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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