FEATURE ARTICLES

3 Introduction to this issue

Bonnie Marshall and Rebecca Crowder (APUA News Staff)

4 The cost of methicillin-resistant Staphylococcus aureus in pediatric neck and pharyngeal

infections

Michael E. McCormick, MD (Medical College of Wisconsin, Milwaukee, WI)

6 MIC creep

Ian M. Gould, MD (Aberdeen Royal Infirmary, Aberdeen, UK)

9 Swine livestock production as a risk factor for community-associated MRSA in

Pennsylvania

Joan A. Casey, MA and Brian S. Schwartz, MD, MS (Johns Hopkins Bloomberg School of Public Health, Baltimore, MD)

13 Diagnostics for invasive infection: Biomarkers and antibiotic utilization

Devandra N. Amin, MD, FCCM, FCCP (Morton Plant Hospital, Clearwater, Florida, Univ. of South Florida School of

Medicine) and Philipp P. Schuetz, MD, MPH (Univ. Hospital Basel, Basel Switzerland)

MRSA FIELD REPORTS & RELATED NEWS

17 Characterization of methicillin-resistant Staphylococcus aureus isolated in Bulgarian

hospitals, 2005-2011

Dimitar Nashev (National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria)

20 Methicillin-resistant Staphylococcus aureus in Cuba

Gilda Toraño Peraza, PhD and Alexis Monzote López, MD (Pedro Kouri Institute, Havana, Cuba)

22 MRSA News

23 APUA Headquarters and Chapters in Action

24 Obituaries; Upcoming Events

25 APUA Leadership and Chapter Awards

26 Policy Updates

27 News and Publications of Note

NEWSLETTER PUBLISHED CONTINUOUSLY SINCE 1983 BY THE ALLIANCE FOR THE PRUDENT USE OF ANTIBIOTICS

December 2013

Volume 31, No. 3

Healthcare- and Community-Associated MRSA

Clumps of MRSA bacteria, magnified 2390x Source: CDC

Visit our website Support our work

2 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA

Chief Executives Stuart B. Levy, President

Thomas F. O’Brien, Vice President

Board of Directors Stuart B. Levy, Chairman

Sherwood Gorbach

Gordon W. Grundy

Bonnie Marshall

Thomas F. O’Brien

Arnold G. Reinhold

Dennis Signorovitch

Philip D. Walson

Mary Wilson

APUA Staff Barbara Lapinskas, Administrative Director

Jane Kramer, Program Director

Kathleen Young, Projects Consultant

Stuart B. Levy, Newsletter Editor Bonnie Marshall, Associate Editor

Rebecca Crowder, Assistant Editor

Michelle Haan, Contributor

Advisory Board Jacques F. Acar, France

Werner Arber, Switzerland

Fernando Baquero, Spain

Michael l. Bennish, USA

Otto Cars, Sweden

Patrice Courvalin, France

Jose Ramiro Cruz, Guatemala

Julian Davies, Canada

Abdoulaye Djimde, Mali

Paul Farmer, Haiti

Walter Gilbert, USA

Herman Goossens, Belgium

Sherwood l. Gorbach, USA

Ian M. Gould, Scotland

George Jacoby, USA

Sam Kariuki, Kenya

Ellen L. Koenig, Dominican Republic

Advisory Board (cont.) Calvin M. Kunin, USA

Jacobo Kupersztoch, USA

Jay A. Levy, USA

Scott McEwen, Canada

Jos. W.M. van der Meer, The Netherlands

Richard P. Novick, USA

Iruka Okeke, USA & Nigeria

Maria Eugenia Pinto, Chile

Vidal Rodriguez-Lemoine, Venezuela

José Ignacio Santos, Mexico

Mervyn Shapiro, Israel

K. B. Sharma, India

Atef M. Shibl, Saudi Arabia

E. John Threlfall, United Kingdom

Alexander Tomasz, USA

Thelma e. Tupasi, Philippines

Anne K. Vidaver, USA

Fu Wang, China

Thomas E. Wellems, USA

Bernd Wiedemann, Germany

APUA Project Partnerships: The Bill and Melinda Gates Foundation

The Pew Charitable Trusts

U.S. National Institute of Health (NIH)

Pan American Health Organization

(PAHO)

U.S. Agency for International Develop-

ment (USAID)

U.S. Department of Agriculture

U.S. Office of Homeland Security

National Biodefense Analysis and Coun-

termeasures Center

The World Bank

World Health Organization (WHO)

Centers for Disease Control and Preven-

tion (CDC)

U.S. Food and Drug Administration

Ministries of Health

U.S. Defense Threat Reduction Agency

Supporting Chapters: APUA—Abu Dhabi

APUA—South Korea

Australian Society for Antimicrobials

(APUA-Australia)

British Society for Antimicrobial Chemo-

therapy (APUA-UK)

APUA gratefully acknowledges unrestrict-

ed grants from corporate sponsors:

Leadership Level ($20,000+) Clorox Healthcare

Bayer Healthcare Pharmaceuticals

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Alere Inc.

bioMérieux

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Introduction to this issue

Staphylococcus aureus has proved to be as an extremely

versatile pathogen—having emerged with penicillin resistance

in 1942, erythromycin, streptomycin and tetracyline resistances

in the 1950s, followed by resistance to methicillin in 1961. By

the early 2000s, it manifested as a multidrug-resistant super

pathogen exceeding 50% of all S. aureus in US intensive care

units, Latin America and the Asia-Pacific. The responsible

culprit was a mobile genomic element—the staphylococcal

cassette chromosome (SCC), carrying mecA and a PBP2a

transpeptidase gene with reduced affinity for beta-lactam

antibiotics.

The appearance of VISA (vancomycin-intermediate S. aureus)

in 1996 was also of growing concern and ultimately heralded

the onset of full-blown resistance to vancomycin—a drug of

last resort for multi-resistant staph. Currently still rare (13

cases of VRSA reported in the US since 2002), its occurrence

appears predisposed by chronic underlying

conditions such as skin ulcers and diabetes,

prior infections, colonization by MRSA or

Enterococcus and previous treatment with

vancomycin. Appearing some 40 years after

the advent of vancomycin, this resistance was

mediated by the vanA gene, acquired from

Enterococcus.

Concurrently, a new pandemic was spread-

ing outside the hospital, starting with the

appearance in the 1990’s of distinct strains

that caused purulent skin infections or

pneumonia within Australian youth having

no health-care contact. While generally

more susceptible to antibiotics, community-

associated S. aureus (CA-MRSA) commonly

carried the highly virulent Panton-Valentine

leukocidin gene (PVL gene). With their

considerable propensity for evolution, these

strains soon entered hospitals and began

causing invasive infections, thus blurring the

“community” distinction.

Currently MRSA clones are identified by

pulsed-field gel electrophoresis (PFGE)

patterns (e.g., USA 100), by multilocus

sequence typing and by spa typing, which

indicates variants of the polymorphic X

region of the protein A gene (spa). Five major pandemic clones

account for ~70% of hospital MRSA: Iberian, Brazilian,

Hungarian, New York/Japan (or USA100) and Pediatric. The

major MRSA clones are believed to have arisen from

successful epidemic methicillin-sensitive S. aureus (MSSA).

Strain USA 300, which spread rapidly across the US, is now

the predominant cause of skin and soft tissue infections in the

community setting. With the identification of a distinguishable

cluster of genes known as ACME (arginine catabolic mobile

element), it is now postulated that these genes were assembled

in the commensal skin bacterium Staphylococcus epidermidis

and only recently transferred horizontally into the ancestor of

the current USA 300 strain. The speG gene of this cluster

reportedly confers a set of multiple selective advantages over

other clones, including enhanced adhesion and biofilm

properties, resistance to antibiotics and also to polyamines,

by Bonnie Marshall and Rebecca Crowder (APUA staff)

Introduction • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 3

Introduction continued on Page 5

The Cost of Methicillin-resistant Staphylococcus aureus

in Pediatric Neck and Pharyngeal Infections

Michael E McCormick, MD

Assistant Professor, Division of Pediatric Otolaryngology, Medical College of Wisconsin and Children's

Hospital of Wisconsin

The incidence of methicillin-resistant Staphylococcus aureus

(MRSA), especially community-acquired-MRSA (CA-MRSA),

infections has been increasing over the last decade.1,2 Not

confined to adults, the troubling trend of increased MRSA in

the pediatric population is the focus of a great deal of research.3

While MRSA obviously presents treatment challenges with

regard to antimicrobial resistance, there exists another growing

problem associated with the rise of MRSA: the socioeconomic

implications. Studies have demonstrated an overall increase in

resource utilization associated with MRSA.4 Most of this

increased burden comes from longer hospital stays, inadequate

or delayed antibiotic use, and the use of newer, more expensive

antimicrobial agents needed to treat patients with MRSA

appropriately.

The overall increased incidence of

MRSA in children has been

paralleled by a rise in the incidence

of MRSA in head and neck

infections, including cellulitis and

deep neck abscesses.5-7 We re-

cently published our database

analysis of more than 3500 children

treated across the United States for

MRSA cervical infections.8 The average cost of each child’s

hospitalization was more than $20,000, and almost twenty

percent of children had hospitalization charges in excess of

$25,000. Most stayed in the hospital more than 4 days,

especially younger ones. Sixty percent of children required at

least one surgical procedure during their hospitalization, most

commonly incision and drainage of an abscess.

One of the keys to combating rising costs when fighting a

particular disease or illness is being able to identify patients

who may require additional resources to treat that disease.

There exists a known increase in the prevalence of MRSA in

non-white communities in the United States.9,10 It has been

proposed that this difference may be confounded by factors

such as socioeconomic status or the increased prevalence of

comorbid conditions in certain populations. For instance,

diabetes mellitus and HIV infection are more prevalent in

blacks in the United States. These illnesses are known to be

associated with compromise of the patient’s native immune

functions.

Issues with access to care have also been described for lower

socioeconomic groups, and it is plausible that this discrepancy

in access to care can explain the increased severity and

mortality associated with MRSA infections in some of these

populations. Our study found longer hospitalizations and an

increased need for surgical drainage in non-white children. In

addition, children from lower socioeconomic backgrounds also

required surgical drainage more frequently than other children.

We can potentially explain this finding

by suggesting that children from lower

socioeconomic groups who might have

issues with access to care are

presenting to the hospital with more

advanced MRSA infections. Therefore,

they are potentially undergoing surgical

drainage procedures at an earlier point

in their hospitalizations.

Healthcare in the United States will be

undergoing major changes in 2013 and 2014 (and beyond),

primarily as a result of the Affordable Care Act and budget

sequestration.11 More than ever, the “cost” of the care we

provide will be scrutinized and analyzed. The growing

incidence and associated cost of MRSA in today’s medical

environment will remain a microbiological and socioeconomic

challenge in both adult and pediatric medicine. Understanding

the socioeconomic aspects of a disease like MRSA can allow

researchers and healthcare providers to quickly identify and

treat patients infected with, carrying, or at risk for MRSA.

References

1. Johnigan RH, Pereira KD, Poole MD. Community-acquired

methicillin-resistant Staphylococcus aureus in children and

adolescents: changing trends. Archives of otolaryngology--head &

neck surgery. 2003;129(10):1049-52.

References Continued on Page 8

4 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • McCormick

“Most of this increased burden comes from longer hospital stays, inadequate or delayed antibiotic use, and the use of newer, more expensive antimicrobial agents needed to treat patients with MRSA appropriately.”

Introduction, continued from Page 3

which are native skin compounds that confer a natural tolerance

to other MRSA clones.

