The Perfect Storm

The Perfect StormRobert S Jones, MSc, DO, FACP, FIDSA

Day in Pediatrics

Friday, October 3, 2014

Robert S. Jones MSc DO FACP FIDSA

RHPN Infectious Diseases

October 3, 2014

Antibiotic Armageddon

An all-destroying war: a final and decisive war or conflict

Armageddon:

How does resistance occur?

What are some basic antibiotic principles?

How big is the problem?What can we do as

physicians to prevent resistance?

How does technology play a role?

What is the drug supply/pipeline for the future?

Instructional Objectives

Antibiotic Armageddon

Year

Resistan

ceN

ew

An

tim

icro

bia

ls

We are here

Antibiotic resistance (AR) is a growing problem that has recently been identified as a major public health threat and priority by several expert committees, including those of the Institute of Medicine, the American Society for Microbiology, as well as by the U.S. Office of TechnologyAssessmentAmerican Society of Microbiology. Report of the ASM Task Force on Antibiotic Resistance. Washington,

D.C., 1994.

U.S. Congress, Office of Technology Assessment. Impacts of Antibiotic Resistant Bacteria(OTA-H-629). Washington, D.C., 1995.

American Society of Microbiology. New and Reemerging Infectious Diseases: A Global Crisis and Immediate Threat to the Nation’s Health, The Role of Research. Washington,D.C., 1997.

Institute of Medicine, Forum on Emerging Infections. Antimicrobial Resistance: Issues and Options. Washington, D.C., 1998

Q1. What percentage of antibiotics used in the hospital are inappropriate?

1 2 3 4 5 6

17% 17% 17%17%17%17%1. 10%2. 20%3. 30%4. 40%5. 50%6. 60%

When antibiotic use began, the genes encoding antibiotic resistance already existed unseen, either as mutants in infecting strains awaiting antibiotic selection or elsewhere in the larger bacterial world awaiting antibiotic mobilization

Three billion years of bacterial evolution had invented them, but only 70 years of antibiotic use has now selected, mobilized, and spread these resistance genes through infecting bacteria

Bacterial Resistance

Antimicrobial resistance is not a new problemArticles published >50 years ago in NEJM

decried the overuse of antibiotics and the irrational use of fixed combinations

An article on the transmissibility of staphylococci noted that the administration of tetracycline to hospitalized patients increased the rate of nasopharyngeal colonization with S. aureus, much with showed resistance to tetracycline

Concern of Resistance

Bernsten CA, McDermott W. Increased transmissibility of staphylococci to patients receiving an antimicrobial drug. N Engl J Med 1960;262:637-42.Reversing the tide of antibiotic resistance. N Engl J Med 1960;262:578-9

Altering the target site of the antibiotic

Preventing access to the target site

Inactivating the antibiotic

Three basic mechanisms of resistance

Conventional Antibiotics and their Targets

DHFA THFA

DNA RNA

Ribosomes

30S

50S

Protein Synthesis30S InhibitorsTetracyclinesGlycylglycinesAminoglycosides50S InhibitorsMacrolidesChloramphenicolLincosamidesStreptogramin BOthersOxazolidinonesEverninomycin

Cell Wall Synthesis InhibitorsPenicillins BacitracinCephalosporins VancomycinMonobactams TeicoplaninCarbapenems CycloserineRamoplanin Phosphomycin

Cell WallFolic Acid MetabolismInhibitorsSulfonamidesTrimethoprim

CellMembrane

Cell MembraneAgentsPolymyxinsDefensinsMagainins

DNA Topoisomerase InhibitorsQuinolones2-Pyridones

RNA Synthesis InhibitorRifamycins

In 1944 it was first recognized that S aureus could produce beta-lactamase and was resistant to penicillin

From 1944-1947, staphylococci in the hospital went from 100% susceptible to <25% susceptible

By 1960 almost 95% of community isolates were penicillin resistant and we began to see the beginning of MRSA

