A is for Antibiotics After that we are STUCK

Steve McGloughlin The Alfred

SEPSIS

Sepsis is

Severe Infection (sepsis)………

Age GCS Temp

HR MAP

pH P/F Ratio Creatinine

51 13 39 125 55

7.14 180 140

ARISE

PROCESS

PROMISE

APACHE 25

Age GCS Temp

HR MAP

pH P/F Ratio Creatinine

55 13 39 125 55

7.14 150 140

ARISE

PROCESS

PROMISE APACHE 25

MORTALITY 45%

In Intensive Care………

SevereInfection

?SevereInfection

ED and ICU

Intensivists

Intensivists

Intensivists

SevereInfection ?

Support Fluids

Dialysis

Goal Directed Therapy?

SevereInfection ?

Definitive Antibiotics

Source Control

SevereInfection ?

Support

Antibiotics

Source Control

We need something else!

Sepsis is

What do we have….

Treatment Effect of Antibacterials for CAP • CID 2008:47 (Suppl 3) • S219

Figure 2. Mortality rates among patients with pneumococcal pneumonia in different age groups, in relation to treatment with serum or sulfonamidesand to bacteremia status, as summarized by Finland [5, 18]. Published with permission from the Connecticut State Medical Society [18].

the observed treatment difference greatest among patients con-sidered to have poor condition at baseline. This study remainsvaluable because of its suggestion that baseline condition in-fluences outcome and treatment effect, an important consid-eration for the design of current studies.

Treatment of pneumococcal pneumonia with antibacterialdrugs: observational studies. Finland [5, 18] summarizedmortality among patients with pneumococcal pneumonia whowere seen at Boston City Hospital from 1929 to 1941. Thiscohort included patients who received no specific therapy from1929 to 1940 ( ), patients who received treatment withn p 2832serum from 1929 to 1938 ( ), and patients who re-n p 1029ceived treatment with sulfonamides from 1939 to 1941 (n p

).1220As shown in figure 2, the overall difference in mortality rate

between patients who received no specific therapy and patientswho received a sulfonamide derivative was 24% ( ).41% ! 17%A greater treatment difference was observed for bacteremic pa-tients (all ages combined) than for nonbacteremic patients (allages combined): 48% ( ) versus 17% ( ).78% ! 30% 28% ! 11%Mortality increased substantially with age among both bacter-emic and nonbacteremic patients. These data are summarizedin table 2.

Dowling and Lepper [19] compared case-fatality rates amongpatients who received no specific treatment ( ) withn p 1087those among patients given treatment with pneumococcal an-tiserum ( ), sulfonamides ( ), or penicillin orn p 889 n p 1274other antibiotics, such as tetracyclines ( ). The anti-n p 920bacterial treatment groups were studied from 1938 to 1950,

whereas the group receiving no specific treatment and the se-rum treatment group were historical control patients studiedat Boston City Hospital from 1939 to 1940 and described inearlier publications [21–24]. Overall case-fatality rates (regard-less of bacteremia status or age) were 30.5% among patientswho received no specific treatment, 16.9% among patients whoreceived serum treatment, 12.3% among patients who receivedsulfonamide treatment, and 5.1% among patients who receivedantibiotic therapy (penicillin or tetracyclines), as summarizedin table 2. In this report, mortality was again shown to increasewith age and with the presence of bacteremia, regardless oftreatment.

Austrian and Gold [20] reported survival according to dayof illness for patients with bacteremic pneumococcal pneu-monia given treatment with penicillin from 1952 to 1962( ), those given treatment with pneumococcal antise-n p 298rum ( ), and those given no specific therapy ( ).n p 93 n p 384The last 2 groups were historical control patients described byTilghman and Finland [4]. As shown in figure 3, at day 21 ofillness, the survival rate was 85% among patients given treat-ment with penicillin, 50% among patients given treatment withpneumococcal antiserum, and 17% among patients who re-ceived no specific antipneumococcal therapy. The difference insurvival between the groups given treatment with penicillin andthe historical control group receiving no specific treatment was68% at day 21, 60% at day 14, and 22% at day 7. No differencewas observed in the first 5 days of illness.

In the same publication, Austrian and Gold [20] also re-ported mortality rates according to treatment for a different by guest on June 10, 2016

http://cid.oxfordjournals.org/D

ownloaded from

NNT

Feature Articles

Critical Care Medicine www.ccmjournal.org 1753

regression model uses the same seven time periods as shown in Table 1. Figure 2 illustrates the trend in hospital mortality over timing to first antibiotic, relative to suspicion of sepsis. Table 2 shows that the adjusted hospital mortality odds ratios steadily

increase from 1.00 to 1.52 as time to antibiotic administration increases from 0 to greater than 6 hours where 0–1 hour is the referent group. The probability of mortality increases from 24.6% to 33.1% and is based on a subject having the following characteristics: from the United States, admission source is the ED, and the SSS is 52 (median of all observations).

