Bioburden Continuum: Systemic Infections and Antibiotic ... · Bioburden Continuum: Systemic Infections and Antibiotic Stewardship. Disclosures •Speakers Bureau- Organogenesis Inc,

Kara S. Couch, MS, CRNP, CWCN-APSecretary, AAWC

Bioburden Continuum: Systemic Infections and Antibiotic Stewardship

Disclosures• Speakers Bureau- Organogenesis Inc,

Urgo North America, Molnlycke

Definitions

Antimicrobial: an agent that kills microorganisms or inhibits their growth

Microorganism: a microscopic organism, especially a bacterium, virus, or fungus.

Antimicrobial Mode of Action

Etebu E, Arikekpar I. Antibiotics: Classification and mechanisms of action with emphasis on molecular perspective. Int J of Appl Microbiol and Biothech Res. 2016; 4: 90-101. Petchiappan A, Chatterji D. Antibiotic resistance: Current perspectives. ACS Omega 2017, 2, 7400−7409. McDonnell G, Russell A. Antiseptics and disinfectants: Activity, action, and resistance. Clin Microbiol Rev. 1999; 12: 147–79.

Antimicrobials: an agent that kills microorganisms or inhibits their growth

Antibiotic

(e.g. Penicillin, minocycline, vancomycin, bacitracin)

Antiseptic

(e.g., Ionic silver, cadexomer iodine, hypochlorous acid, gentian violet,

Polyhexamethylene biguanide [PHMB] )

1. Action only against bacteria, with species specificity

2. Single mode of action: Inhibits cell wall synthesis, inhibits

protein synthesis, or blocks key metabolic pathways

3. Singular mode of action increases likelihood of effective

resistance mutation

4. Generally, systemically tolerable

1. Broad spectrum activity; both bacteria and fungi

2. Simultaneous multimodal action

3. Less likely to develop resistance to multimodal, broad

spectrum antiseptic activity

4. Toxic when ingested

Risk for Wound Infection is Multifactorial

Inadequately Managed Etiology

Ineffective host defense

Wound Environment

Wound ChronicityIneffective

dressing

Reepithelialisation delay

Granulation delay

InflammationMMP’s/pH

Host

PAD/venous insufficiency

Malnutrition

Diabetes

Immune Suppression

Hypoxia

Obesity

Frail

Poor Self-Care

Disability

Home/Facility Environment: Cleanliness,

Pets

Wound Environment

Necrotic tissue

Exudate Management

Expired Dressing

action

ExposedHardware/Structure

Periulcer breakdown

Practitioner skill

MicroorganismsBacteria & Fungi

QuantityVirulence

Biofilm

ResistanceAnaerobes

Polymicrobial

Cross Contamination

Recontamination: Incontinence

Synergism

Risk for Wound Infection is Multifactorial

Microbes• Virulence• Cross contamination• Quantity • Biofilm

The Host/Person• Comorbid conditions, nutritional status, hygiene, disability, habits

The Wound Environment• Wound bed characteristics such as presence of necrotic tissue, exudate

management/expired dressing action, exposed structure

Wound Chronicity • Inadequately managed etiology, ineffective dressing,

reepithelialization delay

Inadequately Managed Etiology

Expired Action

Biofilm

Disabled/Frail

Necrotic Tissue

Wound Infection

• A wound infection results from microbial invasion into the tissue in adequate numbers to elicit a host response which results in impaired wound healing. 1

1. Association for the Advancement of Wound Care (AAWC). Quality of Care Wound Glossary. Copyright 2012. Available on line: https://s3.amazonaws.com/aawc-new/memberclicks/AAWC-Quality-of-Care-with-I-CVIswebsitev3.pdf.

Wound Infection

• Wound Infection risk can involve a compromised host, compromised wound bed environment, a wound that for one reason or the other remains nonhealing, and/or a wound harboring significant numbers or virulent microbes.

• Interestingly all of these factors can also increase the likely presence of microbial biofilm in a wound.

