Upload
lamkhanh
View
214
Download
1
Embed Size (px)
Citation preview
Tips for Antimicrobial Prescribing in an era of multi‐drug resistance.
Robert Orenstein, DOChair Division of Infectious Diseases
Mayo Clinic ArizonaAssociate Professor, Mayo Clinic College of Medicine and Science
AOMA Fall Conference Nov 12, 2017
Disclosures
NONE except….
Opportunities for Improvement
• Has anyone in this room ever prescribed Azithromycin for a URI?
• Has anyone given ciprofloxacin for asymptomatic bacteriuria?
• Has anyone prescribed Amoxicillin or Clindamycin to prevent Prosthetic hip infections before dental work?
Reckless Drivers cause Accidents
Stop killing beneficial bacteria
Collateral Damage
• Average child receives 10‐20 courses of antibiotics before age 18
• Antibiotics affect our resident microbiota and may not fully recover after a course of antibiotics
• Overuse of antibiotics may be contributing to obesity, DM, IBD, allergies, and asthma
Blaser M et al Nature 2011;476:393
How Big is the Problem?• Antibiotics are the second most commonly used class of drugs in the United States
• More than 8.5 billion dollars spent annually
200‐300 million antimicrobials prescribed annually
53% for outpatient use
Bronchitis, pharyngitis and sinusitis account for 75% of all office‐based Rx for antibiotics
• Almost half of hospitalized patients receive antibiotics
• 50% of antibiotic use is either unnecessary or inappropriate across all type of health care settings
BMC Med 2014;12:96 Clin Infect Dis 2007; 44:159‐177
But it won’t impact MY patients..
• Impact on urinary, respiratory and skin flora
• Effect is greatest in month after but may last 12 months
• Potential driver of community resistance
• Dose response for Amox and TMP‐SMX
Fewest Abx for shortest duration
BMJ 2010; 340 doi: http://dx.doi.org/10.1136/bmj.c2096
Objectives for Today
• Know how to treat common infections
• Know which organisms are frequently resistant to antibiotics
• Know what antimicrobials can be used for commonly drug resistant infections
• Know how to prevent multi‐drug resistant infections
How to treat common infectionsTips for the Clinician
• Treat the patient not the culture
– Think before even getting a culture
• Prevent resistance before it starts
– Build up the host, treat the whole patient
• What to use when prevention fails
• New therapeutics for MDROs
Common Infections
• URTI ‐ Strep throat, OM, ABRS
• LRTI – AECOPD, CAP, HAP
• SSTI – Cellulitis, MRSA
• UTI – Cystitis, Pyelo, Prostatitis
• STDs – GC, Chlamydia, Mycoplasma
• C. difficile diarrhea
• Acute bronchitis
• Common colds
• Sinusitis with symptoms less than 7 days
• Pharyngitis not due to Group A Streptococcus spp.
• Most infectious diarrhea
Gonzales R, et al. Annals of Intern Med 2001;134:479Gonzales R, et al. Annals of Intern Med 2001;134:400Gonzales R, et al. Annals of Intern Med 2001;134:521
Tip #1 Viral Infections don’t require antibiotics
Tip #2 – Prepare before you prescribe
• Use Biomarkers when available– Procalcitonin
• Use Rapid Diagnostic tests –– Multiplex PCR
– Rapid AG tests
• Patient education – handouts‐ CDC Get Smart
• Opportunity to Vaccinate– Influenza, Pertussis, Strep pneumoniae
• OMT – enhance the host’s ability
Managing URTI Strep throat, OM, ABRS
• Group A Strep Pharyngitis– NO Resistance to Penicillins, Cephalosporins– Resistance is to Macrolides – Azithro, Clarithro– Make a Dx via rapid test or Culture– Treatment is one dose IM Benzathine PCN or oral for 10 days
• OM– H. flu, S. pneumoniae resistance rates rising– Vaccinate children!– Watchful waiting, OMT– Amoxicillin is still first line
Otitis Media Therapy and AntibioticsWhat’s the evidence
• 80% of acute OM resolves in 3 days without Rx
• ABX do not influence subsequent OM or deafness at 1 month
• May reduce # of children still in pain 2-7 days but for each 1 improved 3 will develop ABX related side effects
• Repeated courses may make recurrent infection more likely
Rhinosinusitis Tips• One in 7 Americans, diagnosed each year
• In top 5 for Abx Rxs
• But…90‐98% of these are viral
• When to prescribe….
