Antibiotic-Use-Misuse-and-Abuse

Asymptomatic Bacteruria • Antibiotic therapy for asymptomatic UTI’s may even be harmful per studies • In a trial women treated for asymptomatic bacteruria were found to have a higher in

Antibiotic Use, Misuse, and

Abuse

Brian Levy, MD

Current Antibiotic Trends

• In the United States, we are NOT very good

about treating patients with antibiotics, in both the inpatient and outpatient settings

• Per the CDC, numerous studies have shown that 30-50% of antibiotics prescribed in hospitals are unnecessary or inappropriate

• Efforts to improve antibiotics are necessary to improve patient outcomes while reducing

overall healthcare costs

Problems with Antibiotic Misuse

• Global problem of antibiotic resistance which

is a public health crisis

• Clostridium difficile infections

• Health care costs

• Adverse reactions to antibiotics

• Drug interactions with antibiotics

Antibiotic Resistance

Antibiotic Resistance

• Antibiotic resistance occurs after the

administration of antibiotics where millions of bacteria may undergo selective pressure and the bacteria can develop mutations as well as the acquisition of new genes on plasmids

• Per the CDC, in the US, there are at least 2

million people infected with antibiotic resistant bacteria and 23,000 will die as a result

Antibiotic Resistance

• Even if not fatal, these infections can

significantly have effects on extended hospital stays and costs

• Many medical advancements such as joint

replacements, organ transplants, cancer

therapy, and treatment of chronic diseases

such as diabetes, asthma, cystic fibrosis,

bronchiectasis, and rheumatoid arthritis

depend on the ability to fight infections

• 2002 Vanc resistant staph

• 2011 ceftaroline R-Staph

Unfortunately Doctors Are Largely to Blame

What Can Doctors and Hospitals Do?

• Is the antibiotic indicated at all?

• Is the appropriate antibiotic being given?

• Is the right amount of time given for the

antibiotic as opposed to a more extensive

duration?

• Is the right dose of the antibiotic being given?

Common Clinical Scenarios

Asymptomatic Bacteruria

• One of the most common abuses of antibiotics

• Asymptomatic bacteruria extremely common in hospital patients, notably diabetic, elderly women, indwelling

catheterized patients, spinal cord injury patients

• Screening for and treating asymptomatic bacteruria is

only warranted for 2 sets of patients: pregnancy and

patients undergoing a urologic intervention such as a

TURP or other urologic procedures where mucosal

bleeding anticipated, renal transplant patients in the first

3 months of a transplant

Asymptomatic Bacteruria

• Antibiotic therapy for asymptomatic UTI’s may even

be harmful per studies

• In a trial women treated for asymptomatic bacteruria were found to have a higher incidence of a

symptomatic UTI over the next year over women

who did not receive antibiotics (Clin Infect Dis 2012,

55 (6):771).

• Bacteruria in the absence of symptoms is very

common among catheterized patients and again

does not warrant treatment

Community Acquired Pneumonia

• Sputum and blood cultures should be obtained to help guide treatment However, no pathogen identified in majority of cases and viral pathogens more common than bacterial (N Engl J Med 373: 315, 2015).

• In community acquired infections (not HAP, VAP,

aspiration), most common bacterial organisms or

Strep pneumoniae and atypicals such as

chlamydophilia and mycoplasma).

• Antibiotic recommendations in regards to above:

ceftriaxone plus azithromycin or levofloxacin

Community Acquired Pneumonia

• Duration of treatment: 5-7 days (N Engl J Med, 370:543, 2014)

• Antibiotics can be discontinued safely after 5

days in patients who are afebrile for 48 hours

and have no more than one of following: SBP <

90, HR > 100, RR > 24, O2 sat < 90% (JAMA

Intern Med, 2016 , Sep 1, 176 (9), 1257-65)

• Improved outcome with B-lactam plus macrolide

vs B-lactam alone (Thorax 68:493, 2013)

Community Acquired Pneumonia

• Coverage for MRSA? Not generally indicated as

uncommon, about 2% of cases (Clin Infect Dis 54:1126, 20120

• Exceptions for covering for MRSA in CAP: in IVDU or influenza associated

• Can use nasal swab PCR for Staph Aureus to exclude MRSA as the etiology of CAP with a negative predictive value of 99.2% (Antimicrob Agents Chemother 58:859, 2014)

• Above guidelines refer to hemodynamically stable CAP

Community Acquired Pneumonia

• How about the use of procalcitonin?

• Procalcitonin is a serum biomarker that helps distinguish bacterial infections from other

sources of infection such as viral or

non-infectious etiologies and can also be used to

guide when to stop antibiotics for CAP

• If level < 0.10, bacterial infection thought to be very unlikely, , 0.10 to 0.25 unlikely, 0.25-.0.50 likely, and >0.50 very likely

Community Acquired Pneumonia

• There is emerging evidence that normalization of serum procalcitonin level can shorten treatment duration for CAP When levels are followed and

trend down, can safely discontinue antibiotics

(Inf Dis Clin No Amer 2017, 31:435).