In 1961 we started to see MRSA

Staphylococcal Resistance

Prospective study on the development of ciprofloxacin resistance in S. aureus in the Atlanta VA

After the introduction of ciprofloxacin to the formulary all S. aureus isolates were screened for resistance

All resistant isolates, both MRSA and MSSA were collected (6/88-7/89)

Rapid Development of Ciprofloxacin Resistance in Methicillin-Susceptible and Resistant

Staphylococcus aureus

Blumbert, etal JID 1991;163:1279-1285

Results:After 3 months of ciprofloxacin use, high-level

resistance (MIC90, 64µg/ml) developed in MRSA

Resistance rose from 0% to 79% in MRSA in a one year period

High-level ciprofloxacin resistance also developed in MSSA, increasing to 13.6% over the same period

Conclusion: ciprofloxacin resistance can develop rapidly in S. aureus

Rapid Development of Ciprofloxacin Resistance in Methicillin-Susceptible and Resistant

Staphylococcus aureus

Blumbert, etal JID 1991;163:1279-1285

How quickly does resistance develop?

Depends on:the drug and the bugindication (widespread vs restricted use)

concerns for impact on resistance

Drug Organism Time to resistance

Ciprofloxacin MRSA < 1 yearCiprofloxacin pneumococci > 10 yearsNitrofurantoin UTI organisms decadesPenicillin S. pyogenes decades

NDM-1 (New Delhi metallobeta-lactamase 1): refers to transmissible genetic element encoding multiple resistance genes, not a specific bacteria

MDR TBMalariaESKAPE

E. faecium (VRE)S. aureusKlebsiella pneumoniaeAcinetobacter baumanniiPseudomonas aeruginosaEnterobacter species

Emergence of superbugs

Enterococcus faecium Staph. aureus (MRSA)Clostridium difficileAcinetobacter baumanii (MDR)Pseudomonas (MDR)Enterobacteriaciae (MDR)

“E.S.C.A.P.E.” Bugs

New drugs

No drugs

The Origin and Spread of NDM-1.

Moellering RC Jr. N Engl J Med 2010;363:2377-2379.

New Delhi metallo-B-lactamase containing plasmid

First detected in 2008 in IndiaSpreading in fall of 2010 to UK, Canada,

Japan and US as residents and visitors travelCarries 14 drug resistance genes making

them resistant to nearly all known antibiotics

Promiscuous plasmid that is easily spread between unrelated GNRs

Most commonly seen in E. coli and Klebsiella pneumoniae

NDM-1

Highly resistant Escherichia coli

Map 4 Proportion of invasive isolates with resistance to fluoroquinolones in 2009

Proportion of 3rd generation cephalosporins resistant

isolates in 2009

Source: ECDC, Antimicrobial resistance surveillance in Europe 2009

Medical advancesPeople are living longerAs the body ages, its host defenses diminishAdvances in treatment of cancer, cardiovascular disease

and renal disease extends peoples lives by 10-20 years Improvements in trauma and surgery Introduction of intensive care unitsExposure over time to numerous antibiotic treatments (OP,

IP, long-term care)1988 the National Academy of Sciences/Institute of

Medicine estimated that nearly half of the total annual production of antibiotics is directed to use in farm animals

Reliable testing for viral illnesses and other diseases

Other Factors

“When you grow up every 20 minutes, you get smart

pretty fast.”

Louis Rice MD, Brown University

The association between increased rates of antimicrobial use and resistance has been documented for nosocomial infections and resistant community-acquired infections

Most antimicrobial use in humans is for treatment of OP infections

Otitis media is the second leading cause of office visits to physicians and accounts for over 40% of all outpatient antimicrobial use in children

Resistance

Drug-resistant infections take a staggering toll in the United States and across the globe. Just one organism, methicillin resistant Staphylococcus aureus (MRSA), kills more Americans every year than emphysema, HIV/AIDS, Parkinson’s disease, and homicide combined