In the landscape of life-threatening “superbugs,” only MRSA

infection trends have demonstrated some reason for

encouragement: recent surveillance reports suggest an actual

decline in the national rate of invasive MRSA (31.2% between

2005-2011). For the first time, the incidence of invasive

hospital-onset MRSA has fallen below that among community

residents who lack significant health-care contact. In contrast,

community-associated MRSA (CA-MRSA) infections remain

stable or have declined only slightly (5%).

Nonetheless, MRSA remains a challenging pathogen and a

major cause of morbidity and mortality worldwide, with

significant economic consequences. In the US alone, >80,000

invasive MRSA infections still occur each year, the majority of

which have community or outpatient onset. In-hospital

mortality of MRSA bloodstream infections is ~30%, and in

some centers, as high as 65%, resulting in >11,000 deaths

annually.

This issue of the APUA Newsletter features several diverse

examinations of the S. aureus resistance problem. McCormick

presents a perspective on the escalating costs of community-

based infections localized to the head and neck. The article by

Gould looks at the phenomenon of “MIC creep” and the

problems it poses in treatment of MRSA with vancomycin—

one of few remaining drugs for the most resistant MRSA

strains. Casey and Schwartz examine the impacts of antibiotic

use in high-density livestock farming on the incidence of

MRSA infections in the farming community. The articles by

Nashev and by Peraza and Lopez present international

perspectives of the MRSA problem from Bulgaria and Cuba,

respectively. These studies examine more closely the specific

strains that are circulating in non-industrialized countries on

two different continents. Lastly, this issue takes an in-depth

look at the tracking of procalcitonin levels as a new diagnostic

tool for the recognition and management of bacterial sepsis.

Procalcitonin testing is one approach to addressing the nagging

problem of discerning between bacterial- and viral-mediated

illnesses. Reliable differentiation of these two is crucial to

antimicrobial stewardship decision-making and can be highly

instrumental in reducing the unnecessary use of antibiotics for

infections by viruses and other non-bacterial agents.

Sources

Stryjewski ME and Corey GR. ( 2014) Methicillin-resistant Staphylococcus

aureus: an evolving pathogen. Clin Infect Dis 58: (Supple1) S10-S18.

Dantes R, Mu Y, Belflower

R et al (2013) National

Burden of invasive meth-

icillin-resistant Staphylo-

coccus aureus infections,

United states, 2011. JAMA

Intern Med 173:1970-78.

Lowy D. (2013) Methicillin-

resistant Staphylococcus

aureus Where is it coming

from and where is it going?

JAMA Intern Med 173:1978

-9.

Planet PJ, LaRussa SJ, Dana

A et al. (2013) Emergence

of the epidemic methicillin-

resistant Staphylococcus

aureus strain US300 co-

incides with horizontal

transfer of the arginine

catabolic mobile element

and SpeG-mediated adapt-

ations for survival on skin.

mBio online. 4(6)

Introduction, cont. • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 5

MIC Creep

Ian M. Gould, MD

Department of Medical Microbiology, Aberdeen Royal Infirmary, Aberdeen, UK

The term “MIC creep” has come to be associated with the

complicated issues around the dose response to vancomycin

when used in the treatment of staphylococcal infection, most

usually due to methicillin-resistant Staphylococcus aureus.1

The MIC (minimum inhibitory concentration) is a standard

measurement for assessing bacterial susceptibility to an

antibiotic and indicates the likely clinical response if the

antibiotic is used to treat infection. While it is a well-

established measurement, the MIC has its limitations,

particularly in the limits of reproducibility. An additional

problem when considering vancomycin MIC creep is the

breakpoint (BP), which is currently 2mg/L vancomycin for

both CLSI and EUCAST.*

“Creep” has come to mean elevated MICs within the

breakpoint—so technically still susceptible. The question

arises: elevated from what? Here is the first difficulty, as there

is no clear evidence of what the vancomycin MIC should be for

a wild-type strain of staphylococcus—that is, one that has

never been exposed to vancomycin (or another glycopeptide).2

As vancomycin has been in use since 1955, it is not even

certain that such strains exist anywhere and so one must

assume that such a figure would be the lowest that is currently

measured in community isolates (with presumably only a small

potential for exposure to glycopeptides), which would be an

MIC of 0.25/0.5mg/L. Unfortunately, as the reproducibility of

standard doubling dilution MIC tests is + 1 dilution, it is

difficult to identify MIC creep with confidence. An MIC of 1

mg/L one day may be as low as 0.5mg/L on another day or as

high as 2mg/L i.e. exactly on the BP.3 With the understanding

that different, commonly used, MIC tests all have bias up or

down from the reference micro-dilution test, and that storage of

organisms (as often happens prior to testing in surveys) can

affect the MIC, one can see nothing but increasing confusion!4-

5 But it is important that we try to resolve these issues, as the

response of serious staphylococcal infections seems quite

critically dependent upon the MIC. Perhaps the problem is the

actual MIC, rather than MIC creep; however understanding

whether creep actually exists will help us understand the

dynamics of the organism’s response to antibiotics, the ways in

which resistance can develop and the likely future utility of

vancomycin.6 The latter is immediately important as that utility

seems to be balanced on a knife’s edge at the moment. With a

BP of 2mg/L and most series showing modal MICs of 1, 1.5 or

2mg/L, we can see immediately that there is little room for

maneuver. Indeed many experts now hold that it is already too

late for vancomycin as the BP should really be reclassified to

1.0 or 1.5mg/L, depending on the method used to measure the

MIC. I would certainly concur with this position for treatment

of life-threatening infection. The evidence here is uniformly

consistent and weighty that organisms with such an MIC

respond poorly to vancomycin (or teicoplanin). However, this

also may be partly explained by the other changes (e.g. in

autolysis, accessory gene regulation and biofilm formation)

that occur simultaneously in such organisms with an elevated

MIC.

6 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • Gould

Figure 1. E test MIC of S. aureus on Mueller Hinton

agar

The antibiotic test strips above are vancomycin (VA)

and teicoplanin (TP). The MIC is read from the gradient scale at the

point of complete inhibition of bacterial growth; thus the MIC

of VA is 1.5mg/L and TP is 1.0mg/L.

*CLSI: Clinical Laboratory Standards Institute (U.S); EUCAST:

European Committee of Antimicrobial Susceptibility Testing

Some authors have maintained that the observed elevated MICs

are actually a demonstration of MIC leap—i.e., a strain

change—but the evidence for this is weak. On the other hand

there is mounting evidence that creep is an ongoing process

over years of persistent vancomycin exposure in hospital

strains, and represents sequential acquisitions of multiple

mutations in several areas of cell wall manufacture that

ultimately lead to intermediate or full GISA status.7 Such

strains can accumulate up to 20 or 30 mutations through several

different pathways, which has prevented the development of

any single molecular detection tests so far. There is mounting

evidence that storage of such organisms, even just for a few

months, leads to either loss of expression of the mutations or

loss of the mutations themselves.4,5

So what can we do to clarify the situation and ensure the best

treatment for our patients? A few suggestions for further

research are included in Table 1. One interesting debate centers

on the quest for accuracy versus reproducibility or precision.

Traditionally, the latter has been the gold standard in

susceptibility testing, particularly in surveillance surveys of

MICs and resistance where isolates are often stored for up to

several years, before testing in a central laboratory under

strictly controlled conditions. With recent observations of MIC

regression following storage, a debate has arisen on whether

striving for reproducibility produces unacceptable loss of

accuracy and rather does not reflect the actual MIC at time of

isolation.8 This is, presumably, the MIC we strive to measure,

as it will best reflect what is happening in the patient and what

the likely clinical response will be to treatment. Unfortunately,

most studies of MIC creep poorly define whether and how

isolates are stored. This, we now understand, may well affect

the results obtained from such studies and have important

implications for many future surveillance studies, even for other

classes of antibiotics.4,5

In conclusion, much work is required before we achieve clarity

on these issues. In the meantime, I recommend use of the E test

gradient MIC measurement in serious staphylococcal infection

and a BP of 1mg/L for conventional dosing schedules and 1.5

mg/L for high-dose schedules. A loading dose of either

vancomycin or teicoplanin is also necessary to rapidly achieve

therapeutic levels, as well as trough serum monitoring for

teicoplanin. New agents such as daptomycin9-10 and linezolid

are costly, but these and other drugs will almost certainly

provide benefits to critically ill patients, providing they too are

dosed properly. Lastly, if it is not possible to measure an E test

MIC, then a risk factor analysis can be performed on the

patient.11

References

1. Gould IM. 2008. Clinical relevance of increasing glycopeptide MICs

against Staphylococcus aureus. Internat J Antimicrob Agents. 31

Suppl 2:1-9.

2. Gould IM, Cauda R, Esposito S et al. 2011 Management of serious

methicillin-resistant Staphylococcus aureus infections: what are the

limits? Internat J Antimicrob Agents 37(3):202-9.

3. Lawes T, Edwards B, Gould IM. 2013. Comment on: Lack of

upward creep of glycopeptide MICs for methicillin-resistant

Staphylococcus aureus (MRSA) isolated in the UK and Ireland 2001-

07. J Antimicrob Chemother 68(7):1691-2.

4. Ludwig F, Edwards B, Lawes T, et al. 2012. J Clin Microbiol.

Effects of storage on vancomycin and daptomycin MIC in susceptible

blood isolates of methicillin-resistant Staphylococcus aureus. J Clin

Microbiol Oct;50(10):3383-7.

5. Edwards B, Milne K, Lawes T et al. 2012. Is vancomycin

MIC “creep” method dependent? Analysis of methicillin-resistant

Staphylococcus aureus susceptibility trends in blood isolates from

North East Scotland from 2006 to 2010. J Clin Microbiol 50(2);318-

25.

6. Gould IM. 2010. International Journal of Antimicrobial Agents. Is

vancomycin redundant for serious staphylococcal infection? Internat J

Antimicrob Agents 36 (Suppl 2):S55-7.

MIC creep • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 7

Relationships between different MIC testing methods and

clinical outcome

Storage of organisms before testing versus testing at time

of isolation

Strain types versus MIC

Should the break point be reduced?

Can increased vancomycin dosing compensate for MIC

creep?

Do new antibiotics give better outcomes?; are they cost

effective?

Better define the PK/PD target for glycopeptides

MICs/resistance mechanisms versus different glycol/lipo

peptide

Does MIC creep occur with other antibiotic groups?

Better define mutations/expression/stability; develop

molecular tests

Compare E test with other gradient methods

Table 1. Research Issues in MIC Creep

7. Hafer C, Lin Y, Kornblum J et al. 2012. Contribution of selected

gene mutations to resistance in clinical isolates of vancomycin-

intermediate Staphylococcus aureus. Antimicrob Agents Chemother

56;11:5845-51.

8. Reynolds R, Hope R, Warner M et al. 2012. Lack of upward creep

of glycopeptide MICs for methicillin-resistant Staphylococcus aureus

(MRSA) isolated in the UK and Ireland 2001-07. J Antimicrob

Chemother 67 (12):2919-26.

9. Ammerlaan H, Seifert H, Harbarth S et al. 2009. Adequacy of

antimicrobial treatment and outcome of Staphylococcus aureus

bacteremia in 9 Western European countries. Clin Infect Dis 49

(7):997-1005.

10. Dong H, Wang X, Dong Y et al. 2011. Clinical pharmacokinetic/

pharmacodynamic profile of linezolid in severely ill Intensive Care

Unit patients. Internat J Antimicrob Agents.38:296-300.

11. Lubin AS, Snydman DR, Ruthazer R et al. 2011. Predicting high

vancomycin minimum inhibitory concentration in methicillin

resistant staphylococcus aureus bloodstream infections. Clin Infect

Dis 52 (8):997-1002.

