Back to the Future

Juan D. Diaz, DO, FACP Infectious Disease & Tropical Medicine

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“… the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out which can be passed on to other individuals and perhaps from there to others until they reach someone who gets a septicemia or a pneumonia which penicillin cannot save. In such cases the thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism. I hope this evil can be averted.”

“The evolution of resistant strains is a natural phenomenon that happens when microorganisms are exposed to antimicrobial drugs, and resistant traits can be exchanged between certain types of bacteria”.

“The misuse of antimicrobial medicines accelerates this natural phenomenon. Poor infection-control practices encourage the spread of AMR.”

World Health Organization 2014

Infections caused by resistant microorganisms often fail to respond to the standard treatment, resulting in prolonged illness, higher health care expenditures, and a greater risk of death.

World Health Organization 2014

cdc.gov

cdc.gov

cdc.gov

new study has uncovered dozens of species of bacteria in a 4 million-year-old cave that harbor resistance to both natural and synthetic antibiotics.

93 bacterial strains tested from the cave, most were resistant to more than one of the 26 different antimicrobials. Some bacteria were resistant to more than a dozen antibiotics

Lechuquilla cave image courtesy of Max Wisshak

Bhullar K, Waglechner N, Pawlowski A, Koteva K, Banks ED, et al. (2012) Antibiotic Resistance Is Prevalent in an Isolated Cave Microbiome. PLoS ONE 7(4): e34953. doi:10.1371/journal.pone.0034953

The optimal selection, dose, & duration of an antimicrobial that results in the best clinical outcome for the treatment of infection, with minimal toxicity to the patient & the least impact on the subsequent development of resistance.

Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology

of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

Inappropriate therapy associated with higher mortality

Indiscriminate use of broad spectrum antibiotics driving resistance.

Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology

of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

cdc.gov

CDC Report "Antibiotic Resistance Threats in the United States, 2013"

ENCOURAGE: AVOID:

Appropriate initial therapy

Improve outcomes

Unnecessary antibiotics

Adverse outcomes

Side-effects

Combat the emergence of

resistance

Improve clinical outcomes

Control costs

Education is considered to be an essential element of any program designed to influence prescribing behavior & can provide a foundation of knowledge that will enhance & increase the acceptance of stewardship strategies (A-III).

education alone without incorporation of active intervention, is only marginally effective in changing antimicrobial prescribing practices & has not demonstrated a sustained effect (B-II).

Addresses the concern of a literal return to the pre-antibiotic era for many types of infections

2 important factors in resistance epidemic:

- microbes do not need humans to develop resistance

- humans can affect the rate of spread of bacterial resistance by applying selective pressure via exposure to abx’s both in patients & livestock

The overuse of antibiotics on healthy animals to make them grow larger has led to human resistance to the drugs’ effects.

Farmers and ranchers will for the first time need a prescription from a veterinarian before using antibiotics in farm animals, in hopes that more judicious use can be accomplished.

9/2005: the Food and Drug Administration (FDA) finally withdrew its approval for use of fluoroquinolone antibiotics (FQs) in poultry.

This is the first time the FDA has banned an agricultural antibiotic due to concerns about antibiotic resistance.

Issues a challenge: “…physicians must take care to prescribe antimicrobials appropriately, to minimize the rate of spread of drug resistance”.

Primary Goal: - optimize clinical outcomes while minimizing the

unintended consequences of antibiotic use - Toxicity - selection of pathogenic bacteria - emerging resistance

Secondary Goal: reduce healthcare costs without

compromising quality of care.

Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

Prospective audit with intervention & feedback

Formulary restriction/preauthorization

Dellit TH, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of

America Guidelines for developing an institutional program to enhance Antimicrobial Stewardship. Clin Infect Dis. 2007; 44:159-177.

Concurrent review of patients receiving antimicrobials

Inappropriate orders initiate interaction between antimicrobial team members & the prescriber

Goal: to enhance antimicrobial stewardship – optimize selection, dose, duration, route

Advantages: avoids loss of autonomy for prescriber

Crates incentives for physicians to improve performance

Disadvantage: compliance is voluntary

less effective unless it distinguishes between appropriate & inappropriate prescribing

Controls antimicrobial use & costs, conflicting results on decreasing antimicrobial resistance

Advantages: - provides most direct control over antimicrobial

use.

Disadvantages: prescribers may feel loss of autonomy

Must have contingency plans for off hour approvals

May discourage appropriate antibiotic use May delay receiving appropriate therapy initially.

