source

Villegas M, Hartstein A. Infect Control Hosp Epidemiol. 2003;24:284-295

Acinetobacter outbreaks 1977-2000

Extensive Literature review and summary of 51 Acinetobacter outbreaks
Characteristic
Publication year: 1977-1990 1991-2000

Number of reports
24 27

Comment
The majority of the reports occurred over the last 9 years

ICU setting

38

75 percent of reports were exclusively or predominantly ICU related outbreaks or clusters

Patient age category: Adult Pediatric

45 6

88 percent of all outbreaks were in an adult population

Villegas M, Hartstein A. Infect Control Hosp Epidemiol. 2003;24:284-295

Acinetobacter outbreaks 1977-2000

Studies with a focus on antimicrobial resistance Antimicrobial class Aminoglycosides

Number of studies reporting new or increasing resistance

6

Multiple classes Carbapenems

14 3

Villegas M, Hartstein A. Infect Control Hosp Epidemiol. 2003;24:284-295

Acinetobacter outbreaks 1977-2000

13 Studies with a common source outbreak with a respiratory cluster:
Clonal transmission confirmed by PFGE or PCR-based typing

Setting:
Adult ICU Adult,neonatal and pediatric ICU Adult mixed ICU Surgical and medical ICU Adult ICU Neonatal ICU Adult mixed ICU

Common Source:
Ventilator spirometers Reusable ventilator circuits In line temperature monitor probes Ventilator temperature probes Y piece of ventilator Suction catheter and bottle Peak flow meter

Villegas M, Hartstein A. Infect Control Hosp Epidemiol. 2003;24:284-295

Acinetobacter outbreaks 1977-2000

12 Studies with a common source outbreak without a respiratory cluster:
Clonal transmission confirmed by PFGE or PCR-based typing

Setting:
Medical Wards Medical ICU Cardiac Catheterization Lab Dialysis center Burn unit Hospital wide Pediatric oncology war

Common Source:
Bedside humidifiers Warming bath water Hospital prepared distilled water Heparinized saline solution Patient mattresses Feather pillows Water taps in staff room with mesh aerators

Villegas M, Hartstein A. Infect Control Hosp Epidemiol. 2003;24:284-295

Acinetobacter outbreaks 1977-2000

16 Studies with a predominant respiratory site outbreak without an identifiable common source 8 Studies with a predominant non-respiratory site outbreak without an identifiable common source Settings Medical ICU Surgical ICU Shock-Trauma ICU Medical Wards Nursery Mixed Medical/Surgical ICU Burn and Plastic Surgery Wards

Villegas M, Hartstein A. Infect Control Hosp Epidemiol. 2003;24:284-295

Reservoirs of Acinetobacter: Where do these organisms reside?

Environmental Contamination with Acinetobacter

Bed rails Bedside tables Ventilators Infusion pumps Mattresses Pillows Air humidifers Patient monitors X-ray view boxes Curtain rails Curtains Equipment carts Sinks Ventilator circuits Floor mops

Factors Promoting Transmission of of Acinetobacter in the ICU

Long survival time on inanimate surfaces
In vitro survival time 329 days
(Wagenvoort JHT, Joosten EJAJ. J Hosp Infect 2002;52:226-229)

11 days survival on Formica, 12 days on stainless steel

(Webster C et al. Infect Control Hosp Epidemiol 2000;21:246)

Up to 4 months on dry surfaces

(Wendt C et al. J Clin Microbiol 1997;35:1394-1397)

Extensive environmental contamination Highly antibiotic resistant High proportion of colonized patients Frequent contamination of the hands of healthcare workers

Acinetobacter Transmission in the Hospital Setting

Direct or indirect contact
Contaminated hands of healthcare workers

Airborne transmission via aerosol production (e.g., hydrotherapy) may occur

Simor AE et al. Infect Control Hosp Epidemiol 2002;23:261-267.

Evidence for Airborne Transmission of Acinetobacter

Sedimentation plates placed in 7 patients rooms with respiratory infection or colonization
80% 60% 75% 60% 57% 40% 28%

% of plates growing 40% Acinetobacter

20% 0%

42%

5 7 Distance (feet)

11

Brooks SE et al. Infect Control Hosp Epidemiol 2000;21:304.

Acinetobacter spp Skin Colonization

Body site Forehead Ear Hospitalized Healthy patients (n=40) controls (n=40) 33% 35% 13% 7%

Nose
Throat Axilla Hand Groin

33%
15% 33% 33% 38%

8%
0% 3% 20% 13%

Perineum
Toe web

20%
40%

3%
8%

Any site

75%

42.5%
Seifert H et al. J Clin Microbiol 1997; 35:2819-2825.

A. baumanii isolated from 2 patients & 1 control only

Acinetobacter Transmission in the Hospital Setting

Colonization of Healthcare Workers

Outbreak of multidrug resistant A. baumanii in a Dutch ICU involving 66 patients with an epidemic strain Nursing staff were cultured (nares & axilla, same swab)
15 nurses found to harbor epidemic strain All were culture negative when re-cultured (nose, throat, axilla, perineum)

Wagenvoort JHT et al. Eur J Clin Microbiol Infect Dis 2002;21:326-327.