McCormick references, continued from Page 4

2. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-

resistant Staphylococcus aureus infections in the United States.

JAMA. 2007;298(15):1763-71.

3. Brook I. The increased risk of community-acquired methicillin-

resistant Staphylococcus aureus in neck infections in young children.

Curr Infect Dis Rep. 2012;14(2):119-120.

4. Schorr AF LT. Burden of methicillin-resistant Staphylococcus aureus

8 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • Gould; McCormick cont.

on healthcare cost and resource utilization. ISMR Update. 2006;1(2).

5. Brook I. Role of methicillin-resistant Staphylococcus aureus in head

and neck infections. J Laryngol Otol. 2009;123(12):1301-7.

6. Naseri I, Jerris RC, Sobol SE. Nationwide trends in pediatric

Staphylococcus aureus head and neck infections. Otolaryngol Head

Neck Surg. 2009;135(1):14-16.

7. Thomason TS, Brenski A, McClay J, Ehmer D. The rising incidence

of methicillin-resistant Staphylococcus aureus in pediatric neck

abscesses. Otolaryngol Head Neck Surg. 2007;137(3):459-64.

8. McCormick ME, Chun RH, Lander L, Shah RK. Socioeconomic

implications of pediatric cervical methicillin-resistant

Staphylococcus aureus infections. JAMA Otolaryngol Head Neck

Surg. 2013;139(2):124-28.

9. Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant

Staphylococcus aureus disease in three communities. New Eng J

Med. 2005;352(14):1436-44.

10. Laupland KB, Church DL, Mucenski M, Sutherland LR, Davies HD.

Population-based study of the epidemiology of and the risk factors

for invasive Staphylococcus aureus infections. J Infect Dis.

2003;187(9):1452-59.

11. CCH Incorporated. Patient Protection and Affordable Care Act;

Health Care and Education Reconciliation Act of 2010 : text of P.L.

111-148, as signed by the President on March 23, 2010; text of P.L.

111-152, as signed by the President on March 30, 2010 : JCT

technical explanation of P.L. 111-148 and P.L. 111-152. Chicago,

IL: CCH; 2010.

Swine livestock production as a risk factor for

community-associated MRSA in Pennsylvania

Joan A. Casey, MA and Brian S. Schwartz, MD, MS

Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Over 80% of antibiotics in the United States are sold for use in

livestock feeds,1 most commonly in very large, industrial

operations with a high density of animals, but with insufficient

land acreage on which to spread, and thus dispose of, the

produced manure (Fig. 1). Because of this antibiotic use, the

manure produced at these operations contains antibiotics,

antibiotic-resistant bacteria, and resistance genes.2 This

manure, spread on crop fields, sometimes near human

dwellings, may put people at

risk for antibiotic-resistant

infections; however, no prior

studies have formally evaluated

this question.

Methicillin-resistant Staphylo-

coccus aureus (MRSA) colon-

ization was first linked to high-

density livestock operations in

studies from Europe.3-5 A

landmark 2005 study3 reported

that the pre-valence of MRSA

colonization in Dutch farmers

was 760 times that of the

general population. In Europe,

a strain of MRSA called

sequence type 398 (ST398) has been the most common

colonizer of swine and their owners.4,6 In the United States, the

incidence of community-associated MRSA (CA-MRSA)

infection appeared to increase throughout the early 2000s,

without good explanation or understanding of the drivers of the

epidemic.7,8 Genetics has proven useful to the epidemiologic

investigation of MRSA, and shown that nearly all CA-MRSA

in the US carries the Panton-Valentine leukocidin (PVL)

genes.9 We hypothesized that high-density livestock operations

could play a role in the CA-MRSA epidemic.

Methods

To evaluate this, we first used electronic health records (EHR)

from 2001 to 2010 from the Geisinger Health System (GHS) in

Pennsylvania to characterize MRSA infection in a large,

geographically diverse population with urban and rural areas

and many animal feeding operations. The EHR dataset

included over 150 million records on 450,000 patients. Incident

MRSA cases were identified using EHR data, classified as CA-

MRSA or healthcare-associated (HA-MRSA) and frequency-

matched to randomly selected controls and patients with skin

and soft tissue infection (SSTI) but without a history of MRSA.

We then estimated the incidence of CA-MRSA, HA-MRSA,

and SSTIs.

To assess high-density live-

stock production as a risk

factor for MRSA infection and

SSTIs, we conducted a nested

case-control study. Using

nutrient management plans,

two individual-level exposure

variables were created, based

on the distance between

patients’ home addresses and:

(1) the location and number of

animals (livestock model); and

(2) the location of crop fields,

their acreage, and the volume

of manure applied (crop field

model). We used multilevel logistic regression to assess the

association between exposure and case status, while adjusting

for potential confounding variables: age, sex, race/ethnicity,

smoking status, antibiotic order in the two years preceding

diagnosis, Medical Assistance for health insurance as a

surrogate for low family socioeconomic status, residential

community (city, borough, or township), and community-level

socioeconomic deprivation.

We also prospectively collected MRSA isolates from a

subsample of GHS patients with MRSA infections throughout

2012 and collaborated with New York University to

characterize them molecularly. Here, the goal was to identify

particular strains of MRSA infection associated with high-

density livestock production in Pennsylvania.

Swine livestock production as a risk factor • The APUA Newsletter Vol. 31. No. 3 • © 2013 • APUA • 9

Figure 1. A swine concentrated animal feeding

operation (CAFO)

Source: USDA.gov

Findings

We identified 1,734 CA-MRSA cases, 1,519 HA-MRSA cases,

and 78,216 SSTI cases during the study period. CA-MRSA

incidence increased from 69.5 to 204.3 per 100,000 person-

years between 2005 and 2010 (the period of complete data), an

average annual increase of 34% (Fig. 2).10 Age, season,

community socioeconomic deprivation, obesity, smoking, and

antibiotic use were identified as risk factors for CA-MRSA.10

Next, we found that people with higher swine livestock

production exposure were at an increased risk of CA-MRSA

infection as well as SSTI.11 This risk was associated with both

manure-applied crop fields and operations where the animals

are raised. We also saw a significant trend across quartiles of

exposure. Patients in the highest quartile of swine crop field

exposure had a 38% increased odds of CA-MRSA infection

compared to those in the lowest (adjusted odds ratio = 1.38,

[95% CI: 1.13, 1.69]). We estimated, using the population

attributable fraction method,12 that approximately 11% of CA-

MRSA infections and SSTIs could have been prevented if the

third and fourth quartile of swine crop field exposure could be

eliminated.

Compared to patients with all other strains of MRSA,

community-onset-PVL-negative MRSA was significantly

associated with swine livestock and dairy/veal crop field

exposures, comparing quartile 4 to quartiles 1-3, with adjusted

odds ratios of 4.24 (95% CI: 1.60, 11.25) and 4.88 (95% CI:

1.40, 17.00), respectively.13 This is of interest because few

community-onset infections are PVL-negative and almost no

MRSA isolated from swine carries the PVL genes.14,15

Interestingly, we did not isolate any ST398.

Implications and recommendations

CA-MRSA infection costs Americans between $0.5 and $2.2

billion annually.16 Despite recent evidence that CA-MRSA

incidence is declining in cities,17 we found no such evidence

across a large and varied geography in 38 counties in

Pennsylvania.

Prior studies have reported associations of MRSA colonization

and high-density livestock production, which does not directly

contribute to this healthcare burden. We conducted the first

study of MRSA infection in the community and high-density

livestock production. We found that both livestock operations

where swine were raised, as well as crop fields where their

manure was applied, were associated with increased risk of CA

-MRSA infection and SSTI.

Our work suggests that studies of colonization could

potentially lead to erroneous conclusions about infection risk.

While there is ample evidence that those in contact with

livestock have increased prevalence of ST398 MRSA col-

onization,3,4,14 data suggest ST398 MRSA infection is rare.18-20

We demonstrated that other molecular types of MRSA beyond

ST398 might be associated with these practices.

Our findings have implications for the role of livestock

operations in the MRSA epidemic, the different roles of

colonization and infection studies, and the identification of

other MRSA strains that may be arising from high-density

livestock production. Our data suggest that beyond the

established risk of MRSA in underserved urban populations,

livestock production may pose risk to residents in a range of

residential settings, from rural to suburban and small town

settings. We used novel, inter-disciplinary methods and

collaborated among multiple institutions to add to the mounting

evidence that antibiotic use in livestock feeds bears these

previously unrecognized public health externalities.

10 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • Casey & Schwartz

Figure 2. Incidence of MRSA infection and SSTI*

CA-MRSA = community-associated MRSA, HA-MRSA =

healthcare-associated MRSA, SSTI = skin and soft tissue infection

*per 100,000 person-years among the Geisinger Clinic’s primary-care

patients, 2005-2009. Published figure differed slightly due to a

programming error that excluded 48 MRSA cases from the analysis.

Swine livestock production as a risk factor • The APUA Newsletter Vol. 31. No. 3 • © 2013 • APUA • 11

Based on our results, we recommend three actions, ranging

from simple to more difficult:

1. Replication of our findings

2. Communication of the results to the agricultural sector to

help them understand the public health externalities of

current practices

3. Removal of antibiotics from livestock feeds

References 1. Love DC, Davis MF, Bassett A, et al. Dose imprecision and

resistance: free-choice medicated feeds in industrial food animal

production in the United States. Environ Health Perspect. 2011;119

(3):279-83.

2. Elmund GK, Morrison S, Grant D, Nevins M. Role of excreted

chlortetracycline in modifying the decomposition process in feedlot

waste. Bull Environ Contam Toxicol. 1971;6(2):129-32.

3. Voss A, Loeffen F, Bakker J, et al. Methicillin-resistant

Staphylococcus aureus in pig farming. Emerg Infect Dis. 2005;11

(12):1965-66.

4. Graveland H, Wagenaar JA, Heesterbeek H, et al. Methicillin-

resistant Staphylococcus aureus ST398 in veal calf farming: human

MRSA carriage related with animal antimicrobial usage and farm

hygiene. PLoS One. 2010;5(6):e10990.

5. Juhász-Kaszanyitzky, Jánosi S, Somogyi P, et al. MRSA

transmission between cows and humans. Emerg Infect Dis. 2007;13

(4):630.

6. Lewis HC, Molbak K, Reese C, et al. Pigs as source of methicillin-

resistant Staphylococcus aureus CC398 infections in humans,

Denmark. Emerg Infect Dis. 2008;14(9):1383-89.

7. Crum NF, Lee RU, Thornton SA, et al. Fifteen-year study of the

changing epidemiology of methicillin-resistant Staphylococcus

aureus. Am J Med. 2006;119:943-951.

8. Liu C, Graber CJ, Karr M, et al. A population-based study of the

incidence and molecular epidemiology of methicillin-resistant

Staphylococcus aureus disease in San Francisco, 2004-2005. Clin

Infect Dis. 2008;46:1637-46.

9. David MZ, Daum RS. Community-associated methicillin-resistant

Staphylococcus aureus: epidemiology and clinical consequences of

an emerging epidemic. Clin Microbiol Rev. 2010;23:616-87.

10. Casey JA, Cosgrove SE, Stewart WF, et al. A population-based study

of the epidemiology and clinical features of methicillin-resistant

Staphylococcus aureus infection in Pennsylvania, 2001-2010.

Epidemiol Infect. 2013;141(6):1166-79.

11. Casey JA, Curriero FC, Cosgrove SE, et al. High-density livestock

operations, crop field application of manure, and risk of community-

associated methicillin-resistant Staphylococcus aureus infection in

Pennsylvania. JAMA Intern Med. 2013.

