Health CareAssociated Infections A Meta-analysis of Costs and Financial Impact on the US Health Care System

Eyal Zimlichman, MD, MSc1,2; Daniel Henderson, MD, MPH1; Orly Tamir, PhD, MSc, MHA1; Calvin Franz, PhD3; Peter Song, BSE1; Cyrus K. Yamin, MD1,4; Carol Keohane, BSN, RN1,5; Charles R. Denham, MD6; David W. Bates, MD, MSc1,7

The total annual costs for the 5 major infections were $9.8 billion (95% CI, $8.3-$11.5 billion), with surgical site infections contributing the most to overall costs (33.7% of the total), followed by ventilator-associated pneumonia (31.6%), central lineassociated bloodstream infections (18.9%), C difficile infections (15.4%), and catheter-associated urinary tract infections (<1%).

JAMA Intern Med. Published online September

02, 2013

The Extended Prevalence of Infection in the ICU Study: EPIC II

Objective: To provide an up-to-date picture of the extent and patterns of infection in intensive care units around the world. Data was collected from 14,414 patients in 1265 participating ICUs from 75 countries on the study day On the day of the study, 51% of patients were considered to be infected. 71% percent of all patients were receiving antibiotics 64% percent of infections were of respiratory origin, and 70% of infected patients had positive microbiological isolates; Gram-negative organisms were isolated from 62% of infectious episodes, Gram-positive organisms from 47%, and fungi from 19%. Gram-negative organisms were much less prevalent in North America, Europe and Oceania than in other regions. Patients who had longer intensive care unit stays prior to the study day had higher rates of infection, especially infections due to resistant staphylococci, Acinetobacter, Pseudomonas species and fungi. Intensive care unit (25 versus 11%) and hospital (33% versus 15%) mortality rates were more than double in infected than in noninfected patients (both P<0.001).

To expect that all patients undergoing major surgery can have unflawed outcomes is not realistic. Surgery is performed by humans on humans and always will have complications such as nosocomial infections. Despite the progress in surgery and anaesthesia, the risk of developing nosocomial infections remains a real threat as more patients of greater age and with more co-morbidity are to be operated on

Patrique Segers Bas A. de Mol Intensive Care Med (2009) 35:14971499

Ventilator-associated pneumonia in patients undergoing major heart surgery: an incidence study in Europe
Javier Hortal1*, Patricia Muoz26, Gregorio Cuerpo3, Hector Litvan4, Peter M Rosseel5,Emilio Bouza26, the European Study Group on Nosocomial Infections and the European Workgroup of Cardiothoracic Intensivists Critical Care 2009, 13:R80 doi:10.1186/cc7896

Patients undergoing major heart surgery (MHS) represent a special subpopulation at risk for nosocomial infections. Postoperative infection is the main noncardiac complication after MHS and has been clearly related to increased morbidity, use of hospital resources and mortality

Incidence of nosocomial infections among 971 patients undergoing major heart surgery in Europe.
BACT = bacteraemia; CRBI = catheter-related bloodstream infection; MEDIAST = postsurgical mediastinitis; SWI = surgical wound infection; TB = tracheobronchitis; UTI = urinary tract infection; VAP = ventilator-associated pneumonia. Hortal et al. Critical Care 2009 13:R80 doi:10.1186/cc7896

Definitions

NOSOCOMIAL INFECTIONS
Infection in a hospitalized patient Not present or incubating on admission

Hospital acquired infection

Incidence of VAP
Kollef et al. reported incidences of NP of 21.6% in patients admitted to a cardiothoracic ICU, 14% in other surgical ICU, and 9.3% in a medical ICU.