Nearly 2 million Americans per year develop hospital-acquired infections (HAIs), resulting in 99,000 deaths – the vast majority of which are due to antibacterial-resistant pathogens

Based on studies of the costs of infections caused by antibiotic-resistant pathogens versus antibiotic-susceptible pathogens, the cost to the U.S. health care system of antibiotic resistant infections is $21 billion to $34 billion each year and more than 8 million additional hospital days

Some Facts About Resistance

Impact of (resistance) MRSA on SSIs

MSSA (N=165)

MRSA(N=121)

Mortality, 90 days postsurgery 6.7% 20.7%*

LOS: median days after surgery 14 (7-25)* 23 (12-38)*

LOS: median days after infection 10 (4-17) 15 (7-30)†

MRSA increased mortality, even after multivariate analysis (P=.003)

*P<.001.†P=.001.Engemann JJ et al. Clin Infect Dis. 2003;36:592-598.

Percentage of MRSA and VRE isolates from TRHMC

05

101520253035404550

1995 1998 2000 2002 2004 2006 2008 2011

Year

% o

f M

RSA

and

VR

E

isol

ates MRSA

VRE

Need new technologiesEducationFollow treatment guidelinesInfection control programsKnow local resistance patterns (antibiogram)Evidence based medicineAntibiotic stewardship programImmunize our patients

What can we do?

The FilmArray is a multiplex PCR reaction designed for simultaneous detection and identification of:

Adenovirus Coronavirus HKU1 Coronavirus NL63 Human Metapneumovirus Influenza A Influenza B Parainfluenza 1 Parainfluenza 2 Parainfluenza 3 Parainfluenza 4 Rhinovirus/Enterovirus Respiratory Syncytial Virus

The Laboratory

New technologies for quicker and more accurate identificationC diffInfluenzaBlood cultures (FISH for Enterococcus, yeast,

Staph)MRSARSV antigenMRSA screenEnterovirus PCR on spinal fluidEBV and CMV antibodyHSV-1 and HSV-2PBP2 test on cultures

The Laboratory

Confusing direct smear with cultureConfusing Staph. aureus with coag. neg.

Staph. Very different organisms Very different clinical implications

Confusing MRSA, MRSE, MSSA, MSSEWaiting for susceptibilities on organisms

that may not be tested (CNS, etc.)Assuming a culture is final when sensi’s

appear on 1 organism from polymicrobial culture

Confusing bottles vs. sets (bacteremia)Confusing UA with UC

Common Errors in Interpreting Culture Reports

Appropriate Antibiotic Use

There’s More to I.D. than….

“Vanco-Zosyn”

“Pan-culture”

Q2. Vancomycin is a “stronger” antibiotic than Nafcillin for Staphylococcus aureus

1 2

50%50%

1. True2. False

Principles of Selection

Bug

DrugHost

Immune statusSite of infectionFunction of body systems responsible for

absorption and elimination of drugAllergiesAgePregnancy

Host Characteristics

Pharmacokinetics (absorption, distribution into body tissues and elimination)

Pharmacodynamics (mechanism of action, bacteriocidal or bacteriostatic nature of the antimicrobial effect, and the rate at which it occurs)

Important Drug Features

Gram stainCollect specimen prior to starting

antibiotics when possibleCollect appropriate specimens (site and

type of culture, AFB, Fungal, Anaerobes, etc)

Immunologic or Molecular methodsBacteriologic statistics: application of

knowledge of the organisms most likely to cause infection in a given clinical setting

Identification of Organism

Probably most important aspect of host factors

Site of Infection

Define the pathogen Any culture (from relevant site) beats none Contact outside labs for early culture results Reculture if new fever (etc.), new abx

Treat the patient, not the cultureMatch aggressiveness of Rx to

severity and tempo of diseaseSource control

Drain, debride, discontinue devices Imaging, interventionalists

Basic Principles

Antibiotics are not always benign; use with care Allergy and ADEs (rash, GI, fever, cytopenias, renal,

etc.) Drug-drug interactions

TMP-SMZ, FQs, flagyl + warfarin --> high INR, bleedingLinezolid + SSRIs --> seretonin syndromeFQs, macrolides + (multiple drugs) --> long QT, torsadesFQs, doxy, mino + Ca, Mg, Al, Fe --> drug inactivation

Resistance: current bug, next bug, C. difficile, population

Treat as narrowly and briefly as possibleContain the contagion (infection control)Prevention (immunize, hygiene, vents &

lines…)

Basic Principles (cont.)