• JW Costerton was the first to describe the link between biofilm and infection 1

• Presence of biofilm in a wound stimulates a cellular inflammatory response 2,3 involving increased production of MMPs, resulting in a chronically inflamed, nonhealing wound.4, 5

1. Costerton JW, Irvin RT, Cheng KJ. The bacterial glycocalyx in nature and disease. Annu Rev Microbiol 981;35:299–324. 2. Costerton JW. Bacterial biofilms in nature and disease. Ann Rev Microbiol. 1987; 41: 435–64. 3. Costerton J, Stewart P, Greenberg E. Bacterial biofilms: a common cause of persistent infections. Science. 1999; 284: 1318–22. 4. Keast D, Swanson T, Carville K, Fletcher J, Schultz G, Black J. Ten top tips … understanding and managing wound biofilm. Wounds International. 2014; 5: 20–3. 5. Pavlík V, Sojka M, Mazúrová M, Velebný V. Dual role of iodine, silver, chlorhexidine and octenidine as antimicrobial and antiprotease agents. PLoS One. 2019;14(1)

Critical Colonisation(established microbial population,wound not progressing, microbial

imbalance, no signs of infection)

Biofilm Formation in Wounds

Adhesion

ExopolymericSubstances

CLIMAXCOMMUNITY

(Synergy, Quorum Sensing)

G +ve’s(Aerobes)

G +ve’sG -ve’s(Aerobes)

G +ve’sG -ve’sAerobesAnaerobesYeasts

Progression &Accumulation

Detachment &Dissemination



Contamination(host control)

Colonisation(established microbial

population, host control, microbial balance)

Infection(microbial control)

Systemic Antibiotics &Topical Antiseptic Agents

Host Resistance

Topical Antiseptic

Agents

Micro-organism(load x virulence)



Percival & Bowler. WOUNDS; 2004.Bacteria & Infection

Used with permission from Wounds International: Biofilms Made Easy, Volume 1, Issue 3, May 2010

Biofilm may be the oldest life form on earth with planktonic bacteria evolving as a dispersal mechanism

Planktonic bacteria versus Biofilm bacteria

• Planktonic: free-living / swimming; isolated; susceptible

• Biofilm: surface-attached; communities; protected; tolerant

Biofilm Diversity

• Biofilm bacteria on rock surfaces in alpine stream water

outnumber planktonic bacteria in stream water by up to

10,000:1 (Costerton & Geesey, 1989)

• Biofilm bacteria corrode metal by stealing electrons; planktonic

bacteria do not have the same capability (Costerton & Boivin,

1991)

• Medical device-associated infections (e.g. CAUTI)

• Chronic infections (e.g. associated with cystic fibrosis, wound)

Biofilm is ubiquitous in natural & pathogenic ecosystems

Biofilm and wound healing

• “…biofilms are the principle cause of wound chronicity ”1

• “…biofilms represent a fourth major pillar of chronic wound pathogenesis”2

• Biofilm creates a sustained low-grade & ineffective inflammatory response2

• Biofilm impairs epithelial migration & granulation tissue formation2

• Individual bacterial species possess distinct levels of biofilm virulence3

• Multi-species biofilm delays healing more than single-species biofilm4

• Bacteria from patients with persistent infections are positive for biofilm

formation5

• Biofilm present in a majority of non-healing chronic wounds (60-75%)6, 7, 8

• Biofilm delays wound healing: a review of the evidence9

1. Wolcott et al. Chronic wounds and the medical biofilm paradigm. J Wound Care 2010;19:45-53

2. Gurjala et al. Development of a novel, highly quantitative in vivo model for the study of biofilm-impaired cutaneous wound healing. WRR 2011;19:400-10

3. Seth et al. Quantitative comparison and analysis of species-specific wound biofilm virulence using an in vivo, rabbit ear model. J Am Coll Surg 2012; 215:388-99

4. Seth et al. Comparative analysis of single-species and polybacterial wound biofilms using a quantitative, in vivo, rabbit ear model. PLoS ONE 2012;7:e42897

5. Sanchez et al. Biofilm formation by clinical isolates and the implications in chronic infections. BMC Infect Dis 2013;13:47

6. James et al. Biofilms in chronic wounds. Wound Repair Regen 2008;16:37-44

7. Kirketerp-Møller et al. Distribution, organization, and ecology of bacteria in chronic wounds. J Clin Microbiol 2008;46:2712-22.