Figure 3. Crop field locations and MRSA rates

12 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • Casey & Schwartz

12. Rockhill B, Newman B, Weinberg C. Use and misuse of population

attributable fractions. Am J Public Health. 1998;88(1):15-19.

13. Casey JA, Shopsin B, Cosgrove SE, et al. Molecular characterization

of MRSA infection and association with high-density livestock

production in Pennsylvania (in press). Environ Health Perspect.

2013.

14. Smith TC, Male MJ, Harper AL, et al. Methicillin-resistant

Staphylococcus aureus (MRSA) strain ST398 is present in

midwestern U.S. swine and swine workers. PLoS One. 2009;4

(1):e4258.

15. Sunde M, Tharaldsen H, Marstein L, et al. Detection of methicillin-

resistant Staphylococcus aureus sequence type 8 in pigs, production

environment, and human beings. J Vet Diagn Invest. Mar 2011;23

(2):348-50.

16. Lee BY, Singh A, David MZ, et al. The economic burden of

community-associated methicillin-resistant Staphylococcus aureus

(CA-MRSA). Clin Microbiol Infect. 2013;19(6):528-36.

17. Dantes R, Mu Y, Belflower R, et al. National burden of invasive

methicillin-resistant Staphylococcus aureus infections, United States,

2011. JAMA Intern Med. 2013.

18. Golding GR, Bryden L, Levett PN, et al. Livestock-associated

methicillin-resistant Staphylococcus aureus sequence type 398 in

humans, Canada. Emerg Infect Dis. 2010;16(4):587-94.

19. Salmenlinna S, Lyytikainen O, Vainio A, et al. Human cases of

methicillin-resistant Staphylococcus aureus CC398, Finland. Emerg

Infect Dis. 2010;16(10):1626-29.

20. Wulf MW, Verduin CM, van Nes A, et al. Infection and colonization

with methicillin-resistant Staphylococcus aureus ST398 versus other

MRSA in an area with a high density of pig farms. Eur J Clin

Microbiol Infect Dis. 2012;31(1):61-65.

APUA’s Antibiotic Stewardship Webinar Series

Past webinar available for viewing:

Containing Healthcare Associated Infections Through

Antibiotic Stewardship

This webinar:

Describes trends of major HAIs including MRSA, ESBLs

and C. difficile Reviews the causes and mechanisms driving antibiotic

resistance problems Explains the link between antibiotic overuse and the

emergence of resistant infections Reviews effective ASP practices and the importance of

diagnostics in improving antibiotic treatment and

minimizing resistance Illustrates specific examples to enhance hospital-based

antimicrobial stewardship

Presenters:

Stuart Levy, MD and Shira Doron, MD, MS

Tufts University School of Medicine

VIEW HERE

Biomarkers and antibiotic

utilization

Procalcitonin and Antibiotic management

Respiratory tract infections (RTI) remain the most common

illness in humans, responsible for the most physician or

emergency room visits and the most frequent cause of sepsis.

While mortality is primarily associated with bacterial

pneumonia or severe influenza, most patients have a mild viral

illness.1 Interestingly, 75% of all antibiotic doses are prescribed

for acute RTI, the majority of which are viral and not bacterial

in etiology.2 Early differentiation between viral and bacterial,

as well as severity of infection, are key to managing acute RTI,

especially given evidence from studies that demonstrate that

early and appropriate antibiotic use improves survival.3

Concurrently, the need for prudent antibiotic utilization

avoiding overuse and prolonged use—is important for

minimizing antibiotic-related complications, including side

effects, drug interactions, development of resistance, and

secondary infection such as Clostridium difficile colitis. Initial

history, physical signs, imaging studies and current laboratory

data do not reliably differentiate viral from bacterial infection.4

Blood cultures have a low sensitivity, and sputum cultures, if

available, have a low specificity due to quality, contamination

and colonization issues.5

An innovative approach to assessing the likelihood and

severity of a bacterial infection is the use of blood biomarkers

that reflect the host response to infection. Although there are

many markers of an acute inflammatory response, only a few

have undergone rigorous, randomized clinical trials that

evaluate the clinical outcome associated with antibiotic

management strategies. Procalcitonin (PCT) has been

evaluated in numerous such studies and has been shown

to be more specific for bacterial infection than traditional

white cell count and C-reactive protein.5 In response to a

bacterial infection, PCT is released from multiple tissues

via direct stimulation of cytokines, including interleukin-

1β, interleukin-6, and tumor necrosis factor 1α (TNF1α).

The degree of up-regulation of PCT correlates with the

severity of bacterial infection.6-8 Conversely, interferon g

is the cytokine released in response to a viral infection.

This blocks up-regulation of PCT, resulting in a higher

specificity of PCT for bacterial infections.9,10

Quantitatively, PCT may help distinguish severe

bacterial infections from mild viral syndromes.11 PCT

shows a consistent kinetic profile over time with rapid up

-regulation within 6-12 hours of a severe bacterial

infection and a predictable daily decrease by 50% as

infection is controlled by host defenses, source control

and antibiotics12 (Fig. 1).

Given these characteristics, many studies have evaluated

the usefulness of PCT for improving clinical

management of patients with respiratory tract infection in

four important areas: diagnosis, initiation of antibiotics,

severity of illness and antibiotic duration.

Biomarkers and antibiotic utilization • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 13

Devandra N. Amin, MD, FCCM, FCCP Morton Plant Hospital, Clearwater, Florida, Univ. of South Florida School of Medicine

Philipp P. Schuetz, MD, MPH Univ. Hospital Basel, Basel, Switzerland

Figure1. PCT plasma concentrations (ng/ml) in infection

PCT plasma concentrations (ng/ml) following infusion of a patient with a

solution that was accidentally contaminated with Acinetobacter baumanii.

During the first phase of induction (<6h), PCT increased by approximately

0.5 ng/ml per hour after a latency phase of about 2-3 hours, followed by

massive PCT production at the rate of approximately 50 ng/ml per hour.

Adapted from Brunkhorst F.M. et al. 13

PCT for diagnosis of significant bacterial respiratory tract

infection

Numerous studies have investigated the PCT for initial

diagnosis of a bacterial infection and differentiation from viral

infection. In one study of 925 patients with community-

acquired pneumonia (CAP), 7.9% of patients were bacteremic.

PCT was significantly increased in bacteremic patients

compared to non-bacteremic patients. Less than 1% of patients

had a positive blood culture if the initial PCT level was

<0.25mg/L, which increased to greater than 20% in patients

with initial PCT >2.5mg/L.5 Another study investigated 103

patients with confirmed influenza A (H1N1). PCT had an area

under the curve (AUC) of 0.90, differentiating the 48 patients

with bacterial super-infection from patients with viral

pneumonia only (PCT cut off of 0.8 mg/L). The negative

predictive value was 91% for excluding bacterial co-infection.11

Prognostic value for prediction of adverse outcomes

Clinical risk scores, such as APACHE or SAPS II, are

somewhat limited in assessing disease severity and these scores

are only validated when admission values are available.14,15

Indeed, the utility of monitoring these scores over the course of

sepsis is not well-established. Thus, there is interest in

predictive use of biomarkers that: 1) are objectively and rapidly

measurable; 2) respond to clinical recovery and 3) add relevant,

reliable, real-time information.16 A recent derivation-validation

cohort study using retrospective data from two independent

U.S. critical care institutions found a high prognostic value

when considering the 72-hour PCT kinetic for sepsis

mortality.17 A PCT decrease of >80% over 72 hours had a

negative predictive value of 90% (and 91% to exclude ICU

mortality) which may aid in identifying individuals at reduced

risk—thus good early ICU discharge candidates. Conversely,

no decrease, or an increased PCT, had a positive predictive

value of 35-50%, helping to flag patients who were at high

mortality risk and likely to require treatment escalation.

PCT and antibiotic management

To date, a total of 14 randomized controlled trials with over

4,000 patients have assessed the efficacy and safety of using

PCT for antibiotic initiation, duration and cessation in a range

of respiratory illnesses—including acute exacerbation of

COPD, bronchitis, asthma, community acquired pneumonia,

sepsis, ventilator associated pneumonia and postoperative

pneumonia. All studies used somewhat similar protocols,

which recommended initiation or discontinuation of antibiotics

based on PCT levels. Several cutoff ranges were used reflecting

the increase in likelihood of bacterial infection with higher PCT

levels. Cutoff levels were adapted to the clinical setting or

acuity of the patient.18

In low-acuity settings (primary care) and low-acuity conditions

(bronchitis), PCT levels were used to withhold or prescribe

antibiotics. In higher acuity patients with more severe findings

(patients with pneumonia requiring hospitalization and ICU

patients with sepsis), PCT was used not for initiation of

antibiotics, but rather for discontinuation when a predetermined

drop in PCT levels was achieved with concordant clinical

improvement.

In all 14 studies this strategy proved to be highly effective in

reducing antibiotic exposure. In patients with a lower risk of

recurrent infection, PCT guidance reduced antibiotic

prescription rates by 40-75% in primary care patients with

upper and lower respiratory symptoms; by 60-75% in patients

with bronchitis; and by 30-45% in patients with an acute

exacerbation of COPD. In higher acuity patients with

community-acquired pneumonia, PCT guidance reduced

antibiotic duration by 35-55% and by about 35% in patients

with ventilator-associated pneumonia. Crucially, there was no

increase in mortality or other adverse events during the course

of the various studies.18 In addition, a prospective real-life

multicenter, multinational evaluation of a PCT guidance

algorithm study also found significant reduction in antibiotic

usage, without increase in adverse outcomes.19

Utilization of PCT in the antibiotic management of patients

with respiratory infection

Algorithms for the diagnosis, prognosis and therapy of both

low-acuity and high-acuity patients are presented in Figure 2.

In general, for the low-acuity patient with a PCT <0.25mg/L,

antibiotics can be withheld—or withdrawn, if the PCT remains

stable (Fig. 2A). For high-risk patients with severe respiratory

infection, empiric antibiotic therapy should not be delayed,

even with a low initial PCT (0.25mg/L). The progression and

response to effective treatment of severe infection is dynamic,

and serial PCT measurements at 0, 12, 24 and 48 hours help

with assessing severity of infection. PCT usually peaks within

12-48 hrs.—as the patient responds to treatment, the levels

drop by 50% per day. Catching the peak level is important for 3

reasons:

1. Prognostication—the higher the peak level, the higher the

morbidity;

2. Treatment duration can be optimized (see Fig. 2B therapy);

3. Failure to drop by 50% every 1-2 days suggests treatment

failure. Reassessment of infection source and treatment are

strongly recommended. 19

14 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • Amin & Schuetz

Biomarkers and antibiotic utilization • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 15

AB = antibiotic; CAP = community-acquired pneumonia; PCT = procalcitonin25

For patients already on antibiotics: If PCT <0.25mg/L, repeat PCT at 12-24 hours; if again <0.25mg/L, consider discontinuing antibiotics and look

for nonbacterial source of infection. If PCT >0.25mg/L, reassess PCT every 2 days. Discontinue antibiotics if patient shows clinical recovery and

PCT decreases to 0.25 mg /L (or by at least 80% to 90% from the peak level). With suspected pneumonia showing pulmonary infiltrates and >2

PCT levels <0.25mg/L over 24-48 hours, consider antibiotic discontinuation and investigate other causes (e.g., viral pneumonia, fungal

infections—including pneumocystis jiroveci pneumonia, Bronchiolitis Obliterans Organizing Pneumonia (BOOP), atelectasis, heart failure and

pulmonary emboli. If PCT levels are <0.25mg/L and bacterial infection is strongly suspected based on clinical, imaging and or microbiological

data, continue antibiotics, but consider early discontinuation and diagnostic workup for alternative causes.