Q3. Penicillin allergy reporting is inaccurately reported in more than

85% of patients

1 2

50%50%

1. A. True2. B. False

A total of 150 patients (mean age 42 years; SD 16 years

46% men; 47% black) were enrolled The false-positive rate for self-reported

penicillin allergy was 137 of 150 (91.3%; 95% CI 85.3% to 95.1%).

.

Raja AS, Lindsell CJ, Bernstein JA, Codispoti CD, Moellman JJ. The use of penicillin skin testing to assess the prevalence of penicillin allergy in an emergency department setting. Ann Emerg Med. 2009 Jul;54(1):72-7

We will be offering skin testing in select populations within the next several months

Not appropriate for everyoneNot universally acurate

Penicillin skin testing

Do I need to use an antibiotic? If so . . .What would be the best drug?What is the best dose for what I’m treating?What is the best route of administration?How long should I treat?What are the potential side effects and

collateral damage?Does the patient have allergies or potential

drug interactions?What are the other host factors to consider?

Antibiotic Selection Questions

Q4. What is the optimal treatment for acute uncomplicated cystitis?

1 2 3 4 5

20% 20% 20%20%20%1. Nitrofurantoin monohydrate/macrocrystals 100mg twice daily for 10 days

2. Rimethoprim-sulfamethoxazole (160/800 mg (DS tablet) twice daily for 3 days

3. Moxifloxacin 400mg daily for 3 days

4. Ciprofloxacin 500 mg twice daily for 3 days

5. Amoxicillin 500 mg three times a day for 7 days

Clinical manifestations of cystitis consist of dysuria, frequency, urgency, suprapubic pain, and/or hematuria

Dysuria may also be a manifestation of vaginitis or urethritis

Physical examination should include assessment for fever, costovertebral angle tenderness, and abdominal examination

A pelvic examination is indicated if factors suggesting vaginitis or urethritis are present

Urinalysis for evaluation of pyuria is the most valuable laboratory diagnostic test for UTI

Diagnosis of UTI

Nitrofurantoin monohydrate/macrocrystals 100 mg twice daily for 5 days (A-1)

Trimethoprim-sulfamethoxazole DS one tablet twice daily for 3 days (A-1)

Fosfomycin 3g single dose (A-1)Fluoroquinolones (ofloxacin, ciprofloxacin an

levofloxacin) x 3 days (A-1), but have collateral damage and should be reserved for important uses other than acute cystitis and should be considered alternate antimicrobials for acute cystitis

Recommendations for the treatment of acute uncomplicated cystitis

Gupta et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A2010 Update by the IDSA and the European Society for Microbiology and Infectious Diseases. Clin Inf Dis 2011;52(5):3102-e120.

B-lactam agents, including amox-clav, cefdinir, cefaclor, and cefpodoxime-proxetil, in 3-7 day regimens when other recommended agents cannot be used (B-1)

Amoxicillin or ampicillin should not be used for empirical treatment due to poor efficacy and high prevalence of resistance (A-III)

The threshold of 20% as the resistance prevalence at which the agent is no longer recommended for empirical treatment of acute cystitis is based on expert opinion derived from clinical, in vitro and mathemetical modeling studies (B-III)

Recommendations for the treatment of acute uncomplicated cystitis

Gupta et al. International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A2010 Update by the IDSA and the European Society for Microbiology and Infectious Diseases. Clin Inf Dis 2011;52(5):3102-e120.

Q5. Group A and B streptococci are always susceptible to penicillin?