DISCUSSIONThe results of this study confirm, in the largest population of patients with severe sepsis and septic shock reported to date, that delay in antibiotic administration was associated with increased in-hospital mortality. In addition, we confirm the increasing risk associated with delay—there was a linear increase in the risk of mortality for each hour delay in anti-biotic administration from the first through the sixth hour after patient identification This relationship between delay in antibiotic administration and mortality has been demon-strated before by Kumar et al (5). However, the population in that study was patients with septic shock, and the delay was from the onset of hypotension. Our study findings are distinct and unique in the population studied and the location of these patients in the hospital: similar results were found in patients with either severe sepsis or septic shock, and consistent results were also seen when patients were stratified by severity (num-ber of organ failure) and whether sepsis was identified in the ED, on the wards, or in the ICU. This study demonstrates, for

Number of acute organ dysfunction

1 1,898 (40.1) 2,078 (45.2) 1,363 (45.1) 777 (44.8) 458 (44.2) 275 (43.0) 942 (42.1)

< 0.001

2 1,653 (35.0) 1,587 (34.5) 1,060 (35.1) 608 (35.1) 358 (34.5) 227 (35.5) 732 (32.7)

3 847 (17.9) 681 (14.8) 436 (14.4) 268 (15.5) 154 (14.9) 99 (15.5) 387 (17.3)

4 265 (5.6) 207 (4.5) 131 (4.3) 68 (3.9) 51 (4.9) 31 (4.8) 134 (6.0)

5 65 (1.4) 42 (0.9) 30 (1.0) 13 (0.8) 16 (1.5) 8 (1.3) 41 (1.8)

Cardiovascular

No cardiovascular dysfunction

376 (7.9) 379 (8.3) 265 (8.8) 168 (9.7) 115 (11.1) 57 (8.9) 349 (15.6)

< 0.001

Cardiovascular dysfunction no hypertension

803 (17.0) 1,004 (21.8) 659 (21.8) 402 (23.2) 174 (16.8) 116 (18.1) 403 (18.0)

Total shock 3,549 (75.1) 3,212 (69.9) 2,096 (69.4) 1,164 (67.2) 748 (72.1) 467 (73.0) 1,484 (66.4)

Lactate > 4 260 (5.5) 332 (7.2) 249 (8.3) 117 (6.8) 64 (6.2) 26 (4.1) 114 (5.1)

Vasopressors only

2,273 (48.1) 1,938 (42.2) 1,309 (43.3) 769 (44.4) 522 (50.3) 346 (54.1) 1,126 (50.4)

Lactate > 4 and vasopressors

1,016 (21.5) 942 (20.5) 538 (17.8) 278 (16.0) 162 (15.6) 95 (14.8) 244 (10.9)

IQR = interquartile range, LOS = length of stay, ED = emergency department.ap value based on Pearson chi-square test for categorical variables and Wilcox rank-sum test for continuous variables.

TABLE 1. (Continued). Patient Characteristics by Timing in Hours to the First Antibiotic

Patient Characteristic, n (%)

Antibiotic Timing (Hr)

pa0.0–1.0 1.0–2.0 2.0–3.0 3.0–4.0 4.0–5.0 5.0–6.0 > 6.0

Figure 2. Predicted hospital mortality and the associated 95% CIs for time to first antibiotic administration. The results are adjusted by the sepsis severity score (SSS), ICU admission source (emergency department [ED], ward, vs ICU), and geographic region (Europe, United States, and South America). Probability of hospital mortality is based on the subject having the following specific characteristics: the patient is from the United States, admission source is the ED, and the SSS is 52 (median of all observations).

Why Not?

Sick Very Sick

Which Antibiotic? I want you to be honest?

The thoughtless person playing with penicillin treatment is morally responsible for the death of the

person who succumbs to infection with the penicillin resistant organism.

Pandrug resistant

214000 neonatal sepsis deaths attributable to

resistant pathogens

Series

170 www.thelancet.com Vol 387 January 9, 2016

have been documented by various studies from Asia: a multi-country analysis estimated the average prevalence of MRSA in Asian hospitals at 67·4%, with the lowest rate of 22·6% in India and the highest rate of 86·5% in Sri Lanka.27 Community-acquired MRSA averaged 25·5% across the eight countries in the study, with the lowest rate of 2·5% in Thailand and the highest rate of 38·8% in Sri Lanka.