Ventilator-associated pneumonia in patients undergoing major heart surgery: an incidence study in Europe
Javier Hortal, Patricia Muoz, Gregorio Cuerpo, Hector Litvan, Peter M Rosseel, Emilio Bouza, the European Study Group on Nosocomial Infections and the European Workgroup of Cardiothoracic Intensivists
Critical Care 2009, 13:R80 doi:10.1186/cc7896

Key messages One or more nosocomial infections were detected in 4.4% of the patients. VAP was the most frequent nosocomial infection (2.1%, 13.9 episodes per 1000 days of mechanical ventilation). The principal microorganisms responsible for VAP in this study were: Enterobacteriaceae (45%),Pseudomonas aeruginosa (20%) and methicillin-resistant Staphylococus aureus (10%). Risk factors for VAP were: ascending aorta surgery, number of blood units transfused and need for re-intervention. Death was significantly more frequent in patients with VAP

(35% vs 2.3%).

1st principle of infection prevention

at least 35-50% of all healthcare-associated infections are associated with only 5 patient care practices:

Use and care of urinary catheters Use and care of vascular access lines Therapy and support of pulmonary functions Surveillance of surgical procedures Hand hygiene and standard precautions

Definitions: The ATS/IDSA Guidelines

HAP Pneumonia occurring 48 hours posthospital admission
VAP Pneumonia occurring 48-72 hours postintubation HCAP Includes HAP and VAP Pneumonia in patients
Hospitalized for 2 days in an acute care facility within 90 days of infection, residing in a nursing home or LTC facility Attending a hospital or hemodialysis clinic Receiving immunosuppressive therapy or wound care within 30 days of infection

HAP=hospital-acquired pneumonia HCAP=healthcare-associated pneumonia LTC=long-term care; VAP=ventilator-associated pneumonia

Am J Respir Crit Care Med. 2005;171:388-416.

Pneumonia types The 2005 ATS/IDSA guidelines distinguish the following types of pneumonia:

Hospital-acquired (or nosocomial) pneumonia (HAP) is pneumonia that occurs 48 hours or more after admission and did not appear to be incubating at the time of admission. Ventilator-associated pneumonia (VAP) is a type of HAP that develops more than 48 to 72 hours after endotracheal intubation.

Healthcare-associated pneumonia (HCAP) is defined as pneumonia that occurs in a non-hospitalized patient with extensive healthcare contact, as defined by one or more of the following:
Intravenous therapy, wound care, or intravenous chemotherapy within the prior 30 days Residence in a nursing home or other long-term care facility Hospitalization in an acute care hospital for two or more days within the prior 90 days Attendance at a hospital or hemodialysis clinic within the prior 30 days

Recommended measures for prevention of VAP

Generally recommended general measures

alcohol-based hand disinfection use of microbiologic surveillance monitoring and early removal of invasive devices programs to reduce antimicrobial prescriptions Generally recommended specific measures avoidance of endotracheal intubation avoidance of reintubation preference of noninvasive ventilation (NIV) preference of orotracheal intubation and orogastric tubes maintainance of the ET cuff pressure at approximately 20 cmH2O avoidance of flushing the condensate into the lower airway or to in-line medication nebulizers patient positioning (semirecumbent position)

Additional measures which might be helpful in distinct settings and populations continuous aspiration of subglottic secretions endotracheal tubes coated with antiseptics preference of heat-moisture exchangers (HMEs) over heater humidifiers (HH) oral decontamination selective decontamination of the digestive tract (SDD)

Guidelines for the management of adults with hospitalacquired, ventilator-associated, and healthcareassociated pneumonia
Am J Respir Crit Care Med 2005;171:388416

Regarding therapy, the guidelines emphasize:

use of early and appropriate therapy, in correct doses avoiding excess use of antibiotics and de-escalating the initial therapy based on culture results and the patients clinical response limiting the duration of therapy to the minimal effective period of time

Antibiotic therapy
In patients with pneumonia, a lack of appropriate antimicrobial therapy is associated with increased mortality There is clear evidence that antibiotic therapy should be given early to improve survival A strong association between the administration of inappropriate antibiotic therapy and mortality has also been described in VAP Archives Internal Med 2004:164:637-644 Chest 2002; 122:262-268 AJRCCM 1997; 156:196-200