Figure 2. Clinical Use of Procalcitonin

9. Christ-Crain M, Müller B. Biomarkers in respiratory tract infections:

diagnostic guides to antibiotic prescription, prognostic markers and

mediators. Eur Respir J . 2007; 30(3): 556-573.

10. Linscheid P, Seboek D, Zulewski H , et al. Autocrine/paracrine role of

inflammation-mediated calcitonin gene-related peptide and

adrenomedullin expression in human adipose tissue. Endocrinology.

2005; 146(6): 2699-2708.

11. Cuquemelle E, Soulis F, Villers D, et al. A/H1N1 REVASRLF Study

Group. Can procalcitonin help identify associated bacterial infection in

patients with severe influenza pneumonia? A multicentre study.

Intensive Care Med. 2011; 37 (5): 796-800.

12. Becker KL , Nylén ES , White JC , et al . Clinical review 167:

Procalcitonin and the calcitonin gene family of peptides in

inflammation, infection, and sepsis: a journey from calcitonin back to

its precursors. J Clin Endocrinol Metab. 2004; 89 (4): 1512-25.

13. Brunkhorst FM, Heinz U, Forycki F. et al., Kinetics of procalcitonin in

iatrogenic sepsis. Intensive Care Med 1998, 24: 888-89.

14. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et

al. Surviving Sepsis Campaign guidelines for management of severe

sepsis and septic shock. Critical care medicine. 2004;32(3):858-73.

15. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign:

international guidelines for management of severe sepsis and septic

shock: 2008. Critical care medicine. 2008; 36(1):296-327.

16. Schuetz P, Wolbers M, Christ-Crain M, et al. Prohormones for

prediction of adverse medical outcome in community-acquired

pneumonia and lower respiratory tract infections. Crit Care. 2010;14

(3):R106.

17. Schuetz P, Maurer P, Punjabi V, et al. Procalcitonin decrease over 72

hours in US critical care units predicts fatal outcome in sepsis patients.

Crit Care. 2013;17(3):R115.

18. Schuetz P , Chiappa V, Briel M , Greenwald JL . Procalcitonin

algorithms for antibiotic therapy decisions: a systematic review of

randomized controlled trials and recommendations for clinical

algorithms. Arch Intern Med. 2011; 171 (15): 1322-31

19. Schuetz P, Amin DN, Greenwald JL. Role of procalcitonin in

managing adult patients with Respiratory Tract Infections. Chest

2012;141(4):1063-73.

20. Sponholz C, Sakr Y, Reinhart K , Brunkhorst F. Diagnostic value and

prognostic implications of serum procalcitonin after cardiac surgery: a

systematic review of the literature. Crit Care. 2006; 10 (5): R145.

21. Schuetz P, Affolter B, Hunziker S, et al . Serum procalcitonin, C-

reactive protein and white blood cell levels following hypothermia

after cardiac arrest: a retrospective cohort study. Eur J Clin Invest.

2010; 40 (4): 376-81.

In patients suspected of respiratory infection complicating

major surgery, trauma or cardiogenic shock, PCT levels may

reflect the underlying cytokine response to major tissue injury,

and not necessarily reflect an infectious process alone. Serial

procalcitonin levels may be suggestive of infection when a

secondary elevation is seen if the underlying condition is stable

or improving.20,21

These recommendations and guidelines are valid only with

highly sensitive PCT assays and should not be applied to

patient populations that have not been studied, e.g., immune-

compromised patients, neonates and pregnant females.

Importantly, no diagnostic test should be used in isolation, out

of clinical context, for decision-making. PCT does not replace

good clinical evaluation and judgment. The correct

understanding of PCT levels is predicated on the physician’s

pretest probability for the test. Given the appropriate clinical

situation, the addition of the highly sensitive PCT biomarker

appears to help in the diagnosis of upper and lower respiratory

tract bacterial infection and more importantly, aids in guiding

antibiotic duration, based on its strong negative predictive

value.

References

1. Macfarlane JT , Colville A, Guion A, Macfarlane RM, Rose DH.

Prospective study of etiology and outcome of adult lower-respiratory-

tract infections in the community. Lancet. 1993; 341 (8844): 511-14.

2. Carlet J. Rapid diagnostic methods in the detection of sepsis. Infect Dis

Clin North Am. 1999; 13 (2): 483-94.

3. Kumar A, Roberts D, Wood KE, et al . Duration of hypotension before

initiation of effective antimicrobial therapy is the critical determinant

of survival in human septic shock. Crit Care Med. 2006; 34 (6): 1589-

96

4. Müller B, Harbarth S, Stolz D, et al. Diagnostic and prognostic

accuracy of clinical and laboratory parameters in community-acquired

pneumonia. BMC Infect Dis. 2007; 7: 1.

5. Müller F, Christ-Crain M, Bregenzer T, et al ProHOSP Study Group .

Procalcitonin levels predict bacteremia in patients with community-

acquired pneumonia: a prospective cohort trial. Chest 2010; 138 (1):

121-29.

6. Schuetz P, Christ-Crain M, Albrich W, et al. ProHOSP Study Group.

Guidance of antibiotic therapy with procalcitonin in lower respiratory

tract infections: insights into the ProHOSP study. Virulence. 2010;1

(2):88-92.

7. Christ-Crain M, Stolz D, Bingisser R , et al. Procalcitonin guidance of

antibiotic therapy in community-acquired pneumonia: a randomized

trial. A m J Respir Crit Care Med. 2006; 174 (1): 84-93.

8. Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro- versus anti-

inflammatory cytokine profile in patients with severe sepsis: a marker

for prognosis and future therapeutic options. J Infect Dis. 2000; 181

(1): 176-80.

16 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • Amin & Schuetz

distribution. These two spa types comprised the majority

(43.2%) of MRSA isolates in the present study. This lineage

has been reported in many European countries, including those

neighboring to Bulgaria. ST239 is widely distributed in Greece

and is the predominant endemic clone in the University

hospital in Patras.5 Spa type t030 has been described as the

prevalent MRSA spa type in Turkey6 and Romania.1 Therefore,

the prevalence of ST239 related spa types in Bulgaria is not

surprising. The majority of Bulgarian t030/t037 MRSA strains

reflected the ST239 multi-resistance pattern (Table 1).

Spa types t010 and t002, (SCCmec IV and negative for PVL-

genes) were frequently associated with ST5-IV, known as

Pediatric clone (http://spa.ridom.de/mlst.shtml). According to

spa-server, t010 was detected in Austria, Belgium, Czech

Republic, Denmark, France, Germany, Island, Ireland,

Netherlands, Poland, Spain, Sweden, Switzerland and UK, but

not reported in Bulgaria’s neighbors, Greece, Turkey and

Romania (http://spa.ridom.de/frequencies.shtml). In the present

study, most of the ST5-IV related isolates were resistant only to

beta-lactams. Sporadic t010 isolates showed resistance to

kanamycin, gentamicin or tetracycline.

As reported previously, spa type t300 and t1143 were

associated with ST30.7,8 PVL-positive ST30-IV is an important

pandemic community-associated clone known as Southwest

Pacific Clone, USA1100 or West Samoan Phage Pattern

(WSPP) clone. Interestingly, in the present study, t1143

isolates were found to be hospital-associated. However, CA-

MRSA has been increasingly associated with nosocomial

infections with various reports of CA-MRSA isolation in

European hospitals.9,10

As shown above, ST239 associated spa-types t030/t037 and

ST30 related t1143 and t300 were clustered together in spa CC

1143. The wrong clustering of spa types of ST239 with those

found in CC30 has been reported previously and could be

explained by recombinative replacement of a large stretch of

Characterization of methicillin-resistant Staphylococcus

aureus isolated in Bulgarian hospitals, 2005-2011

Dimitar Nashev, MD, PhD

Staphylococcal Reference Lab at the National Center for Infectious and Parasitic Diseases, Sofia, Bulgaria

In collaboration with: L. Bizeva1, D. Merdzhanov1, E. Keuleyan2, T. Kantardjiev1 1Microbiology Dept., National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria 2Microbiology Dept., Medical Institute of Ministry of Interior, Sofia, Bulgaria

Reports documenting the clonal spread of MRSA in Bulgaria

are still limited in number and focused mainly on single

hospital outbreaks, isolates collected in a short period of time

or sporadic cases of community-associated MRSA infections.1,2

We aimed to define the most prevalent spa types of MRSA

found in Bulgarian hospitals in the period 2005-2011 and to

associate them with the corresponding sequence types (ST),

SCCmec type, PVL (Panton-Valentine leukocidin) production

and phenotype of antibiotic resistance.

A total of 293 MRSA isolated between 2005 and 2011 from 31

hospitals in 20 cities were studied. The isolates were grouped

according to their antibiotic resistance phenotypes and 104

representative isolates were selected for further genotyping,

including spa sequence typing, SCCmec typing3 and PCR

detection of the genes encoding PVL.4 The existing sequence

database for spa types (http://spa.ridom.de) and literature data

were used to associate spa types with a particular MLST

sequence type (ST).

Among 18 spa types defined, the most prevalent was t010

(33.7%), followed by t037 (28.8%), t030 (14.4%), t1143 and

t1368 (2.9%). The remaining spa types were sporadically

isolated. The isolates belonging to spa types t030 and t037

possessed SCCmec type III, whereas all other isolates were

found to carry SCCmec type IV. Only isolates with spa types

t1143, t300 and t1368 were positive for PVL genes. (Table 1)

Using the BURP (Based Upon Repeat Pattern) algorithm

integrated in Staphtype software v.2.2.1, two spa-clusters were

defined: spa–clonal complex (CC) 1143 (t030, t037, t300,

t1143, t1507, t3140) and spa CC 010 (t002, t010, t442, t855,

t2695) (Table 1). Eight isolates were defined as singletons

(t024, t056, t731, t1368, t1531, t1872, t2143, t2970) and one

spa type was excluded (t386).

Spa types t030 and t037 are associated with ST239, a

pandemic MRSA lineage characterized by worldwide

Field report—Bulgaria • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 17

18 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • Nashev, et al

Table 1. Characteristics of MRSA spa types in Bulgarian hospitals (2005-2011)

Spa Type n (%) Antibiotic resistance

phenotype SCCmec PVL Inferred ST

t010 35 (33.7 %) Ox, K-R/S, G-R/S IV - ST5 (Pediatric)

t037 30 (28.8%) Ox, K, G, T, Er/Cli const,

Cip, TMP/SMX III -

ST239 (Brazilian/

Hungarian)

t030 15 (14.4%) Ox, K, G, T, Er/Cli ind,

Cip, Rif, Chl-R/S III -

ST239 (Brazilian/

Hungarian)

t1143 3 (2.9 %) Oх IV + ST30

t1368 3 (2.9%) Ox, K, G, T, Er/Cli ind IV + -

t002 2 (1.9%) Ox IV - ST5 (Pediatric)

t442 2 (1.9%) Ox, K, G, Er/Cli const IV - ST478

t2970 1 Ox, Er/Cli const IV - ST398

t1531 1 Ox IV - -

t2695 1 Ox, K, G, T IV - -

t855 1 Ox IV - -

t1507 1 Ox IV - CC30

t300 1 Ox IV + ST30

t3140 1 Ox, Er/Cli ind IV - CC30

t386 1 Ox, K, G, Er/Cli const,

Cip IV - ST1

t024 1 Ox, K, G, Er/Cli ind,

TMP/SMX IV -

ST8 (EMRSA-2/6;

USA500)

t2143 1 Ox IV - ST45(Berlin;

USA600)

t1872 1 Ox IV - -

Ox = oxacillin, K = kanamycin, G = gentamicin, Cip = ciprofloxacin, T = tetracycline, Er = erythromycin, Cli ind =

clindamycin inducible resistance phenotype, Cli const = clindamycin constitutive resistance phenotype, Chl = chloramphenicol,

TMP/SMX = tr imethopr im/sulfamethoxazole, PVL = Panton-Valentine leukocidin, ST = MLST sequence type

chromosomal DNA in MRSA isolates of CC8 by a stretch

originating from CC30 and including the spa gene.11

The PVL-negative spa types t3140 and t1507 were also

grouped in the spa CC-1143 clonal complex. Data on their

corresponding ST were not found in the spa-server, but

according to BURP-clustering they could probably belong to

CC30.