Hand Contamination in HCWs

40 35 30 25 20 15 10 5 0 Gram-negative rods
Bauer TM et al. J Hosp Infect 1990;15:301-309.

% of HCWs (n=328) with hand contamination

36 29 Physicians Nurses

18

18

S. aureus

Opportunities for cross transmission are multiple

Treatment of Acinetobacter infections

Acinetobacter Susceptibility, US, 2002-2003

100 80 60 47 40 20 0
Pip Cefotaxime Imipenem Cipro Gent TMP/SMX

% susceptible

86

Increasing rate of antibiotic resistance

47 37 21

33

TSN Database. http://www.geis.ha.osd.mil/GEIS/SurveillanceActivities/AntimicrobialResistance/AcinetobacterGraphs.htm

Antibiotic Resistance

Community vs. Hospital Acquisition

Comparison of A. baumanii isolates obtained from the hands of homemakers to isolates obtained from 2 US hospitals 23/222 (10.4%) homemakers had A.baumanii isolated from hands
Antimicrobial resistance 3rd generation cephalosporins Carbapenems Aminoglycosides Multidrug resistant* Hospital (n=101) 88% 64% 43% 37% Community (n=23) 9% 4% 4% 0% Odds Ratio (CI95) 78 (15-553) 39 (5-811) 16 (2-337) Not calculable

*3rd gen. cephalosporins + carbapenem + aminoglycoside

Zeana C. Infect Control Hosp Epidemiol 2003;24:275-279.

Polymyxin antibiotics
A group of polypeptide antibiotics that consists of 5 chemically different compounds (polymyxins A E). Only polymyxin B and polymyxin E (colistin) have been used in clinically. Intravenous colistin should be considered for the treatment of infections caused by gram-negative bacteria resistant to other available antimicrobial agents, confirmed by appropriate in vitro susceptibility testing

Polymyxin antibiotics:
History
Used extensively worldwide in topical otic and ophthalmic solutions for decades Intravenous Colistin was initially used in Japan and in Europe during the 1950s, and in the United States in the form of colistimethate sodium in 1959 The intravenous formulations of colistin and polymyxin B were gradually abandoned in most parts of the world in the early 1980s because of the reported high incidence of nephrotoxicity Colistin was mainly restricted during the past 2 decades for the treatment of lung infections due to multidrug-resistant (MDR), gram-negative bacteria in patients with cystic fibrosis

Polymyxin antibiotics

colistin sulfate: oral, used for bowel decontamination colistimethate sodium: (also called colistin methanesulfate, pentasodium colistimethanesulfate, and colistin sulfonyl methate)- Intravenous formulation
Clinical Infectious Diseases 2005;40:1333-1341

Polymyxin antibiotics
Mechanism of action:
Target:
Bacterial cell membrane Colistin binding with the bacterial membrane occurs through electrostatic interactions between the cationic polypeptide (colistin) and anionic lipopolysaccharide (LPS) molecules in the outer membrane of the gram-negative bacteria
leads to a derangement of the cell membrane The result of this is an increase in the permeability of the cell envelope, leakage of cell contents, and, subsequently, cell death.

Polymyxin antibiotics
Sections of a Pseudomonas aeruginosa strain showing the alterations in the cell following the administration of polymyxin B (25 g/mL for 30 min) and colistin methanesulfate (250 g/mL for 30 min).

A: untreated cell;
B: cell treated with polymyxin C: cell treated with colistin methanesulfate; D: cell treated with polymyxin B at higher magnification.= 0.1 m

Clinical Infectious Diseases 2005;40:1333-1341

Polymyxin antibiotics
Development of Resistance
Resistance to colistin occurs through mutation or adaptation mechanisms Almost complete cross-resistance exists between colistin and polymyxin B

Polymyxin antibiotics
Important pharmacokinetic parameters
Colistin sulfate and colistimethate sodium are not absorbed by the gastrointestinal tract with oral administration Primary route of excretion is through glomerular filtration Experimental studies have shown that colistin is tightly bound to membrane lipids of tissues, including liver, lung, kidney, brain, heart, and muscles Concentration of colistin in the CSF is 25% of the serum concentration

Polymyxin antibiotics
Spectrum of activity
Most gram-negative aerobic bacilli:
Acinetobacter species, P. aeruginosa, Klebsiella species, Enterobacter species, Escherichia coli, Salmonella species, Shigella species, Citrobacter species, Yersinia pseudotuberculosis, Morganella morganii, and Haemophilus influenzae

No activity against:
Pseudomonas mallei, Burkholderia cepacia, Proteus species, Providencia species, Serratia species, Edwardsiella species, and Brucella

Polymyxin antibiotics
Susceptibility testing:
Disk diffusion- Colistin
Disk diffusion method that uses a 10-ug colistin sulfate disk Isolates is susceptible if the zone of inhibition is >11 mm