1. Symptoms >10 days w/o improvement
2. Severe sxs with fever>102, nasal dc & facial pain>3 days
3. Viral sinus sxs that worsen over 5‐6 days and associated with new fever, headache, more nasal dc
Acute Maxillary SinusitisThe Evidence
Randomized placebo controlled trial of antibiotic
Adults with suspected AMS were referred by GPs for X-rays of the maxillary sinus.
Those with radiographic abnormalities (n = 214) were randomly assigned treatment with amoxicillin (750 mg three times daily for 7 days; n = 108) or placebo (n = 106).
Clinical course was assessed after 1 week and 2 weeks, and reported relapses and complications were recorded during the following year.
• At 2 weeks, symptoms improved substantially or disappeared• 83% AMOX and 77% placebo (a 6% difference). • No influence on the clinical course, frequency of relapses during
the 1-year follow-up. • Radiographs had no prognostic value• Side-effects were recorded in 28% of patients given amox and in
9% (a 19% difference) of those taking placebo (p < 0.01). The occurrence of relapses was similar in both groups (21 vs 17%) during the follow-up year.
Van Buchem Lancet. 1997 May 17;349(9063):1476
How should we treat ABRS ?
• Amox‐Clav for 5‐7 days in adults
• Nasal saline irrigation
AECOPD
• Antibiotics recommended in patients with:– Increased: dyspnea, purulent sputum and volume
– Need for mechanical support
• Mild‐Moderate– 1st line – Doxycycline or Amox/Clav or Cefdinir
– 2nd line – Azithromycin
• Severe– No risk for Pseudomonas – Ceftriaxone
– Risk for PA – Cefepime or Pip‐Tazobactam
CAP Treatment in Era of Stewardship
• General Inpatient– Ceftriaxone + Doxycycline
– Severe beta lactam allergy – Levofloxacin
• ICU or Severe CAP or Risk for P. aeruginosa– Cefepime + Doxycycline or
– Pip‐Tazobactam + Doxy
– Consider addition of tobramycin if MDR PA
– Severe beta lactam allergy –• Aztreonam + Vanco + Doxy
HAP Management
• Vancomycin + Pip‐Tazo or
• Vancomycin + Cefepime
• Consider adding others based on risk:
– Doxycycline – Legionella
– Levofloxacin or Tobramycin
• Risk for MDR – GNB (LTCF, prior IV Abx <90d)
• VAP with risk for MDRO
Treating the Non‐resolving SSTI
• A 68 year old obese, diabetic man presents to the clinic with a hot swollen right leg as shown
• He starts Cefazolin 2 g IV q8h but on hospital day 3 it doesn’t look much better
A. What do you recommend?
B. Switch to IV Vancomycin
C. Switch to Zosyn
D. Continue current treatment
Cellulitis/SSTI
Etiology of Cellulitis
Clinical or biochemical response was observed in the majority of patients the day after treatment initiation. Concordance between clinical and biochemical response was strongest at days 2 and 3. Female sex, cardiovascular disease, higher body mass index, shorter duration of symptoms, and cellulitis other than typical erysipelas were predictors of nonresponse at day 3
Natural Clinical Course of Treated Cellulitis
Predictors of Early Response
• Clinical or biochemical response was observed in the majority of patients the day after treatment initiation.
• Concordance between clinical and biochemical response was strongest at days 2 and 3.