A PVL-positive spa type, t1368, defined as singleton by BURP,

was detected in three isolates (Table 1). We have not found data

on the ST association of this spa-type on the spa server or in the

literature, but the closely related spa-type t9381 was associated

with CC8; ST-72. However, for the exact ST identification,

MLST analysis should be performed.

Along with the prevalent spa types and their relatives, several

minor spa types, classified by BURP as singletons were found.

Their characteristics and ST association are shown in Table 1.

In conclusion, spa types associated with ST239 and ST5-IV

clones were largely predominant among MRSA isolates in 20

Bulgarian hospitals. Sporadic strains belonging to different

MRSA lineages, including PVL-positive CA-MRSA showed

potential for further spread of new clones in Bulgaria, although

in relatively small proportions.

References

1. Grundmann, H., et al., Geographic distribution of Staphylococcus

aureus causing invasive infections in Europe: a molecular-

epidemiological analysis. PLOS Med, 2010. 7(1): e1000215.

2. Nashev, D., L. Bizeva, and K. Toshkova, First cases of infections

caused by Panton-Valentine leukocidin positive community-acquired

methicillin-resistant Staphylococcus aureus in Bulgaria. Euro

Surveill, 2007. 12: 26.

3. Oliveira, D.C. and H. de Lencastre, Multiplex PCR strategy for rapid

identification of structural types and variants of the mec element in

methicillin-resistant Staphylococcus aureus. Antimicrob Agents

Chemother, 2002. 46(7): 2155-2161.

4. Lina, G., et al., Involvement of Panton-Valentine leukocidin—

producing Staphylococcus aureus in primary skin infections and

pneumonia. Clin Infect Dis, 1999. 29(5): 1128-1132.

5. de Sousa, M.A., et al., Two international methicillin-resistant

Staphylococcus aureus clones endemic in a university hospital in

Patras, Greece. J Clin Microb, 2003. 41(5): 2027-32.

6. Alp, E., et al., MRSA genotypes in Turkey: persistence over 10 years

of a single clone of ST239. J Infect, 2009. 58(6): 433.

7. Monecke, S., et al., A field guide to pandemic, epidemic and sporadic

clones of methicillin-resistant Staphylococcus aureus. PLoS One,

2011. 6(4): e17936.

8. Ionescu, R., et al., Molecular characterization and antibiotic

susceptibility of Staphylococcus aureus from a multidisciplinary

hospital in Romania. Microb Drug Resist, 2010. 16(4): 263-72.

9. Otter, J. and G. French, The emergence of community-associated

methicillin-resistant Staphylococcus aureus at a London teaching

hospital, 2000–2006. Clin Microb and Infect, 2008. 14(7): 670-76.

10. Köck, R., et al., The epidemiology of methicillin-resistant

Staphylococcus aureus (MRSA) in Germany. Deutsches Ärzteblatt

International, 2011. 108(45): 761.

11. Strommenger, B., et al., Assignment of Staphylococcus isolates to

groups by spa typing, SmaI macrorestriction analysis, and multilocus

sequence typing. J Clin Microb, 2006. 44(7): 2533-40.

Field report—Bulgaria • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 19

APUA’s Antibiotic Stewardship

Webinar Series

Past webinar available for viewing:

The Clinical Impact of Antimicrobial Stewardship and

Rapid Diagnostic Tests: From Bench to Bedside PACE® credit available until June 11, 2014

This webinar:

Reviews trends in antimicrobial resistance and C. difficile

infections Discusses strategies for implementing antimicrobial

stewardship in acute care hospitals Analyzes various ways in which rapid diagnostics

information can be brought from bench to bedside

Presenter:

Lilian Abbo, MD

Associate Professor of Clinical Medicine

Division of Infectious Diseases, University of

Miami Miller School of Medicine

Dr. Abbo's clinical and research areas of interest are in

antimicrobial stewardship and transplant associated

infections. Dr. Abbo has been an active member of the

Infectious Diseases Society of America Standard and Practice

Guidelines Committee and a committee member of the

International Society of Chemotherapy, Antimicrobial

Stewardship Working Group. She has published numerous

original research and review articles in antimicrobial

stewardship and immune-compromised host-associated

infections.

VIEW HERE

This is the first report of molecular typing of MRSA isolates

from Cuba and shows that the predominant clone is spa-type

149, followed by CA-MRSA USA300. This clone was first

described in the United States, where it has now become en-

demic; it’s finding in Cuba highlights the wide spread of this

strain over Latin America.9

Another study in a Havana paediatric institution between 2010

-2012 confirmed 333 MRSA isolates and revealed that 65.9%

of MRSA isolates caused severe skin and soft tissue infections

requiring hospitalization. Genes encoding PVL were detected

both in community-acquired isolates (86%) and hospital-

associated strains (54.5%), pointing to the possible movement

of MRSA clones to the hospital environment, but also suggest-

ing that hospital isolates could be producing the toxin, thus

reducing PVL as a valuable epidemiological marker.

In conclusion, MRSA is both a hospital and community prob-

lem for Cuba and demands local surveillance on prevalence

and transmission dynamics. Surveillance studies that utilize

molecular typing will lead to a better understanding of its epi-

demiology and permit the design of more assertive control

strategies. However, faced with the inability to conduct com-

prehensive studies of molecular characterization, we must

ensure that the microbiology laboratory can accurately identify

MRSA infections. Physicians must be alerted to control its

spread through prudent use of antibiotics, with an emphasis on

limiting the use of glycopeptides and prolonged therapy. Hos-

pitals must also define appropriate protocols for the manage-

ment or treatment of individuals colonized or infected with

CA-MRSA.

References

1. Holden MTG, Hsu L, Kurt K, et al. A genomic portrait of the

emergence, evolution, and global spread of a methicillin-resistant

Staphylococcus aureus pandemic. Genome Res. 2013;23:653–64.

2. Guzman-Blanco M, Mejia C, Isturiz R, et al. Epidemiology of

methicillin-resistant Staphylococcus aureus (MRSA) in Latin Amer-

ica. Int J Antimicrob Agents 2009;34:304-308.

20 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • Peraza & Lopez

Staphylococcus aureus is responsible for a wide variety of

clinical problems, ranging from skin and soft tissue infections,

to severe systemic and life threatening diseases. The organism

is relevant in the community and is commonly associated with

nosocomial infections. S. aureus possesses a large capacity to

acquire antimicrobial resistance genes, with strains currently

resistant to the majority of available antibiotics—particularly

to methicillin, a resistance reported initially in the hospital

environment (hospital-associated methicillin resistant S. aure-

us, HA-MRSA) and subsequently in the community

(community-associated methicillin resistant S. aureus, CA-

MRSA), has complicated the worldwide control of infection

by this microorganism.1

MRSA is an increasing problem in the Americas and the Car-

ibbean, but in Cuba very little is known about its epidemiolo-

gy and even less about its behavior in the community.2 Some

epidemiological data are available from independent studies of

different hospital institutions and nasal carriage surveys, but

the reports are infrequent and insufficient to estimate the

change in the morbidity and mortality of annual national fig-

ures.3-6 However, the available evidence suggests a MRSA

incidence greater than 50% in Cuban hospitals. 7

A collaborative study between Hospital Canisius-Wilhelmina

in Nijmegen, Netherlands, and Pedro Kourí Institute (IPK) in

Havana, Cuba investigated the molecular epidemiology of 68

MRSA clinical strains (isolated from wounds, bronchial/

tracheal aspirations, blood, skin, abdominal drainage and chest

tissue biopsy), prospectively collected from three major hospi-

tals in Cuba during three months in 2008. Molecular testing

was performed for detection of Panton-Valentine leukocidin

(PVL), mecA , the Sa442 element and spa typing. Forty iso-

lates were mecA positive and confirmed to be MRSA. Spa

typing identified five different spa types: t149 (n = 24), t008

(n = 8), t037 (n = 6), and one each of t4088 (closely related to

t149) and t2029 (closely related to t037). All eight t008 iso-

lates (but none of the other spa types) were PVL-positive.

Multi locus sequence typing (MLST) was performed on t008

isolates and all proved to be CC8 positive.8

Methicillin-resistant Staphylococcus

aureus in Cuba

Gilda Toraño Peraza, PhD and Alexis Monzote López, MD

Bacteriology-Mycology Department, Pedro Kourí Institute, Havana, Cuba; APUA-Cuba Members

Clínico-Quirúrgico Hermanos Ameijeiras de La Habana, Cuba. La

Gaceta de Infectología y Microbiología Latinoamericana. 2012;2

(2):47-54.

7. Latin American Resistance Surveillance Network. Annual report on

the antibiotic resistance monitoring/surveillance network, 2008. ©

PAHO HSD/CD 2011.

8. Hopman J, Toraño G, Espinosa F, et al. USA300 Methicillin-

resistant Staphylococcus aureus in Cuba. Antimicrob Resist Infect

Control. 2012;1:2.

9. Reyes J, Rincon S, Diaz L, et al. Dissemination of methicillin-

resistant Staphylococcus aureus USA300 sequence type 8 lineage in

Latin America. Clin Infect Dis 2009,49:1861-1867.

Upcoming webinar:

Antibiotics: Managing a Medical Treasure

Live Event: Friday, January 31, 2014 1:00 PM EST

PACE® credit available

Antimicrobial agents are a remarkable class of drugs that are

responsible for some of the most dramatic improvements in

medical therapy in history. However, these medicines are

also the only class of drugs whose efficacy diminishes as we

use them. The link between antibiotic use and the

development of resistance has been repeatedly made since the 1950s, yet clinicians have not learned from mistakes that have

occurred with the introduction of new antibiotics. The development of resistance to carbapenems is now one of the greatest

challenges to medicine since there is little on the horizon for patients suffering from carbapenem-resistant, gram-negative

infections. Clinicians must realize how perilously close we are to a ’post-antibiotic’ era.

While no one doubts the importance of infection control practices in limiting the spread of antibiotic-resistant organisms,

optimizing antibiotic use, also known as antibiotic stewardship, remains essential for successful control of the antibiotic

resistance. Approaches to optimize antibiotic use vary in their effectiveness; some interventions are restrictive while others are

persuasive. The overriding premise that antimicrobials are medical treasures, should guide all prescribers whenever these drugs

are used. Once begun, their continued use must be scrutinized. Antibiotic de-escalation is a complex concept comprised of three

questions: Is the patient actually infected at all? Is the patient actually infected with bacteria? How long do you need to treat with

antimicrobials?

This webinar will:

Analyze the relationship between antibiotic use and antibiotic resistance

Review the reasons for the dearth of new antibacterial antibiotics

Discuss the need for antibiotic stewardship

Describe the methods for optimizing antibiotic use including the use of biomarkers, newer diagnostic tools and approaches to

de-escalate antibiotics

Field report—Cuba • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 21

3. Nodarse R. Detection of methicillin-resistant Staphylococcus aureus

by cefoxitin sodium disc. Rev Cub Med Mil 2009;38:3-4 http://

scielo.sld.cu/scielo.php?script=sci_arttext&pid=S0138-

65572009000300004&lng=es.