Gram-negative organisms are by far the biggest threat because of growing resistance to carbapenems, which until recently were eff ective against multidrug-resistant strains. Carbapenem-resistant Enterobacteriaceae (CRE) have now been detected worldwide. New Delhi metallo-β-lactamase (NDM) enzymes, fi rst reported in 2008, are now reported worldwide.28 In the USA in 2012, 4·6% of acute-care hospitals reported at least one CRE healthcare-associated infection. Carbapenem resistance in common Enterobacteriaceae has increased sharply over the past decade: the proportion of Enterobacteriaceae that were CRE increased from 0% in 2001 to 1·4% in 2010, with most of the increase observed in Klebsiella spp.29 The rapid international spread of resistance genes, such as extended-spectrum β-lactamase (ESBL), NDM-1, and Klebsiella pneumoniae carbapenemase (KPC), suggests the nature of the serious threat of antimicrobial resistance. The sharp increase in resistance is clear in the case of β-lactamase antibiotics. Nearly 1000 resistance-related β-lactamases, including novel classes of genes, have been identifi ed, a ten-fold increase since 1990.30

Hospital data from developing countries suggest that pathogens causing neonatal infections (in the fi rst 28 days of life) are frequently resistant to the WHO-recommended regimen of ampicillin and gentamicin: 71% of Klebsiella spp and 50% of Escherichia coli were resistant to gentamicin.17 Resistance has also been reported as high in early-onset, presumably maternally acquired neonatal infections reported from hospital series in developing countries; 60–70% of E coli and nearly 100% of Klebsiella spp are ampicillin-resistant, and 40–60% of Klebsiella spp are resistant to gentamicin (appendix).31 High rates of ESBL production in E coli have restricted use of second-line therapy with extended-spectrum cephalosporins.32 Many newborns in hospitals in South Asia are now treated with carbapenems as fi rst-line therapy for sepsis or presumed sepsis. The emergence of pan-resistant untreatable CRE and Acinetobacter spp infections associated with high mortality in neonatal nurseries is of most concern.33

Figure 2 shows the estimated number of neonatal deaths attributable to resistant sepsis infections in the fi ve countries with the highest numbers of neonatal deaths in the world. Resistance-attributable neonatal sepsis deaths are greatest in India, where 56 524 neonates (33 683 LHS minimum, 89 620 LHS maximum) die each year owing to neonatal sepsis caused by bacteria resistant to fi rst-line antibiotics. These deaths are also high in Pakistan (25 692 deaths; 16 486 LHS minimum, 39 660 LHS maximum), Nigeria (19 405 deaths; 6797 LHS minimum, 35 490 LHS maximum),

Figure 1: Estimated pneumonia deaths avertable in under-5 populations with improved antibiotic access Countries with less than 100 deaths averted are not labelled. Data on under-5 population with suspected pneumonia receiving antibiotics are from 1990 to 2013; data from the most recent year reported is used, when available.

0 20 40 60 80

Trendline weighted bythe under-5 populationof each country

100

0

1

2

3

4

5

6

Pneu

mon

ia d

eath

s (du

e to

Stre

ptoc

occu

s pne

umon

iae a

nd H

aem

ophi

lus

influ

enza

e typ

e b) p

er 10

00 ch

ildre

n ag

ed yo

unge

r tha

n 5 y

ears

Under-5 population with suspected pneumonia receiving antibiotics (%)

IndiaNigeria

DR Congo

Pakistan

China

Ethiopia

Afghanistan

Sudan

Indonesia

Somalia

Mali

Niger

Uganda

Chad

Tanzania

Burkina Faso

Kenya

Yemen

MozambiqueCameroon

Myanmar

Philippines

Côte d’Ivoire

Bangladesh

Guinea

IraqMadagascar

Nepal

Malawi

Ghana

Burundi

Benin

Sierra Leone

UzbekistanZambia

Egypt

Haiti

SenegalIran

Central African Republic

Togo

VietnamMorocco

BrazilRwanda Zimbabwe

Mauritania

Cambodia

Tajikistan

Algeria

Congo (Brazzaville)

Guinea−Bissau

Bolivia

ColombiaTurkey

Thailand

North KoreaLaos

ArgentinaKazakhstanPeru

Timor−Leste

Dominican Republic

Equatorial Guinea

Kyrgyzstan Syria

Gambia

Comoros Swaziland

Honduras

ParaguayUkraine

India (169 760)

Nigeria (49 407)

Nepal (2 434)

Hypothetical under-5 pneumonia deaths averted with universal antibiotic access

1 million Avoidable deaths in 2013 in under 5’s from pneumonia

170 000 deaths in India

avoidable with Antibiotics

We need more than

antibiotics?

A disease caused by an uncontrolled division of abnormal cells in a part of the body.