Clinical pathways/guidelines

De-escalation

Combination therapy

IV PO

Dose optimization

Education

Antimicrobial order forms

Antimicrobial cycling

Physician order entry

The embodiment of de-escalation is that based on microbiology results around the day 3 therapy point; the empiric antibiotic(s) that were started are stopped or reduced in number and/or narrowed in spectrum. example: Meropenem to Cefepime/ciprofloxacin or Aztreonam for pseudomonas aeruginosa

APPROPRIATE INITIAL ANTIBIOTIC TREATMENT

AVOID UNNECESSARY ANTIBIOTICS

Select correct Antibiotics

Combination therapy

Proper dosing & intervals

Monitor cultures & labs

Evaluate micro data to narrow spectrum

Shorten duration

Monitor clinical endpoints

Conduct diagnostic evaluation

Kollef, MH. Drugs. 2003

Early combination antibiotic therapy is associated with decreased mortality in septic shock

Only 30% of patients with presumed septic shock have positive blood cultures

About 25% of presumed septic shock patients remain culture-negative from all sites, but mortality is similar to that for culture-positive counterparts

Crit Care Med. 2010 Sep;38(9):1773-85.

P. aeruginosa:

retrospective analysis /combination antimicrobial therapy as empirical treatment until receipt of the antibiogram : associated with a better rate of survival at 30 days than the use of monotherapy.

combination antimicrobial therapy given as definitive treatment for P. aeruginosa bacteremia did not improve the rate of survival compared to that from the provision of definitive monotherapy.

Antimicrob Agents Chemother. Sep 2003; 47(9): 2756–2764.

most of the available evidence does not suggest that combination therapy is particularly useful in preventing emergence of resistance in P. aeruginosa

Pharmacotherapy. 2011;31(6):598-608.

Agents with equal or high bioavailability:

Quinolones

Metronidazole

Linezolid

TMP/SMX

clindamycin

Fluconazole/voriconazole

Decrease risks of:

Line sepsis

Thrombophlebitis

Medication errors

Excess fluid administration

Dose based on individual patient characteristics:

causative organism

site of infection

pharmacokinetic and pharmacodynamic properties

renal function

susceptibilities.

Underdosing - increases risk of resistance

Overdosing- leads to side effects, adverse events, intolerance, and even perception of allergies

Its a scheduled replacement of one antibiotic for another, in order to avoid the development of bacterial resistance.

Initial studies suggest that this strategy could be useful in reducing the rates of bacterial resistance as well as the incidence of nosocomial infections caused by Gram-negative bacilli in intensive care unit patients.

does not prevent antibiotic misuse and needs to be applied in a complete antibiotic policy program.

Current Opinion in Infectious Diseases: December 2001 - Volume 14 - Issue 6 - pp 711-715

Baseline information on antimicrobial use, expenditures, & susceptibilities at particular institution.

Formulate antimicrobial properties toward individual institutional needs.

Create a multidisciplinary antimicrobial stewardship team.

Need ADMINISTRATION SUPPORT.

Compensate members of the team for their time.

Facilitate acceptance of the program among your institution’s health care providers.

Monitor adherence of healthcare providers to stewardship tactics.

Choice: host factors/safety

local resistance patterns (antibiogram)

antimicrobial history/exposure

Appropriate

- suspected pathogens are susceptible to 1 or more of the administered antimicrobials.

Timely: patients are up 2.1% more likely to die for each 30 minute delay in administration.

Inadequate initial therapy > 48 hrs between time of culture was obtained & initiation of agent to which infecting organism was susceptible increases mortality.

Adequate dosages: exploit pharmacokinetics

Intermittent IV infusion: infusion last 30-60 min

Extended IV infusion: infusion lasting 3-4 hours

Continuous infusion: continuous infusion over a 24 hour period at a fixed rate.

Lodise TP, Lomaestro BM, Drusano JL. Pharmacotherapy 2006;26 (9):1320-1332

Use of extended/continuous are important for optimizing the time above the MIC for agents with time dependent killing ie; B-Lactams to improve microbiological & clinical cure.

In vitro and animal studies have demonstrated that the amount of time in which the free or non–protein-bound drug concentration exceeds the MIC of the organism (fT>MIC) is the best predictor of bacterial killing and microbiologic response for beta-lactams

Concentration-dependent antibiotics achieve increasing bacterial kill with increasing levels of drug. In addition, these agents have an associated concentration-dependent PAE in which bactericidal action continues for a period of time after the antibiotic level falls below the MIC.

www.hopkinsmedicine.org/amp

Clinical pharmacokinetic-pharmacodynamic studies have shown that extended/continuous infusions of beta-lactams increase the chance of maintaining serum drug concentrations above the MIC of the pathogen over a 24 hour period.