4. Toraño G, Quiñones D, Hernández I, et al. Portadores nasales de

Staphylococcus aureus resistente a la meticilina entre niños

cubanos que asisten a círculos infantiles. Enferm Infecc Microbiol

Clin. 2001;19(8):367-70.

5. Hernández IT, Toraño GT, González M, González I. Staphylococcus

aureus resistente a la meticilina: detección de portadores entre

niños hospitalizados y niños sanos de la comunidad. Rev Cubana

Med Trop 2003; 55(3):153-61.

6. Espinosa F, López AL, Hart M, Toraño G. Susceptibilidad antibac-

teriana de cepas de Staphylococcus aureus aisladas en el hospital

Presenter: Robert Gaynes, MD

Professor of Medicine

Emory University School of Medicine

Dr. Gaynes is Chair of the Antimicrobial

Stewardship Committee and Infection Control

Committee at Emory University School of Medicine and the

Atlanta VA Hospital. Dr. Gaynes has authored and/or coauthored

over 145 papers/book chapters on infectious disease topics and in

2011 published a book entitled, Germ Theory: Medical Pioneers in

Infectious Diseases.

APUA’s Antibiotic Stewardship Webinar Series

REGISTER HERE

MRSA News

New compounds may boost antibiotic

efficacy for MRSA, anthrax

Thomas Poulos of University of California - Irvine and Richard

Silverman of Northwestern University have demonstrated an

approach for treating neurodegenerative diseases that may be

applicable to combating bacterial diseases. By using inhibitor

compounds to block neuronal nitric oxide synthase (NOS—an

enzyme that appears to help bacteria resist antibiotics), the

researchers believe they may be able to increase antibiotic

effectiveness. By coupling antibiotics with NOS-inhibitor

compounds, bacteria were killed off more effectively than they

were using antibiotics alone. Testing suggests that combining

the compounds with antibiotics creates a special bond that

increases the efficacy of the drug. The studies, which will be

extended to animal models, have implications for treatment of

severe bacterial pathogens, such as MRSA and anthrax.

MRSA survivors unite for World MRSA Day

Kickoff Event

On September 28, the Chicago-based non-profit MRSA

Survivors Network held its 5th Annual World MRSA Day

Kickoff Event & Global C. difficile Summit. The Chicago,

Illinois gathering brought together MRSA survivors,

physicians and lawmakers at an event designed to raise

awareness in the fight against MRSA and other healthcare-

acquired infections. The Network’s founder, Jeanine Thomas,

declared that the U.S. CDC has underreported MRSA infection

and death rates in its recent studies. Thomas also called upon

Congress to “declare MRSA and C. difficile epidemics and

appropriate funds for prevention and public awareness

campaigns.” The MRSA Survivors Network calls for a

comprehensive approach to MRSA detection and control,

including patient isolation and decolonization, strict adherence

to hand hygiene guidelines, vigilant decontamination of

surfaces, and more prudent usage of antibiotics. The kickoff

event was a precursor to World MRSA Day, (October 2), and

World MRSA Awareness Month (October).

CDC: Community-associated MRSA not

declining

A CDC study published in The Journal of the American

Medical Association (JAMA) in September sought to estimate

the burden of methicillin-resistant Staphylococcus aureus

(MRSA) among US adults. The study, titled “National Burden

of Invasive Methicillin-Resistant Staphylococcus aureus

Infections, United States, 2011,” used laboratory-based

findings to identify MRSA cultures in nine different US cities

between the years 2005 and 2011. In 2011, there were 80,461

total cases of MRSA infections across the nation. Of these,

48,353 were classified as healthcare-associated community-

onset (HACO), 14,156 as hospital-onset infections, and 16,560

as community-associated infections. Between 2005 and 2011,

national incidence rates for HACO infections and for hospital-

onset infections decreased markedly (by 27.7% and 54.2%,

respectively). Community-associated infections, however, only

decreased by 5% across the same six years. Overall, the

decreases in MRSA infection rates are encouraging signs, but

this study makes it clear that increased emphasis must be

placed on decreasing the spread of MRSA outside of the

healthcare setting.

CDC reports on pediatric MRSA

In September, the U.S. CDC published a new study in

Pediatrics that found unexpected results regarding the

incidence and prevalence of invasive MRSA infections in

children. The study, titled, “Trends in Invasive Methicillin-

Resistant Staphylococcus aureus Infections,” found that rates

of invasive pediatric MRSA between 2005-2010 were much

lower than those reported among adults. However, while

national trends in invasive adult healthcare-associated MRSA

have shown dramatic declines, no significant changes were

found among children aged three months to 17 years. Most

alarming is the CDC’s finding that community-associated

MRSA infections are actually increasing among children—

signaling the need for more prevention of MRSA infections

outside of the hospital. Lastly, it appears that both young

infants and black children are disproportionately affected by

serious MRSA infections.

22 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • MRSA news

APUA headquarters and chapters in action

APUA headquarters and chapters in action • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 23

APUA partners with Alere Inc. to build “Test

Target Treat” educational platform

Through an unrestricted educational grant from Alere, APUA

has brought together multiple experts from around the world to

contribute to a diverse collection of educational materials dedi-

cated to antimicrobial stewardship. The materials will include

clinical monographs, case studies addressing six different dis-

ease states, personal perspectives from stake holders within the

healthcare system, recorded interviews, and three educational

webinars. APUA looks forward to the roll-out process, which

will follow in the coming months. Please check here for more

details and updates as new educational pieces are added.

APUA attends ID week – presents “Learning

Lounge”

APUA president, Dr. Stuart Levy, and Executive Director,

Kathleen Young, hosted a booth at this year’s ID Week, which

took place from October 2-6 in San Francisco, CA. ID Week is

an annual collaboration between the Infectious Diseases Socie-

ty of America (IDSA), the Society for Healthcare Epidemiolo-

gy of America (SHEA), the HIV Medicine Association

(HIVMA), and the Pediatric Infectious Diseases Society

(PIDS). Every year, more than 5,500 professionals from 80

different countries attend the five-day meeting, which serves as

an educational and networking event for those with an interest

in infectious diseases.

In addition to hosting a booth that shared APUA’s mission

and recent work, Drs. Stuart Levy and Kavita Trivedi (CA

Department of Public Health) held a “Learning Lounge”

presentation and discussion titled, “Antibiotic Stewardship and

the Role of Diagnostics: Barriers and Opportunities,” which

drew over one hundred participants.

APUA participates in CDC’s Get Smart About

Antibiotics Week 2013

APUA was a proud participant in the U.S. Centers for Disease

Control and Prevention’s (CDC) annual Get Smart About Anti-

biotics Week (November 18-24). The CDC’s campaign com-

bines non-profit partners, for-profit partners, and state-based

campaigns supporting appropriate antibiotic use. The collabo-

ration sets the stage for a week-long observance of antibiotic

resistance and the need for proper usage of antibiotics. APUA

contributed throughout the week with extensive social media

communications, which culminated in a live Twitter chat host-

ed by the CDC.

Boston-area Antimicrobial Research

Network (BAARN) Meeting

Posing the question ‘What does it take to succeed in antibiotic

R&D?’ a group of like-minded stakeholders gathered for a day

-long symposium this fall as the Boston-area Antimicrobial

Research Network or BAARN. The 110 individual partici-

pants, coming from industry, academia, medical centers, and

NGOs, examined the emerging regulatory landscape and avail-

able resources to develop and utilize novel approaches to target

pathogen-directed therapies. APUA and the ~30 other organi-

zations that comprise the network pledged to meet annually

and maintain a website to share information towards their com-

mon goal.

Chapter update: APUA-Ecuador

APUA-Ecuador reports several significant accomplishments in

its recent history. This 180-member chapter has enacted con-

trol over antibiotics and established resistance surveillance

programs in five different specialty hospitals in the capital city

of Quito. In a joint effort with other Ecuadorian scientific soci-

eties, the Chapter has also submitted a letter to the Presidency

and National Assembly, alerting them to the growing issue of

bacterial resistance. The letter serves as a call-to-action and

asks for the government’s support with bacterial resistance

prevention programs. In order to better educate healthcare pro-

viders and patients on the issue of antimicrobial resistance,

APUA-Ecuador has developed a monthly publication that is

delivered to all Specialization Public Hospitals across the

country.

The Chapter also reports the hosting of two upcoming confer-

ences in Ecuador: the Pan American Congress of Infectious

Diseases, and the Pan American Association for Infectious

Diseases, which will be chaired by its leader, Dr. Ana Celi de

la Torre.

Chapter update: APUA-Nepal

Access the tenth annual APUA -Nepal Newsletter, here.

24 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • Obituaries; upcoming events

January 27-29, 2014: American Society for

Microbiology (ASM) BioDefense & Emerging Diseases

Research Meeting, Washington, DC, USA.

March 20, 2014: British Society for Antimicrobial

Chemotherapy’s Spring Meeting 2014, London, UK.

May 10-13, 2014: European Congress on Clinical

Microbiology and Infectious Diseases (ECCMID 2014),

Barcelona, Spain.

May 17-20, 2014: American Society for Microbiology’s

Annual Meeting (ASM 2014), Boston, MA, USA.

June 7-9, 2014: Association for Professionals in

Infection Control and Epidemiology’s Annual Conference

(APIC 2014), Anaheim, CA.

June 23-24, 2014: Annual Global Healthcare Conference

(GHC 2014), Singapore.

July 6-9, 2014: The Australasian Society for Infectious

Diseases (ASID) Annual Scientific Meeting, Melbourne,

Australia.

July 27- August 1, 2014: International Union of

Microbiological Societies’ 2014 Congresses, Montreal,

Canada.

XIVth International Congress of Mycology

XIVth International Congress of Bacteriology and Applied

Microbiology

XVIth International Congress of Virology

September 5-9, 2014: Interscience Conference on

Antimicrobial Agents and Chemotherapy (ICAAC 2014),

Washington, DC, USA.

October 8-12, 2014: Infectious Diseases Society of

America (IDSA), the HIV Medicine Association (HIVMA),

and the Pediatric Infectious Diseases Society (PIDS)’s ID

Week 2014, Philadelphia, PA, USA.

October 31- November 3, 2014 : 5th International

Meeting on Emerging Diseases and Surveillance - “IMED

2014,” Vienna Austria.

Upcoming Events Obituaries

Both of these APUA Scientific Advisory Board members were

instrumental in initiating and supporting the Reservoirs of

Antibiotic Resistance project.

Dr. Donald Low, an internationally

recognized Canadian microbiologist and

member of APUA’s Scientific Advisory

Board, passed away on September 18,

2013 at the age of 68. Low led an active

and meaningful career as microbiologist-

in-chief at Mount Sinai Hospital in

Toronto. He was diagnosed with a brain

tumor earlier this year. Low was most known for his tireless

efforts responding to the 2003 Toronto outbreak of severe

acute respiratory syndrome (SARS), during which he became

a public figure for the city’s response to the outbreak that

claimed 44 lives in Toronto. Over his lifespan, he co-authored

over 400 peer-reviewed articles for scientific journals and

made a name for himself as an expert in necrotizing fasciitis

(flesh-eating disease) caused by Group A Streptococcus. As

evidenced by his role at APUA, Low dedicated himself to

combating the rise of antimicrobial resistance by championing

the appropriate use of antibiotics.