8. Hurlow J et al. Clinical investigation of biofilm in non-healing wounds by high resolution microscopy techniques. J Wound Care 2016;25:S11-22.

9. Metcalf & Bowler. Biofilm delays wound healing: a review of the evidence. Burns Trauma 2013; 1: 5-12.

A clinical algorithm for wound

biofilm identification

1

1. Metcalf DG, Bowler PG, Hurlow J. A clinical algorithm for wound biofilm identification J Wound Care 2014; 23: 137-142.

Step-Down Then Step-Up Treatment Therapy

Modified from Schultz, G., Bjarnsholt, T., James, G.A., Leaper, D.L., McBain, A. J., Malone, M., Stoodley, P., Swanson, T., Tachi, M., Wolcott, R.D.; for the Global Wound Biofilm Expert Panel. Wound Repair and Regeneration: 2017.

MDROs are Increasingly Recognized in Wounds

Bowler et al. 2012. Int Wound J.

Combat / natural disaster wounds

Burns Skin & soft tissue wounds

Surgical wounds

Chronic wounds

ESBL bacteria X X X X

MRSA / CA-MRSA X X X X X

A. baumannii X X X X

C. difficile X X X X

Based on the limited effectiveness of antibiotics against MDROs, wound dressings are

an important consideration in wound infection prevention

(MDRO = multidrug resistant organism)

Antimicrobial agents & dressing technology

Dressing Technology

• Hydrocolloid

• Foam

• Alginate

• Hydrofiber®

• Gel

• Paste

• Film

• Carrier materials, e.g. tulle,

polyethylene mesh

Antimicrobial Agent

• Ionic silver

• Molecular iodine

• Chlorhexidine

• PHMB

• (Honey)

Dressing technology is CRITICAL to the antimicrobial effectiveness of dressings

Treatment..

Source: Livingston,M, Wolvos, T. (2009)

Primary topical- Effective against-

•Bacitracin gram-negative/-positive cocci and bacilli

•Cadexomer iodine ointment broad spectrum, (thryoid caution)

•Gentamicin sulfate gram-negative microbes

•Metronidazole anaerobes

•Mupirocin gram-positive/-negative, MRSA

•Neomycin sulfate broad spectrum, gram-negative/-positive

•Neosporin®broader spectrum than neomycin, bacitracin, or polymyxin

•Peroxide gram-negative microbes, cytotoxic

•Polymyxin B sulfate gram-negative microbes

•Silver suphadiazine broad spectrum, gram-positive/-negative microbes, Candida albican, (sulfa allergy caution)

Treatment..

Source: Livingston,M, Wolvos, T. (2009)

Antiseptics: Effective against:

Acetic Acid Gram-positive/negative, Pseudomonas, must be diluted

Chlorhexidine gluconate Broad spectrum, must be diluted, cytotoxic starting on day 3

Povidone-iodine Gram-positive/negative, yeast, fungi

Sodium hypochlorite Bacteria, viruses, fungi, must be diluted, cytotoxic, BID treatment for efficacy

Hypochlorous acid Gram- positive/negative, yeast, fungi, biofilm disruptor, non-cytotoxic

Treatment..

• Sustained antimicrobial effect to entire wound base• Moist environment• Available as impregnated gauze, foams, island dressings, films, absorptive

fillers, and other forms• Provides a barrier against other microbes• Controls exudate• Protects wound from further trauma