1 2

50%50%1. A. True2. B. False

Q6. All Group A and B streptococci are sensitive to macrolides?

1 2

50%50%

1. A. True2. B. False

Q7. What percent of children with the common cold are treated with

antibiotics?

Journal of Family Practice 1996; 42:357--361

1 2 3 4 5 6

17% 17% 17%17%17%17%1. 20%2. 30%3. 40%4. 50%5. 60%6. 70%

90% of rhinosinusitis is viral

Rhinosinusitis

Onset with persistent symptoms or signs compatible with acute rhinosinusitis, lasting for ≥10 days without improvement

Onset with severe symptoms or signs of high fever (≥39 C) and purulent nasal discharge or facial pain lasting for at least 3-4 consecutive days at the beginning of the illness

Onset with worsening symptoms or signs characterized by the new onset of fever, headache or increase in nasal discharge following a typical viral URI that lasted 5-6 days and were initially improving.

Clinical Presentation of Acute Bacterial Versus Viral Rhinosinusitis

Chow etal. IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults. CID advanced access published March 20, 2012

“Cellulitis”Gout, stasis dermatitis, dermatitis, bug

bite“Pneumonia”

Edema, effusion, atalectasis, aspiration, fibrosis, tumor, vasculitis, hypersensitivity

“UTI”Asymptomatic bacteriuria, vaginitis,

urethritis, contaminated sample

Common Fake-Outs

UTI ABU: none Cystitis

Uncomplicated: 3d (women), 5-7d (men)Complicated: 7-14d

Febrile UTI, pyelo, acute prostatitis: 7-14d Chronic prostatitis: 4-12 weeks

HAP, VAP: 8d (15d if Pseudomonas)CAP: 5-10dCellulitis: 5-14dOsteo: 6 weeks

Duration of Therapy

Bacteremia S. aureus: 14d (?10d?) - 6 weeks CNS: 7d Enterococcus: 14d GNRs: 7-14d Strep, Pneumococcus: 5-7d

COPD exacerbation: 7dAcute Lyme, anaplasmosis: 7-10dC. difficile: 10-14d

Duration of Therapy (cont.)

Combat drug resistance: no action today, no cure tomorrow

Q8. There is an adequate pipeline of new antibiotics

1 2

50%50%

1. True2. False

Is antibiotic development the answer?

President’s Council of Advisors on Science and Technology (PCAST)

President Barack Obama has signed an executive order directing key federal departments and agencies to take action against the rise in antibiotic-resistant bacteria

Strengthen surveillance and response to resistance

Promote fundamental researchAccelerate clinical trials of new abxIncrease economic incentiveImprove stewardship of existing abxLimit use of abx in agricultureEnsure effective international cooperation

Dennis Maki MD 1998 IDSA Meeting

“The development of new antibiotics without having mechanisms to insure

their appropriate use is much like supplying your alcoholic patients

with a finer brandy”

Good antimicrobial stewardship involves selecting an appropriate drug and optimizing its dose and duration to cure an infection while minimizing toxicity and conditions for selection of resistant bacterial strains

Prospective audit of antimicrobial useDirect interaction and feedback to prescriberEducationMultidisciplinary development of guidelinesStreamlining or de-escalation of empirical

antimicrobial therapyComputer-based surveillanceTracking of resistance patterns and side effectsFormulary restrictionCorrect dosing of antimicrobials (dose and frequency)Monitoring of side effects

Elements of antibiotic stewardship

Multidisciplinary Collaboration

Stewardship Team

Pharmacy

Infectious Diseases

Other Medical, Surgical Staff

NursingInfection

Control/Hosp EpiMicrobiology

Informatics

Quality/Safety

Dellitt TH et al. Clin Infect Dis. 2007;44:159-77

Participated in a year-long IHI/CDC programWeight based dosingIV to PO auto switch CAPParticipate in case management roundsPharmacy to dose program for the following

antibiotics: Gentamicin, Vancomycin, Cefepime, Ticarcillin/Clavulanate Potassium, Tobramycin, Cefazolin, Ampicillin/Sulbactam, Fluconazole, Amikacin, Ceftriaxone, Piperacillin/Tazobactam, Acyclovir