Furthermore, prospective and retrospective clinical trials have demonstrated higher clinical cure rates, shorter length of stay, & mortality benefits with extended/continuous infusion beta-lactams vs. intermittent infusions.

www.hopkinsmedicine.org/amp

TIME DEPENDENT KILING

CONCENTRATION DEPENDENT KILLING

B-lactams: Penicillins

Cephalosporins

Carbapenems

Monobactams

Clindamycin

Macrolides

Linezolid

Aminoglycosides

Fluoroquinolones

Daptomycin

Metronidazole

Azithromycin

Promote antibiotic best practices — a first step in Antibiotic Stewardship:

Ensure all orders have dose, duration, and indications

Get cultures before starting antibiotics

Take an “antibiotic timeout,” reassessing antibiotics after 48–72 hours

VRE in stool is just colonization

Piperacillin/Tazobactam PLUS metronidazole for anaerobic coverage

Vancomycin use for Methicillin susceptible staphylococcus aureus for ease of administration in dialysis patients

Staphylococcus aureus bacteremia always requires at least 2 weeks of IV antimicrobial therapy

Oxacillin to treat enterococcus

Quinolones are no longer effective for empiric treatment of Gram negative infections

Hospitalist.org

Interest in biomarkers to discriminate infectious vs non infectious culprits of fever

ESR/CRP are non-specific

Sensitivity of 97% & specificity of 78% for differentiating SIRS from SEPSIS

Role is still unclear…BUT

Levels found to correlate with severity of infection.

Secreted from all parenchymal tissues in response to proinflammatory stimulation, particularly a bacterial infection.

Bacterial infections : (endotoxins & cytokines) induce CALC-1 gene expression, which stimulates the release of PCT.

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After stimuli, levels rise within 2-3 hours & reach plateau after 6-12 hours

Remain elevated for up to 48 hours

Half life is 20-24 hours

Levels decrease with recovery/treatment & indicate a positive prognosis.

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Not affected by renal function.

Autoimmune diseases

Graft rejection

Viral infections

Allergic reactions

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Fungal

Malaria

OKT3 use (stimulate release of proinflammatory cytokines)

Cardiogenic shock

Carcinoid tumors, thyroid carcinomas, & NEC

Pulmonary aspiration/inhalational injuries

Major trauma/burns

Gallstone pancreatitis

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Studies show that serial PCT levels for severe infections have shown to lower the duration of antibiotics: decreased antibiotic associated adverse events, risk of developing resistance, & treatment costs.

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Not all elevated PCT levels indicate a bacterial infection

Not all low levels exclude a severe bacterial infection

THEREFORE, PCT results in CONJUNCTION with other laboratory results & clinical signs can be a valuable tool for clinicians – especially for antimicrobial de-escalation or cessation of antimicrobials.

Idpodcasts.net

Requirement 7C: implement best practice to facilitate the prevention of MDRO infections in acute care hospitals, focusing on MRSA & CDAD.

Requirement 7D: implement best practices for prevention of catheter associated bloodstream infections (CLABSI).

Proposed goals recommend educating staff re; MDRO, measuring MRSA & CDAD rates

CA-UTI

Vascular catheter associated infection

mediastinitis after CABG

Decubuti ulcers (stage 3-4)

Cetain types of falls

Objects left behind in surgery

Air embolism

Blood incompatibility

Staphylococcus aureus disease

CDAD

VAP

Surgical site infections after elective procedures

According to the IDSA/SHEA 2007 Guidelines:

hospitals implementing an ASP consistently demonstrate a decrease in antimicrobial use (22%–36%) and annual savings of $200,000–$900,000

A University of Maryland study showed one antibiotic stewardship program saved a total of $17 million over 8 years.

more than pays for the program in both larger academic hospitals and smaller community hospitals.

(Clinical Infectious Diseases 2007;44:159–77)

Antimicrobial stewardship programs are a “win‐win” for all involved.

Fixing a global problem by acting locally

Helps improve patient care, shorten hospital stay, and decreased costs.

Infectious Disease Society of America (IDSA) Society for Healthcare Epidemiology of America (SHEA) Centers for Medicare & Medicaid Services. Tang,H.,Huang,J.,et al. Effect of Procalcitonin – Guided

Treatment of patients with infections: a Systematic Review and Meta-Analysis. Infection 2009, 37 (6):497-507

idPodcasts.net www.cdc.gov Hopkinsmedicine.org Google.com/images Scientificamerican.com Dellit TH,et al. Clin Infect Dis 2007;44:159-177