Antimicrobial Dressings-

Silver broad spectrum, fungi, viruses, MRSA, VRE

Manuka Honey broad spectrum, MRSA, VRE, deodorizes, debrides

Iodine consider thyroid disruption

Polyhexamethylene Biguanide broad spectrum, MRSA, E coli, Pseudomonas

When to implement antimicrobial dressings

• Contamination/Colonization-• Topical antimicrobial dressings are not indicated because bioburden is

not causing clinical problems• Localized infection-

• Topical antimicrobial dressings indicated• Systemic infection-

• Topical antimicrobial dressings + antibiotics

http://www.woundsinternational.com/pdf/content_10381.pdf

Diabetic Foot Infection: Microbiology

• Staphylococcus aureus

• Streptococcal species

– Especially Group B

– Occasionally Groups C or G

– Less commonly group A

• 89% of DFUs cultured grew two or fewer organisms.1

• Anaerobic species were isolated in only 5% of all cultures. 1

1. Armstrong DG, Liswood PJ, Todd WF. Prevalence of mixed infections in the diabetic pedal wound. A retrospective review of 112 infections. J. Am. Podiatr. Med. Assoc. 85, 533–537 (1995).

Diabetic Foot Infection: Microbiology

• Chronic or more severely infected DFUs tend to be more polymicrobial

• Common Gram Negative Pathogens

– E. coli

– Klebsiella spp.

– Proteus spp.

• Pseudomonas aeruginosa

– Associated with water exposure

– e.g., Puncture wound thru bottom of a shoe

Diabetic Foot Infections: TreatmentAntibiotic Selection Overview: Questions a Clinician Should Consider.

a. Such as high local prevalence of Pseudomonas infection, warm climate, frequent exposure of the foot to water.

Is there clinical evidence of infection or critical colonization?

Do not treat clinically uninfected wounds with antibiotics.

Is there high risk of MRSA?

Include anti-MRSA therapy in empiric regimen if the risk is high or the infection is severe.

Has patient received antibiotics in the past month?

If so, include agents active against gram-negative bacilli in regimen.If not, agents targeted against just aerobic gram-positive cocci may be sufficient.

Are there risk factors for Pseudomonas infection? a

If so, consider empiric antipseudomonal agent.If not, empiric antipseudomonal treatment is rarely needed.

Diabetic Foot Infections: Treatment

Oral antibiotic agents for empiric therapy of mild diabetic foot infections.

Drug Renal Dosing Required? Class

Dicloxacillin No Penicillin

Amoxicillin/Clavulanate†

Yes β-lactam/β-lactamase inhibitor

Cephalexin†

Yes Cephalosporin

Cefdinir Yes Cephalosporin

Levofloxacin†

Yes Fluoroquinolone

Clindamycin† ‡

No Lincosamide

TMP/SMX§

Yes Sulfonamide

Minocycline§

Yes Tetracycline

Doxycycline§

No Tetracycline

† Drugs that have been used in published trials of treatment of diabetic foot infections. ‡Suspect inducible clindamycin resistance if staphylococcal isolate is susceptible to clindamycin but resistant to erythromycin. Confirm with D-test. §Active against community-associated methicillin-resistant Staphylococcus aureus. TMP/SMX: Trimethoprim/sulfamethoxazole

Diabetic Foot Osteomyelitis : Microbiology

Gram Positive Aerobes

• Staphylococcus aureus

– most common pathogen cultured from bone1

• Streptococcus species

• Staphylococcus epidermidis

1. Senneville E, Melliez H, Beltrand E, et al. Culture of percutaneous bone biopsy specimens for diagnosis of diabetic foot osteomyelitis: concordance with ulcer swab cultures. Clin Infect Dis 2006; 42:57–62.

Anaerobes

• Peptostreptococcus spp.

• Peptococcus spp.

• Finegoldia magna

• B. fragilis

Gram Negative Aerobes

• Escherichia coli

• Klebsiella pneumoniae

• Proteus species

• Pseudomonas aeruginosa

Diabetic Foot Infection: Osteomyelitis

• Plain film rarely useful unless late in course• Compromise 30 to 50% of bone mineral content to produce noticeable changes in plain

radiographs

• Good for foreign bodies

• Bone scan nonspecific• Especially in patients with neuropathic osteoarthropathy (Charcot joint)

• Can be useful when MRI is not an option

• MRI (gold standard for radiological diagnosis)

• T1 weighted image (low signal intensity)

• T2 fat-saturated image (hyperintense signal)

• T1 fat-saturated image post-gadolinium (enhancement)• z


• Probing to bone in infected pedal ulcers is a clinical sign of underlying osteomyelitis in diabetic patients1