Early Antibiotic Therapy in Shock

Relationship between the delay of antibiotic administration after the onset of shock and mortality of patients in septic shock Curr Opin Crit Care, Volume 13(5).October 2007.586591

Risk factors for MDR pathogens in HCAP, HAP, and VAP

Prior antimicrobial therapy in preceding 90 days Current hospitalisation of >5 days High frequency of antibiotic resistance in the community or in the specific hospital unit Presence of risk factors for HCAP:
hospitalisation for >2 days in the preceding 90 days residence in a nursing home or extended-care facility home infusion therapy (including antibiotics) chronic dialysis within 30 days home wound care family member with MDR pathogen

Immunosuppressive disease and/or therapy

Prevention of Nosocomial Pneumonia

Handwashing/disinfection(1) NIV(1) Orotracheal intubation(1) Suctioning subglottic secretions (1) Semi-erect position(1) Weaning/Sedation protocols (2) Adequate nursing/resp. therapist staffing (2) Chlorhexidine oral decontamination Post-pyloric feeding to reduce aspiration (2)

Xrepresents VRE culture positive sites

Common Infectious Causes of Fever in the ICU Infectious Causes VAP Sinusitis Catheter-related sepsis Primary Gram-negative septicemia C difficile diarrhea Abdominal sepsis Complicated wound infections

MRSA in Cardiac Surgery

3,443 CABG patients, all received antimicrobial prophylaxis June 1997 through December 2000 Sternal SSI developed in 122 (3.5%) 71 (58.2%) were superficial SSI 51 (41.8%) were deep SSI Gram-positive cocci were most frequently recovered (81%) S aureus was the most frequently isolated pathogen (49%) S aureus bacteremia occurred in 18% and was significantly associated with deep SSI (P=0.002)
CABG=coronary artery bypass grafting. Sharma M et al. Infect Control Hosp Epidemiol. 2004;25:468-471.

Impact of MRSA in Cardiac Surgery

Retrospective review (41 patients)
Poststernotomy S aureus mediastinitis MRSA: 15 patients MSSA: 26 patients
90 80 70 60 50 40 30 20 10 0 MRSA MSSA

Survival Rates

Logistic regression analysis: MRSA was the only independent risk factor for increased mortality, P=0.04

1 month 1 year 3 years

Mekontso-Dessap A et al. Clin Infect Dis. 2001;32:877-883.

Supporting Evidence
Colonization of the oropharynx contributes to VAP Growth of pathogenic bacteria in dental plaque provides a breeding ground for microorganisms that produce VAP.

Risk factors for VentilatorAssociated Pneumonia (VAP)

Patient Age Coma Lung disease Immunosuppression Malnutrition

Devices Invasive ventilation Duration of invasive ventilation Reintubation Medication Prior antibiotic treatment Sedation

Nosocomial Pneumonia
Cumulative incidence = 1-3% per day of intubation Early onset (first 3-4 days of mechanical ventilation) Antibiotic sensitive, community organisms (S. pneumoniae, H. influenzae, S. aureus) Late onset Antibiotic resistant, nosocomial organisms (MRSA, Ps. aeruginosa, Acinetobacterspp, Enterobacterspp)

PREDISPOSING FACTORS Endotracheal intubation ICU Antibiotics Surgery Chronic lung disease Advanced age immunosuppression

ETIOLOGY

Early Onset (10%)-represent community acquired pathogens -Strep pneumoniae, H. influenza, Moraxella catarrhalis Late onset (80%)-typical hospital flora -gram negative aerobes -E. coli, Klebsiella, Pseudomonas -S. aureus

Supporting Evidence
Microorganisms in the mouth translocate and colonize the lung. Dental plaque can be removed by brushing. The American Dental Association recommends that healthy people brush teeth twice daily to remove plaque. Use of an oral care protocol reduces oral inflammation and improves oral health.