Antibiotic indicationJohns Hopkins antibiotic guide on-line

Antibiotic Stewardship Initiatives

1. Pharmacy to Dose

a. Indications

b. Default to pharmacy to dose

c. Training/competency exam implementation

2. IV to PO program

a. Pilot developed for azithromycin

b. Developed exclusions for oral therapy in POM

c. Expansion to institutional wide

d. Costs savings

3. Weight Based Surgical Antibiotic Prophylaxis

a. Developed and implemented guidelines for open heart surgery

b. Pilot in progress for expansion to Orthopedics

4. Highmark Pay for Performance: C. difficile

a. Collect and report data on use of antibiotics associated with C. difficile

b. Helped develop fecal transplant protocol

c. Collect data on use of proton pump inhibitors

1. Internal Medicine Resident Quality Improvement Project

a. Azithromycin IV to PO

b. De-Escalation in CAP

c. Diabetic Foot Infection Protocol Development

2. Penicillin Skin Testing

3. SCIP Post-Op Antibiotic Discontinuation

4. Formulary

a. Restricted 7 formulary antibiotics to Infectious Diseases

b. Developed standard for Amphotericin B Bladder Irrigation

c. Made recommendations for the addition of fidaxomicin to formulary

5. Johns Hopkins Antibiotic Guide

6. Presentations/Publications/Communication

a. Department Meetings

i. Medical Group

ii. Surgery

iii. Family Medicine

b. Prescribing Change – Reading Eagle

c. Grand Rounds: Antibiotic Armageddon – Reading Eagle

d. Validating Penicillin Allergy History

e. Pharmacist Education – Pharmacy to Dose Antibiotics

f. Nursing Memo – Vancomycin Levels

g. Reformatted the Antibiogram

Q9. I agree with:

1 2 3 4 5

20% 20% 20%20%20%

1. I learned something new today and will be more judicious with my antibiotic prescribing

2. Antibiotic stewardship is just another euphemism for cost savings

3. I should be able to write for whatever antibiotic I want

4. Antibiotic resistance is a conspiracy theory to generate more ID consults

5. This is not my problem, the next generation of physicians will have to deal with it

Increase appropriate use: Ensure that infected patients who need antimicrobial therapy have access to quality medicines which conform with policy recommendations and standard treatment guidelines.

Decrease inappropriate use: Discourage the indiscriminate use of antimicrobials in patients unlikely to derive any benefit.

Improving Antimicrobial Use

Post lecture quiz

Q10. Antibiotics fight infections caused by

1 2 3

33% 33%33%1. Viruses2. Bacteria3. Bacteria and viruses

Q11. Bacteria are germs that cause colds and flu?

1 2

50%50%1. A. True2. B. False

Q12. Which of these illnesses should be treated with antibiotics?

1 2 3 4

25% 25%25%25%1. Runny nose2. Flu3. Cold4. Strep throat

Q13. Bacteria that cause infections can become resistant to antibiotics

1 2

50%50%1. True2. False

Q14. I can prevent antibiotic-resistant infections when I

1 2 3 4 5

20% 20% 20%20%20%1. Don’t take an antibiotic for a viral infection

2. Don’t save an antibiotic for the next time I am sick

3. Don’t take an antibiotic prescribed for someone else

4. Take my antibiotic exactly as prescribed

5. All the above

Q15. What can happen if I get an antibiotic-resistant infection?

1 2 3 4 5

20% 20% 20%20%20%1. I may have a longer lasting illness

2. I may have to visit my doctor more often

3. I may have to be hospitalized

4. I may need more costly medicine that may have more side effects.

5. All the above

Q16. Antibiotic resistance has been called one of the world's most pressing public health problems

1 2

50%50%1. A. True2. B. False