• Procalcitonin is not perfect False positives: renal failure, small cell lung CA, severe trauma, cardiac arrest, surgery, pancreatitis, among others False negatives: if drawn too early in course of infection

Cellulitis of the Extremities

• Typically involves rapidly spreading red edematous, tender

plaque-like areas of the skin usually on the lower leg, often febrile.

• A study showed that in patients with extremity cellulitis that was non-purulent, the etiology was almost always identified as beta hemolytic streptococcus (Group A, C, or G) (Infect Dis, 3: Nov 25, 2015)

• The indications to treat for MRSA would be is there is a purulent discharge, an abscess suspected, or in setting of IVDU Otherwise the treatment should be guided towards strep with antibiotics

such as PCN or cefazolin (Vancomycin only if history of PCN

anaphylactic reaction) No need for other broader coverage.

Cellulitis of the Extremites

• Usual duration of therapy is 7-10 days

• Stasis dermatitis due to venous insufficiency often mimics cellulitis It is typically bilateral, chronic, and patient is afebrile (Ann Intern

Med, 142:47, 2005) There is no benefit from giving antibiotics (JAMA 311: 2534, 2014)

What are Hospitals Doing to Stop Combat the

Antibiotic Issues?

Antimicrobial Stewardship

• Numerous professional societies and government

agencies have issued new guidelines and requirements

to address the issues of antibiotic abuse and misuse.

• Antibiotic stewardship refers to the systematic

measurement and coordinated interventions designed

in hospitals to promote optimal use of antibiotics

• The primary goal of antimicrobial stewardships is to

optimize clinical outcomes while minimizing

unintended consequences of antibiotics and the

emergence of resistant organisms

Antimicrobial Stewardship

• Who is part of the antimicrobial stewardship committee in

hospitals? Typically pharmacists with experience in

antimicrobials and with physician guidance, often an infectious disease physician

• There are a number of specific interventions that the members

of the antimicrobial stewardship do in the hospital

• Antibiotic “time outs” A review is done at 48 hours The

following questions are asked: Does this patient have an

infection responding to antibiotics? If so is the patient on the right antibiotic based on culture results and suspected source of infection? If so, can the antibiotic selection be narrowed? How long should the patient receive antibiotics?

Antimicrobial Stewardship

• Prior authorization Some hospitals restrict the use of certain antibiotics based on cost, broad spectrum of activity, or toxicities Some require an ID consult to continue using

• Automatic changes from IV to oral antibiotics when appropriate.

• Dose adjustments in cases of organ dysfunction (i.e renal failure).

• Alerts in situations when it is felt an inappropriate

antibiotic is being used

Antimicrobial Stewardship

• The United Nations committed to the goal of

addressing antibiotic resistance through

stewardship programs (Ann Int Med 2016, 165:

Clostridium Difficile

• C diff deserves special mention as it is a major adverse

consequence to the use of antibiotics.

• It is a gram positive anaerobic bacilli that is a spore former.

• Most significant risk factor is recent antibiotic use, other factors include advanced age, hospitalization, cancer

chemotherapy, and gastrointestinal surgery

• Highly associated antibiotics: fluoroquinolones,

clindamycin, cephalosporins, carbapenems, b-lactams

• Suspect in above risk factors and at least 3 unformed stools

a day

Clostridium Difficile

• Do not test formed stool There is a substantial rate of

C diff asymptomatic carriage, so there may be false

positives Screening for carriage not recommended (Clin Inf Diseases, 2018, 66: 987).

• Not all hospitals offer same diagnostic tests Some use PCR testing (very sensitive, not as specific) Others

uses antigen (sensitive) plus toxin (specific) testing and

if a discrepancy, then do PCR testing (Clin Infect Dis

2018, Jun 28).

• Repeat testing to document cure is not recommended

Clostridium Difficile

• Disease severity can highly vary

• Mild disease, moderate amount of diarrhea

with WBC < 15 and no increase in creatinine

• Severe disease with significant diarrhea, WBC

C Diff Treatment

• The first step is cessation of any inciting antibiotics if clinically allowed

• For non-severe and severe c diff, vancomycin 125 mg qid x 10 days

recommended Fidoxamocin also effective but rarely used due to cost

• Use of PO metronidazole for above no longer recommended It has been associated with treatment failure and recurrence (Clin Infect Dis, 2005, 40 (11): 1586) Metronidazole also associated with higher mortality than vancomycin (JAMA Int Med 177:546, 2017)

• For fulminant C diff with ileus, treatment recommendations are

vancomycin 500 mg qid plus metronidazole 500 mg IV every 8 hours The vancomycin can be given as a rectal enema In most extreme

cases, a colectomy is needed

C Diff Treatment

• In general avoid antiperistaltic medications

• Relapse may occur in up to 20-25% of patients.