Chlorhexidine Evidence
Oral rinse reduced respiratory infections in cardiac surgery patients Reduced nosocomial pneumonia in patients intubated >24 hours. In a more varied ICU population, no difference was observed in VAP, mortality, or length of stay.

Chlorhexidine Evidence
A 2005 meta-analysis found no significant reduction in the incidence of hospitalacquired pneumonia or mortality rate. The CDC guidelines recommend use only during the perioperative period for adult cardiac surgery patients; routine use is not recommended.

Etiology: A typical feature of contemporary NI is that their etiological agents are opportunistic microorganisms that are a part of patient's own microbial flora. Up to 50 % of NI in the last decades are caused by Gram-negative microorganisms from the family Enterobacteriaceae, genus Escherichia, Klebsiella, Enterobacter, Serratia, Proteus, Providencia; genus Pseudomonas and Acinetobacter from the group of Gramnegative non-fermenting aerobes.

NI etiological agents are characterized by significant stability in surrounding environment. Gram-positive cocci can stand dehydration for long periods on surfaces, while Gramnegative survive in humid conditions for months.

Nowadays major prerequisites for the appearance and development of NI are the following: Constantly increasing stream of patients in health care institutions as a result of population aging, chronic diseases, accessibility of medical care, broadened health culture. Hospital overpopulation Concentration of multiple sources of infection and circulation of "hospital strains" of microorganisms

Where do the microbes come from?

patient's own flora cross infection from medical personnel cross infection from patient to patient hospital environment-inanimate objects

-air -dust -IV fluids & catheters -washbowls -bedpans -endoscopes -ventilators & respiratory equipment -water, disinfectants etc

Nosocomial Pneumonia
Cumulative incidence = 1-3% per day of intubation -Early onset (first 3-4 days of mechanical ventilation) Antibiotic sensitive, community organisms (S. pneumoniae, H. influenzae, S. aureus) -Late onset Antibiotic resistant, nosocomial organisms (MRSA, Ps. aeruginosa, Acinetobacterspp, Enterobacterspp)

Epidemiology of VAP

1844 patients after major heart surgery (Madrid) 140 VAP (7.6%; 22.2 per 1000 days of MV) mortality 45.7% vs 2.8% LOS 25.5 days vs 3 days 106 VAP (45.9%) mortality 54.7% vs 34.4% 231 patients after major heart surgery MV > 48h Hortal J et al. ICM 09; 35:1518-25

PREDISPOSING FACTORS Endotrachealintubation!!!!!!!!!!!!!! ICU Antibiotics Surgery Chronic lung disease Advanced age immunosuppression

 PATHOGENESIS
Routes of invasion to LRT
Aspiration of oropharyngealorganisms (most common) Ventilated patients: leakage of bacteria around cuffupper airway colonization, tracheobronchitis Inhalation of infected aerosols (less common)

Hematogenous

Definitions of VAP
VAP was defined according to the following criteria : - Chest X-rays exhibiting lung infiltrates; - Temperature >38C or leukocyte count >12,000/mm3 or <4,000/mm3; - One of the following: 1) sputum modification, 2) suggestive auscultation, 3) low oxyhaemoglobin saturation, or 4) increased pulmonary oxygen consumption; - And one of the following: 1) directed broncho-alveolar lavage (BAL)positive culture at a threshold of 104 cfu/ml in BAL or 103 cfu/ml in mini-BAL , 2) fibreoptic bronchoscopy specimen-positive culture at a threshold of 106 cfu/ml, or 3) one of the following: positive pleural or blood cultures without any other site of infection, pulmonary or pleural abscess, histopathological evidence of pneumonia or cultures positive for specific agents

Bacterial pathogens associated with HAP

Early-onset HAP First 4 days:

Late-onset HAP After 4 days:

Pseudomonas Strept. pneumoniae. aeruginosa. Hemophilus Acinetobacter. influenzae. Enterobacter sp. Moraxella catarrhalis. MRSA. Anaerobes (uncommon).