Dilution method- colistimethate sodium

The MIC break point for susceptibility is <4 mg/L If the MIC is >8 mg/L, the isolate should be considered resistant

Polymyxin antibiotics
Route
Intravenous

Dosage
2.5-5 mg/kg (31,250-62,500 IU/kg) per day, divided into 2-4 equal doses (1 mg of colistin equals 12,500 IU). Modification of the total daily dose is required in the presence of renal impairment Same as IV 40 mg (500,000 IU) every 12 h for patients <40 kg and 80 mg (1 million IU) every 12 h for patients >40 kg For recurrent pulmonary infections, the dose can be increased to 160 mg (2 million IU) every 8 h Intrathecal dosage ranged from 3.2 mg (40,000 IU) to 10 mg (125,000 IU) given once per day Intraventricular dosage ranged from 10 mg (125,000 IU) to 20 mg (250,000 IU) per day (divided into 2 doses)

Intramuscular Inhalation

Intraventricular/ intrathecal (not FDA approved)

Limited data based on case reports

Polymixin adverse effects

Neurotoxicity
Dizziness Weakness Paresthesias-most common Vertigo Visual disturbances Confusion Ataxia Neuromuscular blockaderespiratory failure

Comments
7 % incidence of Colistin associated neurotoxicity 29% incidence in patients with Cystic Fibrosis Toxicity is dose dependent Toxicity is reversible upon discontinuation of medication

Polymixin adverse effects

Nephrotoxicity
The majority of nephrotoxic events are reversible 1970s- incidence of nephrotoxicity was 20.2% More recent studies- incidence of nephrotoxicity ranged from 8%-18%. Lower incidence of Nephrotoxicity at present:
Greater supportive treatment to critically ill patients Close monitoring of renal function Avoidance of co-administered nephrotoxic agents Older formulations of Colistin contained a greater proportion of colistin sulfate (greater nephrotoxicity)

Limiting the cross transmission of Acinetobacter

Preventing Acinetobacter Transmission in the ICU

General Measures
Hand hygiene
Use of alcohol-based hand sanitizers

Contact precautions
Gowns/gloves Dedicate non-critical devices to patient room

Environmental decontamination Prudent use of antibiotics Avoidance of transfer of patients to Burn Unit from other ICUs

Preventing Acinetobacter Transmission in the ICU

Outbreak Interventions
Hand cultures Surveillance cultures Environmental cultures following terminal disinfection to document cleaning efficacy Cohorting Ask laboratory to save all isolates for molecular typing Healthcare worker education If transmission continues despite above interventions, closure of unit to new admissions

Efficacy of Handwashing Agents against Acinetobacter

Experimental study to access removal of A. baumanii from the hands of volunteers
Fingertips inoculated with with either 103 CFU (light contamination) or 106 CFU (heavy contamination)

Removal Rate
Agent Plain soap Light contamination 99.97% Heavy contamination 92.40%

70% Ethyl alcohol

10% Povidone-iodine 4% Chlorhexidine

99.98%
99.98% 99.81%

98.94%
98.48% 91.39%

Cardoso CL et al. Am J Infect Control 1999;27:327-331.

In Vitro Activity of Alcohol Hand Rubs

Each agent diluted 1/10 & tested against a strain of A. baumanii resistant to 3rd generation cephalosporins
Alcohol(s) 60% isopropyl, 0.05% phenoxyethyl 46% ethyl, 27% isopropyl, 1% benzyl 70% ethyl 30% I-propanol, 45% isopropyl 60% isopropyl 0.3% triclosan 0.2% mecetronium 0.5% chlorhexidine Other agents Log -0.02 -0.05 0.3 3.2 >5.0

70% isopropyl
89% isopropyl/ethyl 40% I-propanol, 30% isopropyl 55% isopropyl

0.5% chlorhexidine, 0.45% H2O2

0.1% chlorhexidine 0.1% octenidine 0.5% triclosan

>5.0
>5.0 >5.0 >5.0

Rochon-Edouard S et al. Am J Infect Control 2004;32:200-204.

Chlorhexidine Resistance in Acinetobacter

Biocide resistance in gram-negative organisms is mainly intrinsic & chromosomal (plasmid mediated in gram-positive organism) 10 strains of A. baumanii tested for chlorhexidine susceptibility
Median MIC 32 mg/L Median MBC 32 mg/mL Chlorhexidine resistance increased with increased antibiotic resistance
Kljalg S et al. J Hosp Infect 2002;51:106-113.

Summary
Although commonly found on the skin of healthy humans, Acinetobacter plays the role of an opportunistic pathogen in the critically ill patient High level of antibiotic resistance makes it well suited as a pathogen in areas with high use of antibiotics (e.g., ICU setting) Control requires good hand hygiene, barrier precautions & environmental decontamination
Alcohol-based products containing chlorhexidine should be considered the hand hygiene agents of choice