Life-threatening organ dysfunction due to a dysregulated host response to infection

Cancer is

Sepsis is

One definition?

arises when the body's response to an infection injures its own tissues and organs. It may lead to shock, multiple organ failure, and death, especially if not recognized early and treated promptly.

Heart

Brain

Lung

Infection

Liver

Kidney

From a local infection to a general inflammation A local infection – e.g. in the lung – over-comes the body’s local defense mechanisms. Pathogenic germs and the toxins they produce leave the original site of the infection and enter the circulatory system.

Organ dysfunction This leads to a general inflammatory response: SIRS (systemic inflammatory response syndrome) The function of individual organs starts to deteriorate and may completely fail. Sepsis starts with the onset of at least one new organ dysfunction.

Septic Shock

Several organs stop functioning sequentially or simultaneously, and cardio-circulatory failure leads to a sudden drop in blood pressure. This is called septic shock.

Stag

e 1

Stag

e 2

Stag

e 3

Sepsis

© world-sepsis-day.org |made by Lindgruen-GmbH

The source changes the risk of death

MULTIDRUG-RESISTANTPSEUDOMONAS AERUGINOSA

Pseudomonas aeruginosa is a common cause of healthcare-associated infections including pneumonia, bloodstream infections, urinary tract infections, and surgical site infections.

RESISTANCE OF CONCERN ■ Some strains of Pseudomonas aeruginosa have been found to be resistant

to nearly all or all antibiotics including aminoglycosides, cephalosporins, fluoroquinolones, and carbapenems.

■ Approximately 8% of all healthcare-associated infections reported to CDC’s National Healthcare Safety Network are caused by Pseudomonas aeruginosa.

■ About 13% of severe healthcare-associated infections caused by Pseudomonas aeruginosa are multidrug resistant, meaning several classes of antibiotics no longer cure these infections.

PUBLIC HEALTH THREATAn estimated 51,000 healthcare-associated Pseudomonas aeruginosa infections occur in the United States each year. More than 6,000 (or 13%) of these are multidrug-resistant, with roughly 400 deaths per year attributed to these infections.

 

Percentage of all Pseudomonas aeruginosa healthcare-associated infections that are multidrug-resistant

Estimated number of infections

Estimated number of deaths attributed

Multi-drug resistant Pseudomonas aeruginosa 13% 6,700 440

For more information about data methods and references, please see technical appendix.

6,700 440MULTIDRUG-RESISTANT PSEUDOMONASINFECTIONS

DEATHS

THREAT LEVELSERIOUSThis bacteria is a serious concern and requires prompt

and sustained action to ensure the problem does not grow.51,000 PSEUDOMONAS

INFECTIONS PER YEAR

METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS (MRSA)

80,461 11,285SEVERE MRSA INFECTIONS PER YEAR

DEATHS FROM MRSA PER YEAR

STAPH BACTERIA ARE A LEADING CAUSE OF

HEALTHCARE-ASSOCIATED INFECTIONSTHREAT LEVEL

SERIOUSThis bacteria is a serious concern and requires prompt

and sustained action to ensure the problem does not grow.

Methicillin-resistant Staphylococcus aureus (MRSA) causes a range of illnesses, from skin and wound infections to pneumonia and bloodstream infections that can cause sepsis and death. Staph bacteria, including MRSA, are one of the most common causes of healthcare-associated infections.

RESISTANCE OF CONCERNResistance to methicillin and related antibiotics (e.g., nafcillin, oxacillin) and resistance to cephalosporins are of concern.

PUBLIC HEALTH THREAT CDC estimates 80,461 invasive MRSA infections and 11,285 related deaths occurred in 2011. An unknown but much higher number of less severe infections occurred in both the community and in healthcare settings.

Severe MRSA infections

mostly occur during or soon after inpatient

medical care.

Revised Annualized National Estimates, ABCs MRSA 2005–2011 (updated Nov, 2012)

For more information about data methods and references, please see technical appendix.

The bugs are not the same…

Pathology is not the same

The Narrow Spectrum Era…….

1925

1950

1975

2000

2025

Golden EraNature products

Medicinal Chemistry EraSynthetic tweaking

Resistance eraTarget based, broad spectrum

Narrow-Spectrum eraUnconventionalCombination approachesDiagnostic development

1925

1975

2000

2025

1950

The Narrow Spectrum Era…….

1925

1950

1975

2000

2025

Golden EraNature products

Medicinal Chemistry EraSynthetic tweaking

Resistance eraTarget based, broad spectrum

Narrow-Spectrum eraUnconventionalCombination approachesDiagnostic development

1925

1975

2000

2025

1950

Sepsis is

If ICU and ED want to own sepsis…..

In memory of my sister Bec

Most people spend their time and energy going around problems rather than in trying to solve them.

Henry Ford