Bouza E, Perez A, Munoz P, Jesus Perez M, Rincon C, Sanchez C, MartinRabadan P, Riesgo M: Ventilator-associated pneumonia after heart surgery: A prospective analysis and the value of surveillance. Crit Care Med 2003, 31:1964-1970.

Microorganisms causing VAP vary considerably according to the characteristics of the patients in the different ICU types, the length of hospital stay and intubation. Common pathogens include P. aeruginosa, S. aureus and Enterobacteriaceae . There is no evidence that the microorganisms causing VAP after cardiac surgery are substantially different to those in other types of patients in ICUs.

(American Thoracic Society, 2005)

previously

(American Thoracic Society, 2005)

Selection of initial appropriate therapy (i.e., getting the antibiotic treatment right the first time) is an important aspect of care for hospitalized patients with serious infections.
The most common pathogens include: P. aeruginosa, Acinetobacter species, K. pneumoniae, Enterobacter species, and MRSA

http://www.atsjournals.org/doi/full/10.1164/rccm.200405-644ST

Aerosolized antibiotics have not been proven to have value in the therapy of VAP (Level I) (256). However, they may be considered as adjunctive therapy in patients with MDR gram-negatives who are not responding to systemic therapy (Level III)

Read More: http://www.atsjournals.org/doi/full/10.1164/rccm.200405-644ST

Duration of Therapy:
Efforts should be made to shorten the duration of therapy from the traditional 14 to 21 days to periods as short as 7 days, provided that the etiologic pathogen is not P. aeruginosa, and that the patient has a good clinical response with resolution of clinical features of Infection.
(American Thoracic Society, 2005)

Clinical Resolution of HAP

Clinical Pulmonary Infection Score ( CPIS)
Temperature
WBC count

Oxygenation

Purulent secretions

CXR infilterates

Clinical Pulmonary Infection Score

For every item give score : 0 ,1, 2 . For temperature: normal 0 , up to 38.5 give 1, but if higher give 2 . Count the final score of all items : if < ,or = 6 means clinical resolution but if > 6 means clinical unresolution and unimprovement.

Unresolved HAP
Clinical re-assessment of the patient . Consider differential diagnosis . Exclude another site of infection ( UTI, vascular lines, bed sores, wounds). Re-collect another samples ( ET aspirate, bronchoscopic, pleural fluid, blood). Use multiple antibiotics instead of monotherapy. Consider steroids and open lung biopsy.

Effect of staffing level in late onset VAP

Use and care of urinary catheters

The most frequent pathogens associated with CAUTI (combining both ASB and SUTI) in hospitals reporting to NHSN between 20062007 were Escherichia coli (21.4%) and Candida spp (21.0%), followed by Enterococcus spp (14.9%), Pseudomonas aeruginosa (10.0%), Klebsiella pneumoniae (7.7%), and Enterobacter spp (4.1%). A smaller proportion was caused by other gram-negative bacteria and Staphylococcus spp 5. Antimicrobial resistance among urinary pathogens is an ever increasing problem. About a quarter of E. coli isolates and one third of P. aeruginosa isolates from CAUTI cases were fluoroquinoloneresistant. Resistance of gram-negative pathogens to other agents, including third-generation cephalosporins and carbapenems, was also substantial 5. The proportion of organisms that were multidrugresistant, defined by non-susceptibility to all agents in 4 classes, was 4% of P. aeruginosa, 9% of K. pneumoniae, and 21% of Acinetobacter baumannii.