• For the first relapse, treat with a 10 day course of

vancomycin, followed by a 5 week taper.

• For multiple recurrences, fecal microbia transplantation is done and has shown promise to be successful (J Hosp Med, 11: 56, 2016)

• Prophylaxis with vancomycin to prevent recurrent C diff in patients receiving antibiotics who have had prior c diff

showed decrease in recurrence (Clin Infect Dis 63: 651,

2016).

Gram Negative Bacteremia

Gram Negative Bacteremia

• Gram negative bacteremia is a major cause of

morbidity and mortality in hospitalized patients

• 7 vs 14 days of treatment?

• In hospitalized patients with gram negative

bacteremia who achieved clinical stability before day

7, an antibiotic course of 7 days was non-inferior to

14 days The primary outcome was at 90 days

mortality, relapse, complications, readmission, or

extended hospitalization (Clinical Infect Dis, Dec

2018)

Staph Aureus Bacteremia

Staph Aureus Bacteremia

• Sepsis and septic shock are common

• Mortality rate of 10-20%

• Most common sources of infection: IVDU, intravascular catheters, skin and soft tissue infections (abscesses), bone and joint

infections (osteomyelitis), pneumonia,

endocarditis

• Source not found in about 25% of cases

Staph Aureus Bacteremia

• Staph aureus bacteremia has a high risk of invasive disease if not treated promptly (osteomyelitis,

endocarditis, etc).

• Obtaining an echocardiogram is recommended in staph aureus bacteremia to rule out endocarditis (JAMA 312: 1330, 2014).

• Identify primary and secondary foci of infection to reduce the risk of treatment failure or relapse

(remove indwelling IV catheters, drain abscesses, infected joints aspirated).

Staph Aureus Bacteremia

• Until culture susceptibility results available, Vancomycin should be used as empiric therapy (Clinical Infect Dis 61:

361, 2015)

• Treatment regimens: MSSA – nafcillin / oxacillin or

cefazolin, MRSA – Vancomycin or daptomycin (significantly more expensive, typically reserved for Vancomycin failure).

• For MSSA, Vancomycin has been shown to be less effective with more persistent bacteremia and relapse than beta-

lactam agents and should not be used for MSSA unless the patient has an anaphylactic allergy to beta-lactams

(Medicine (Baltimore), 2003, 82 (5): 33)

Staph Aureus Bacteremia

• For MSSA, cefazolin was found to have comparable

results to anti-staphylococcal penicillins (BMC Infect Dis,

2018, 18: 508)

• Treatment failures were higher with ceftriaxone than

with cefazolin (Open Forum Infect Dis, 2018, May 18, 5 (5))

• Always obtain follow up cultures to document clearance Positive blood cultures after 3-4 days of appropriate

antibiotics is strong predictor of complicated bacteremia (i.e endocarditis, osteomyelitis, persistent abscess).

Staph Aureus Bacteremia

• Persistent bacteremia suggests endovascular infection and poor source control A search for the source with drainage or surgical

debridement should be attempted

Staph Aureus Bacteremia

• Duraton of treatment – typically 2 week for uncomplicated bacteremia (Anti Microb Agents Chemother 57: 1150,

2013) or 4-6 weeks for complicated bacteremia

• What is uncomplicated bacteremia? Resolution of fever

by day 3 of therapy, negative blood cultures by day 3 of

therapy, presence of easily removable focus of infection,

no echocardiographic signs of endocarditis, no

osteomyelitis, no hematogenous secondary focus of

infection, no pre-existing valve abnormalities (i.e

prosthetic valve, rheumatic valve disease, bicuspid aortic valve), no implanted prosthetic device (i.e prosthetic hip)

Staph Aureus Bacteremia

• What is complicated bacteremia? Doesn’t meet the above mentioned criteria for

uncomplicated Treatment for 4-6 weeks

recommended for endocarditis or metastatic infection Treatment for 6-8 weeks for

osteomyelitis

Staph Aureus Bacteremia

• What about treatment failure? This occurs with relapse or prolonged bacteremia while

on appropriate therapy It is more common with vancomycin, MRSA infection,

endocarditis, undrained focus, and

vancomycin with MIC = 2 For strains with an MIC > 2, an alternative agent to vancomycin should be used (JAMA 312: 1152, 2014)

Staph Aureus Bacteremia

• Treatment failure options for MRSA include: daptomycin, ceftaroline (Antimicrob Agents Chemother, 2017: 51 (2)), telavancin (Infect Dis, 47: 379, 2015)