• sensitivity of 66%

• specificity of 85%

• positive predictive value of 89%

• negative predictive value of 56%

• If you can palpate small bones of the feet in diabetics with a chronic ulcer, consider it osteomyelitis until proven otherwise

1. Grayson ML, JAMA 1995;273:721-723


Parenteral or oral antibiotics for empiric therapy of moderate-to-severe DFU infections


Lipsky B et al. 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections. Clinical Infectious Diseases, Volume 54, Issue 12, 15 June 2012, Pages e132–e173

Clinical situation Route of therapy Duration of therapy

No residual infected tissue (e.g., post-amputation)

Parenteral or oral 2–5 days

Residual infected soft tissue (but not bone)

Parenteral or oral 2–4 weeks

Residual infected (but viable) bone Initial parenteral, then consider oral switch

4–6 weeks

No surgery, or residual dead bone postoperatively

Initial parenteral, then consider oral switch

>3 months

The duration of antimicrobial treatment depends on the extent and depth of infection, the bones and microorganisms involved, theextent of surgical debridement, and host comorbid conditions.

Diabetic Foot Ulcers (DUFs)

Risk factors predictive of ulcers and amputation1-4

• Previous foot ulceration

• Neuropathy (loss of protective sensation)

• Foot deformity

• Vascular disease

1. Boulton AJ et al, Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care. 2008;31(8):1679.

2. Pecoraro RE et al, Pathways to diabetic limb amputation. Basis for prevention. Diabetes Care. 1990;13(5):513.3. Singh N et al, Preventing foot ulcers in patients with diabetes. JAMA. 2005;293(2):217.4. Cheer K, Shearman C, Jude EB, Managing complications of the diabetic foot. BMJ. 2009;339:b4905.

Diabetic Foot Ulcers: A High Infection Risk

Sustaining a lower extremity wound of the most common precipitating events for a foot infection1

Variables achieving independent statistical significance as risk factors for foot infection. Data from a 2-year longitudinal outcomes study of 1,666 patients enrolled in a managed care-based outpatient clinic.

For patients who develop a foot infection associated with a DFU present for > 30 days:

• 55.7 times more likely to be hospitalized

• 154.5 times more likely to have an amputation

1. Maderal AD, et al. Hosp Pract. 2012;40(3):102-115.2. Lavery LA, et al. Diabetes Care. 2006;29(6):1288-1293.

2

“Appropriate therapy” includes:

• Antibiotics• at least 42 days for osteomyelitis

• antibiotics should be culture-directed

• PICC line for outpatient management

• Aggressive surgical debridement• remove infected/dead bone, as well as

involved hardware if possible

• Educate & optimize dietary needs• e.g., malnutrition (protein), vitamin D, Vitamin C, Vitamin A, Zinc

• Address comorbidities• e.g., diabetes, venous stasis, smoking cessation, renal/liver failure

• Vascular evaluation/intervention if indicated


• Adjunct HBO2 therapy (not an approved indication for acute osteomyelitis)

• Offloading• total contact cast• walker boot

Management of Skin & Soft Tissue Infections

Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC; Infectious Diseases Society of America. Practice guidelines for the diagnosis and

management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jul 15;59(2):e10-52.

Management of Skin & Soft Tissue Infections

Severe infection:

• Failed incision and drainage plus oral antibiotics

• Systemic signs of infection:

⁻ Temperature >38°C,

⁻ Tachycardia (heart rate >90 beats per minute)

⁻ Tachypnea (respiratory rate >24 breaths per minute)

⁻ Abnormal white blood cell count (<12 000 or <400 cells/μL)

• Immunocompromised patients.

Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC; Infectious Diseases Society of America. Practice guidelines for the diagnosis and

management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jul 15;59(2):e10-52.