Avoid intubation and reintubation Prefer non-invasive ventilation Prefer orotracheal intubation & orogastric tubes Continous subglottic aspiration Cuff pressure > 20 cm H2O Avoid entering of contaminate condensate into tube/nebulizer Use sedation and weaning protocols to reduce duration Use daily interruption of sedation and avoid paralytic agents -

I will prevent disease whenever I can, prevention is preferable to cure.

Modem Versoin (1964)

Hand Hygiene is the single most effective intervention to reduce the cross transmission of nosocomial infections

Handwashing must be "bacteriologically effective" wash hands before any procedure in which gloves and forceps are necessary after contact with infected patient or one colonised with multi-resistant bacteria after touching infective material use soap and water (preferably disinfectant soap) more prolonged and thorough scrub before surgery

Compliance < 40%

Recommendations: Initial Resuscitation and Infection Issues*

A. Initial Resuscitation 1. Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (defined in this document as hypotension persisting after initial fluid challenge or blood lactate concentration 4 mmol/L). Goals during the first 6 hrs of resuscitation: a) Central venous pressure 812 mm Hg b) Mean arterial pressure (MAP) 65 mm Hg c) Urine output 0.5 mL/kg/hr d) Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively (grade 1C). 2. In patients with elevated lactate levels targeting resuscitation to normalize lactate (grade 2C).

B. Screening for Sepsis and Performance Improvement

1. Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy (grade 1C). 2. Hospitalbased performance improvement efforts in severe sepsis (UG).

C. Diagnosis
1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobial(s) (grade 1C). At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hrs) inserted (grade 1C). 2. Use of the 1,3 beta-D-glucan assay (grade 2B), mannan and anti-mannan antibody assays (2C), if available, and invasive candidiasis is in differential diagnosis of cause of infection. 3. Imaging studies performed promptly to confirm a potential source of infection (UG).

D. Antimicrobial Therapy 1. Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C) as the goal of therapy. 2a. Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis (grade 1B).

2b. Antimicrobial regimen should be reassessed daily for potential deescalation (grade 1B).
3. Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C).

4a. Combination empirical therapy for neutropenic patients with severe sepsis (grade 2B) and for patients with difficult-to-treat, multidrug-resistant bacterial pathogens such as Acinetobacter and Pseudomonas spp. (grade 2B). For patients with severe infections associated with respiratory failure and septic shock, combination therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia (grade 2B). A combination of betalactam and macrolide for patients with septic shock from bacteremic Streptococcus pneumoniae infections (grade 2B). 4b. Empiric combination therapy should not be administered for more than 35 days. Deescalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known (grade 2B). 5. Duration of therapy typically 710 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including neutropenia (grade 2C).

6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin (grade 2C). 7. Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause (UG).

E. Source Control 1.A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is made, if feasible (grade 1C).

2.When infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and nonviable tissues has occurred (grade 2B).

3.When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult should be used (eg, percutaneous rather than surgical drainage of an abscess) (UG).

4.If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established (UG).

F. Infection Prevention

1.Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilatorassociated pneumonia; This infection control measure can then be instituted in health care settings and regions where this methodology is found to be effective (grade 2B).

2.Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated pneumonia in ICU patients with severe sepsis (grade 2B).

The last few years have been characterized by the emergence of certain Gram- negative bacteria, especially Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae, which are resistant to almost all currently available antibiotics, except colistin.

Colistina n infecii cu Gram negativi MDR

Etiologia infeciilor tratate cu colistin

Etiologia infeciilor tratate cu colistin
Klebsiella 7.0% Enterobacter 0.4% Stenotrophomonas 0.4%

Pseudomonas 26.4%

Acinetobacter 65.9%

Falagas et al, JAA 2009

CMS should not be confused with colistin base :

1 mg colistin base (CBA) = 2.4 mg of CMS.
1mg CBA = 30,000 -33,333 IU of CMS
(150 mg CBA is equivalent to approximately 5 million units CMS)