Dr. Abigail Salyers, a wor ld re-

nowned research scientist, author and

professor at the University of Illinois at

Urbana-Champaign, passed away at the

age of 70 on November 6, 2013. In

1983, Salyers became the first female

tenured professor in microbiology at

Illinois. She quickly went on to become

a full professor, and received a multitude of awards in the

three decades she taught and researched there. Dr. Salyers

wrote five books and published over 200 peer-reviewed

research articles, book chapters, and reviews that were widely

read and cited. From 2001 to 2002, Abigail was president of

the American Society for Microbiology, where she shone as a

leader and championed her interest in the diversity of

microorganisms on the planet. She was also one of the original

members of APUA's Reservoirs of Antibiotic Resistance

project.

Leadership Award: Dr. Keith Klugman

The distinguished recipient of this year’s 2013 APUA

Leadership Award is Dr. Keith Klugman, who was honored at

a dinner held in San Francisco, CA during ID Week 2013.

Chosen from a pool of highly qualified individuals nominated

for this year’s award, Dr. Klugman received the award for his

work on the pneumococcal vaccine. His research has focused

on the emergence of antibiotic-resistant pneumococci and

factors that spread this resistance. He has published more than

450 scientific papers on pneumonia, meningitis, antimicrobial

resistance, and vaccines for bacterial pathogens and served as

an expert on antimicrobial resistance for numerous committees,

including at the WHO and the CDC. APUA also commends

him for his recent appointment as the Director of Pneumonia

Studies at the Bill and Melinda Gates Foundation.

APUA 2013 Leadership & Chapter Awards

APUA headquarters and chapters in action • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 25

of Microbiological Societies)-sponsored international

conference on antibiotic resistance in Havana, Cuba where

he had the honor of personally presenting APUA’s 2013

Chapter Award. The conference on resistant bacteria and

fungi addressed pressing problems related to antibiotic use in

Cuba. The visit provided an opportunity to share per-

spectives on important global issues and congratulate Cuban

colleagues on their impressive multi-faceted approach to

fighting antimicrobial resistance.

As part of these efforts, APUA-Cuba has hosted multiple

symposia on antimicrobial resistance and the need for new

antibiotics. The chapter’s electronic database allows for daily

communication and serves as an important venue for

discussion of scientific issues. APUA-Cuba has also utilized

four television appearances to educate the public on the

importance of proper use of antibiotics and the consequences

of inappropriate use.

Recently APUA-Cuba unveiled its new San Cristobal sub-

chapter, with an enrollment of 150 members. Before an

audience of almost 200 medical professionals, five

specialists from APUA-Cuba presented updated information

and led discussions on antibiotic stewardship, childhood

pneumonia, the human microbiome, treatment of multi-

resistant infections, and surgical prophylaxis.

Chapter Award: APUA-Cuba

The Alliance for the Prudent Use of Antibiotics was pleased to

bestow its 2013 APUA Chapter Award on APUA-Cuba, in

recognition of the chapter’s exemplary efforts to improve

antibiotic stewardship and awareness in Cuba and throughout

Latin America. In just six years of existence, APUA-Cuba has

enrolled over 2,000 members from 63 medical specialties and

has established 9 provincial chapters nationwide, including a

newly established sub-chapter in San Cristobal.

November 14-16, APUA President Dr. Stuart B. Levy

attended and presented at the 2nd IUMS (International Union

Dr. Keith Klugman (center), recipient of the APUA

Leadership Award, with Dr. Jay Levy (left) and

APUA President Dr. Stuart Levy (right).

APUA President Dr. Stuart Levy (right) with chapter

leader, Dr. Moises Morejon, who received the 2013

Chapter Award on behalf of APUA-Cuba

New Chinese policies promote rational use

of antibiotics

A PLOS Medicine study titled, “Changes in Chinese Policies

to Promote the Rational Use of Antibiotics” evaluates the

success of a recent antimicrobial stewardship program in

China. The Chinese campaign, motivated by the high rates of

morbidity and mortality due to antimicrobial resistance in

China, was designed to promote more rational use of

antimicrobials in healthcare settings. The campaign,

implemented by the Chinese Ministry of Health in 2011, was

coupled with new healthcare reforms and established new

mandatory management approaches, such as the development

of audit and inspection systems, target-setting, and task force

organization. According to the study, the campaign

successfully decreased antibiotic sales by eight percentage

points in one year and reduced prescriptions for

antimicrobials for both outpatients and hospitalized patients.

Despite promising results, the study highlights the need to

improve antimicrobial use in other settings, including over-the-

counter sales and animal husbandry.

Netherlands and Russia to collaborate on

antibiotic resistance effort

In a recently announced partnership, the Netherlands and

Russia are joining forces to combat antibiotic resistance. A

Dutch-Russian commission will be established to examine the

issue of antimicrobial resistance and the best policies for

reducing its impact. The agreement between these two

countries signifies that both governments acknowledge the

serious nature of this growing problem and the potential public

health consequences it may hold for each.

FDA releases guidelines to limit use of

antibiotics in meat production

On Wednesday, December 11 the FDA released the final FDA

Guidance for Industry 213 and the draft Veterinary Feed

Directive (VFD). This is the first time since 1977 the FDA has

taken broad action against the use of antibiotics in livestock.

The two sets of guidelines are designed to encourage

agriculture to voluntarily stop using sub-therapeutic growth-

promoting dosing, and to involve veterinarians in the

administration of antibiotics to farm animals. Although only

voluntary, the FDA guidelines do demonstrate progress

towards the goal of eliminating sub-therapeutic antibiotic use

in food animal production. This positive step will help the

US catch up with EU regulations on agriculture.

APUA played a major role in promoting this policy change

by documenting the science as evidence and publishing in

journals such as Clinical Microbiology Reviews. APUA’s

comprehensive FAAIR (Facts About Antibiotics in Animals

and their Impact on Resistance) report, published in Clinical

Infectious Diseases (CID) was used as evidence and expert

opinion in testimony by advocacy groups. Current legislation

in Congress, the Preservation of Antibiotics for Medical

Treatment Act, would go much further towards eliminating

the use of medically important antibiotics for growth

promotion.

Antibacterials questioned by the FDA

In the face of mounting evidence that questions the safety of

antibacterials in soaps, toothpastes and a multitude of other

household products, the U.S. FDA has moved to require

manufacturers to demonstrate the safety and efficacy of such

chemicals. The antibacterials of concern, triclosan and

triclocarban, are accumulating in groundwater and soils and

have been found in 75% of US urine samples and 97% of

breast milk samples. Following proliferation of these agents

in non-hospital-based products over previous decades,

evidence has accumulated showing hormone disturbances in

children (e.g., decreasing thryroid function). Furthermore,

worries over escalating antibiotic resistance have fueled

concerns over the possible promotion of cross-resistance to

antibiotics. The proposed FDA rule will provide a 1-year

period for manufacturers to demonstrate product safety and

efficacy before requiring removal of the antibacterial

components.

Policy Updates

26 • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • Policy updates

Salmonella outbreak exposes weaknesses in

monitoring of US food chain

A recent news article highlights the weaknesses in the U.S.

Food and Drug Administration (FDA) and U.S. Department of

Agriculture (USDA)’s methods for ensuring the safety of the

food supply. Beginning in October, a virulent, antibiotic-

resistant Salmonella outbreak, traced to three poultry plants in

California, sickened over 300 people across the U.S.

Surprisingly, none of the plants in question failed salmonella

testing in October because inspectors do not test chicken after

processing into parts, such as drumsticks, thighs, and breasts. It

is believed that the Salmonella contamination spread during

this secondary processing step. Under current federal rules, no

more than 7.5 percent of broilers should test positive for the

bacteria, but no rules govern the quantities of salmonella that

are acceptable in chicken parts. The government estimates that

24% of chicken parts are positive.

Even if inspectors had detected an alarming amount of the

bacteria before the outbreak, USDA authority could only have

pressured the plants to improve the processes—not force plant

closure. Such federal policies are just some of many that

expose Americans to the risks of food-borne illnesses that are

becoming increasingly resistant to antibiotics.

Taiwan reports successes of antimicrobial

stewardship program

An antimicrobial stewardship program in a Taiwan

community public teaching hospital has demonstrated marked

success in reducing unnecessary antibiotic use and costs. In a

study published in the American Journal of Infection Control,

researchers examined the effects of a three-year stewardship

program on antibiotic consumption, costs, and quality of

patient care in a 415-bed hospital. The three primary strategies

implemented were: clinical pharmacist-based intervention,

education of prudent antimicrobial use, and regular

announcements of outcomes. The program lowered

consumption of aminoglycosides, first-generation

cephalosporins, and aminopenicillins and successfully

reduced hospital antibiotic costs by 43.4% over the three-year

period—from $21,464 to $12,146 per 1,000 patient-days.

$2.5 million was saved in total hospital costs despite an

estimated labor cost of $3,935 per month. Lastly, patients’

quality of care did not decline, as measured by length of stay,

incidence of healthcare-associated infections, and mortality.

Harmony Institute endows antibiotic

resistance research

In a recent press release The Univ-

ersity of Central Florida College of

Medicine and the Harmony

Institute announced a partnership with the goal of creating an

endowed “Harmony Scholars” chair to embark upon

longitudinal studies in Harmony, Florida, a planned community

specifically designed to accommodate such studies. Because

of the critical nature of antibiotic resistance and the opportunity

for a population study, the Harmony Institute and UCF College

of Medicine are investigating antibacterial resistance as one of

several beginning studies.

This project was first reported in the APUA Newsletter, Volume

31. For further information contact Martha E. Lentz, President

and Founder, The Harmony Institute at

mlel@harmonyinstitute.org.

CDDEP researches free antibiotics programs

Are “free antibiotic programs” doing more harm than good?

Health Economics recently published a new study from the

Center for Disease Dynamics, Economics and Policy (CDDEP)

that gives evidence to the concerns that free antibiotic programs

are contributing to unnecessary drug prescriptions and possibly

to the problem of antibiotic resistance. The study, co-authored

by CDDEP Director Ramanan Laxminarayan, looked at the

consequences of the first free antibiotic program in the U.S.,

started in 2006 as an effort by the Meijer supermarket chain to

improve access to valuable drugs. Researchers found that across

four states, zip codes in which the program operated had 5%

higher rates of antibiotic prescription than those without the

program. Low-income areas, which the program would

ostensibly aid the most, showed a 12% increase in antibiotic

prescriptions. This study shows that such well-intentioned

programs may be inadvertently contributing to over prescription

and overconsumption of antibiotics in the U.S.

News and publications of note

News and Publications of Note • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 27

About us

Antibiotics are humanity's key defense against disease-causing microbes. The growing prevalence of antibiotic resistance

threatens a future where these drugs can no longer cure infections and killer epidemics run rampant. The Alliance for

the Prudent Use of Antibiotics (APUA) has been the leading global non-governmental organization fighting to preserve

the effectiveness of antimicrobial drugs since 1981. With affiliated chapters in more than 65 countries, including 33 in

the developing world, we conduct research, education and advocacy programs to control antibiotic resistance and en-

sure access to effective antibiotics for current and future generations.

Our global network of infectious disease experts supports country-based activities to control and monitor antibiotic

resistance tailored to local needs and customs. The APUA network facilitates the exchange of objective, up-to-date

scientific and clinical information among scientists, health care providers, consumers and policy makers worldwide.

The APUA Clinical Newsletter has been published continuously three times per year since 1983.

Tel: 617-636-0966 • Email: apua@tufts.edu • Web: www.apua.org

APUA global chapter network

of local resources & expertise

200 Harrison Ave, Posner Building (Business) Level 3, Boston, MA 02111

Phone: 617-636-0966 | Fax: 617-636-0458 | E-mail: apua@tufts.org

www.apua.org

“Preserving the Power of Antibiotics”®

About us • The APUA Newsletter Vol. 31. No. 3 • © 2013 APUA • 28