Inpatient vs. Outpatient

• Critical Ischemic Limb

• Systemic Toxicity

• Metabolic Instability

• Necrotizing Soft Tissue Infection

• Substantial Necrosis / Gangrene

• Need for Urgent Diagnostic / Therapeutic Intervention

• Unable To Care For Themselves

Antibiotic use is the single most important factor leading to antibiotic resistance around the world.

http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf


Patients at especially high risk for antibiotic-resistant infections


President’s Council of Advisors on Science & Technology (PCAST) Report on Combating Antibiotic Resistance

1) Slow the emergence & spread of resistant bacteria with help from ANTIMICROBIAL STEWARDSHIP.

2) Strengthen national surveillance efforts.

3) Advance rapid diagnostics.

4) Develop new antibiotics.

5) Improve international collaboration.

Joint Commission mandates all hospitals to have an antimicrobial stewardship program effective Jan 1, 2017.

Outpatient Antimicrobial Stewardship 2020

Tips for Prescribing

Table Antibiotics and their spectrum of activity

Gram (+) Gram (-) Anaerobes

Penicillin Streptococci,

Enterococci

Oral

anaerobes

Cefazolin (1st g) Streptococci, MSSA E coli

Ceftriaxone (3rd g) Streptococci, MSSA E coli

Cefepime (4th g) Streptococci, MSSA E coli, P aeruginosa

Piperacillin/tazoba

ctam (Zosyn®)

Streptococci, MSSA,

Enterococci

E coli, P aeruginosa B fragilis

Meropenem Streptococci, MSSA E coli, P aeruginosa,

Acinetobacter sp.

B fragilis

Vancomycin Streptococci, CoNS,

MRSA/MSSA,

Enterococci

Levofloxacin Streptococci, MSSA H influenzae,

Moraxella, Legionella

Ciprofloxacin E coli, P aeruginosa,

Legionella

Amikacin Enterococci E coli, P aeruginosa

Three ways we use antibiotics:• Prophylaxis

• To prevent an infection or its recurrence (e.g., TMP/SMX and PJP)

• Empiric therapy• Selected therapy has to be

broad to cover organisms likely to be causing the infection.

• Cultures are pending or not available.

• Definitive therapy• Therapy can be narrowed to

target isolated organism(s).

Confirm infection

▪ Careful history and exam

▪ Elevated WBC? Left shift?

▪ WBC in normally sterile fluids (e.g., CSF)?

▪ Other labs (e.g., UTI: urine analysis)

▪ Radiographic imaging

There is a systematic approach to choosing appropriate antimicrobial therapy.

Identify pathogen▪ Obtain relevant cultures.

▪ Pneumonia: sputum, blood

▪ UTI: urine, blood

▪ Meningitis: CSF, blood

▪ Etc.

Systematic approach to choosing antibiotic

Empiric Therapy Considerations

• What are the most common pathogens commonly causing the infection?• E. coli for UTI, S. pneumoniae for CAP

• Resistance in the geographic area (antibiogram)• If resistance is over 20%, the agent is not a good empiric choice.

(e.g.,TMP/SMX for UTI, FQ for HA-UTI).

▪ Think about drug and host factors to guide selection of empiric therapy.

Select agents


Drug factors▪ PK/PD parameters

▪ Side effect profile

▪ Cost - Drug cost

- IV is more expensive than PO.

- Monitoring cost (ex: vancomycin levels)

▪ Intrinsic resistance

▪ Combination therapy: synergy vs antagonism

▪ Drug availability

Host factors

▪ Allergy history ▪ Age▪ Renal and hepatic function▪ Pregnancy/breast-feeding▪ Underlying disease states

(ex: prolonged neutropenia and risk for invasive mold infection)

▪ Other medical co-morbidities▪ Site of infection▪ History of colonization or previous infection due to resistant

organism(s)

▪ Is the infection resolving?

▪ Is the patient tolerating therapy?

▪ Can the antimicrobial regimen be simplified?

▪ IV to PO switch?Monitor clinical response


Conclusions

▪ Antimicrobial resistance is a local, national, and global concern.

▪ Working together - everyone has a vital role in insuring optimal antibiotic use

Thank You For Your Time & [email protected]

Documents

Bioburden Continuum: Systemic Infections and Antibiotic ... · Bioburden Continuum: Systemic Infections and Antibiotic Stewardship. Disclosures •Speakers Bureau- Organogenesis Inc,