1,000,000 IU of CMS = 80 mg CMS= 29.6 mg colistin base

Pharmacokinetics
CMS 3 millions IU every 8 h

Mathematic model:
Loading dose: 9 million UI and then 4,5 million UI every 12 h Loading dose: 12 million UI and then 4,5 million UI every 12 h
12 MUI loading and 4,5 MUI every 12 h

9 MUI loading and 4,5 MUI every 12 h

3 MUI la 8 ore

Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by GramNegative Bacteria

NEW approach in severe infections

Loading dose : 9 mil UI and then 3 mil UI every 8 h

The optimal results of this regimen are influenced by :

o increasing Colistine half-time to 14,4 hours
o avoiding under-therapeutic concentrations during Day 1
Plachouras D et al : 2009 Antimicrob Agents Chemother 53:3430-3436

Bergen 2008, JAC

 a fraction of CMS is absorbed and is then partially converted into colistin within the systemic circulation another fraction of CMS dose is converted into colistin within the lungs and is then partially absorbed within the systemic circulation
- small clinical trials in VAP and NP ( 120-150 pts) - CMS + nebulized CMS versus i.v. CMS alone: clinical cure 79.5% vs.60.5% (p = 0.025). Korbila IP, Falagas ME : 2010 Clin Microbiol Infect 16:1230-1236 - Carbapenems + CMS + nebulized CMS sv. ATB alone: No effect on clinical cure
Rattanaumpawan P et al: 2010 J Antimicrob Chemother 65:2645-2649

Nebulized COLISTIN

- used doses : 1 million IU/8 h (80 mg/8 h)

- it is probably better to administer higher doses of nebulized CMS - the optimal dose is not known - monotherapy nebulized CMS is inappropriate in pneumonia is associated with bacteremia.
Athanassa ZE et al: 2012 Intensive Care Med 38:1779-1786

 In vitro : - colistin acts synergistically with other antibiotics - most frequently combined : rifampicin and carbapenems. - all studies: synergy with rifampicin against P. Aer.and A. baumannii

Combination Therapy

In vivo : - a few clinical studies have investigated CMS in combination therapy. - in critically ill patients are scant, great variability, low number pts. - all are retrospective !
a recent study performed in 258 patients (A. baumannii, P. aeruginosa and K. pneumoniae) combination therapy was not superior to colistin alone!
Falagas ME et al: 2010 J Antimicrob Agents 35:194-199

Colistina profil de siguran Nefrotoxicitate

Nefrotoxicitatea incidena ntlnit este de 6 % 14% n unele studii sau de 32% - 55% n alte studii. Plaja larg a incidenei nefrotoxicitii deriv din aplicarea unor criterii diferite de apreciere a insuficienei renale acute: scor RIFLE, Creatinina seric > 2 mg/dl

Factori de risc: Vrsta naintat Preexistena afectrii renale Hipoalbuminemia Utilizarea concomitent a antinflamatoarelor nesteroidiene Utilizarea vancomicinei

Reversibilitatea afectrii renale peste 88% n studiile care au monitorizat pacienii un interval de 1-3 luni

Colistina profil de siguran Nefrotoxicitate

Riscul de nefrotoxicitate este mai redus dect cel raportat n litaratura anilor 70 80 prin:

Reducerea impuritilor colistimetatului sodic Monitorizarea atent i echilibrarea hidroelectrolitic n seciile de terapie intensiv Evitarea asocierii cu medicamente cu risc nefrotoxic

Ajustarea dozelor de colistin n funcie de clearance-ul de creatinin

posologia: 75.000 150.000 UI/kg/zi, fr a depi 12 MUI/zi.

Agence franaise de scurit sanitaire des produits de sant www.affsaps.fr

 Multiple evidene referitoare la aciunea superioar a combinaiilor cu colistina cel mai frecvent cu carbapeneme Avantajele asocierilor de antibiotice
Lrgirea spectrului de activitate Creterea vitezei de bactericidie Evitarea seleciei de tulpini rezistente