• Female sex, cardiovascular disease, higher body mass index, shorter duration of symptoms, and cellulitis other than typical erysipelas were predictors of nonresponse at day 3
Early Response in Cellulitis: A Prospective Study of Dynamics and PredictorsClin Infect Dis. 2016;63(8):1034-1041. doi:10.1093/cid/ciw463
Summary‐ slowly responsive cellulitis
• Categorize the cellulitis
– Purulent needs drainage
– Most do not
• If non‐purulent watchful waiting and address non‐infection factors
• Consideration of adjuncts
Misuse in Skin and Soft Tissue Infections
Review 322 cases of SSTI @400 bed hospital in Denver 2007
• Positive cultures: 145/150 (97%) – S. aureusor streptococci
Treatment ‐70% got Abx for GNRs
• Imaging (151): Yield‐1%
• Abx duration (median): 14 days
Jenkins T. Clin Infect Dis 2010;51:895
THE ANTI‐MRSA BRIGADEVancomycin, Daptomycin, Telavancin, Linezolid, Tedizolid, Dalbavancin, Oritavancin, Clindamycin, Trimethoprim‐Sulfa, Tigecycline, Minocycline, Ceftaroline, Quinupristin‐dalfopristin, Delafloxacin
Outpatient UTI ManagementUncomplicated Cystitis
• Women with at least 2 sxs: dysuria, urgency, frequency and no vaginal discharge ‐ >90% probability of acute cystitis
– Studies found no benefit to doing testing
Women with relapse or recurrent UTI (>2/6m), complicated infections, Abx exposure or resistance should have a urine culture done
Treatment of Acute Cystitis
• Women – Nitrofurantoin 100 mg BID x 5 days– Fosfomycin 3g x 1 dose– TMP‐SMX DS BID x 3 days (if resistance<20%)
• Men– 7‐14 days
• Inpatients – empirical Rx– Ceftriaxone 1 g/d– Severe beta lactam allergy – Aztreonam and Vancomycin– Risk for MDR
• Pip‐Tazobactam or Cefepime or • Vanco + Aztreonam if severe beta lactam allergy
– Sepsis – Add Vanco
Outpatient management of the MDR‐UTI
• A 74 year old woman with recurrent UTIs has been on oral Trimethoprim‐Sulfa for 3 months and now has dysuria, frequency and malaise for 2 days
• Her UA shows >100 WBC/HPF• Urine Cx ‐ >100,000 colonies E. coli
– Resistant to Amox, Amox/Clav, Ceftriaxone– Resistant to Ciprofloxacin, Amikacin, Gentamicin, Piperacillin‐Tazobactam
– Intermediate to Nitrofurantoin– Sensitive to Meropenem
Which of the following antimicrobials would be the best choice for her UTI?
A. Nitrofurantoin (Macrobid)
B. Ertapenem (Invanz)
C. Ceftolozane/tazobactam (Zerbaxa)
D. Fosfomycin (Monurol)
Fosfomycin (Monurol)
• 3 g oral sachet – dissolves in water
• Inhibits bacterial cell wall synthesis at early stage
• Bactericidal
• Requires Creatinine clearance>20
• Approved for single dose treatment uUTI
• Spectrum: E. coli inc ESBL, Klebsiella, P. aeruginosa, Proteus mirabilis, Staph sapro and E. Faecalis, VRE
Fosfomycin Dosing
• Uncomplicated UTI – 3 g x 1 dose
• Complicated UTI 3g q 3 days x 3 doses
• TUR Prophylaxis 3 g x 2 days periop
• rUTI prophylaxis – 3g q 10 days
• Do not use for Pyelonephritis
• Might work in prostatitis
Fosfomycin
• Expensive – prior auth! $45‐90/dose
• Most labs cannot do Fosfomycin susceptibility
• Low risk for CDI – small bowel absorption
Summary‐ UTI
• For patients with MDR‐cystitis
• Fosfomycin is an oral treatment option
• Alternatives would be IV ‐ Ertapenem
Treat Bacterial Infection, not Colonization
• ≥105 colony forming units is often used as a diagnostic criteria for a positive urine culture
• It does NOT prove infection; it is just implies the culture is unlikely due to contamination
• Pyuria is not predictive on its own
• Symptoms AND pyuria AND bacteruriadenotes infection
Grigoryan L et al JAMA 2014;312:1677‐84
Asymptomatic Bacteriuria is Common
Age (years) Women Men
20 1% 1%
70 20% 15%
>70 + long‐term care 50% 40%
Spinal cord injury 50% 50%(with intermittent catheterization)
Chronic urinary catheter 100% 100%
Ileal loop conduit 100% 100%
Nicolle LE. Int J Antimicrob Agents. 2006 Aug;28 Suppl 1:S42‐8.
Treatment of Asymptomatic Bacteriuria in the Elderly
Multiple prospective randomized clinical trials have shown no benefit
• No improvement in “mental status”
• No difference in the number of symptomatic UTIs
• No improvement in chronic urinary incontinence
• No improvement in survival
Inappropriate Abx Usein Asymptomatic Bacteriuria
• Dalen 2005 Ottawa 52%
• Ghandi 2009 Michigan 33%
• Cope 2009 Houston 32%
• 1/3‐50% get antibiotics despite evidence of no benefit
A Second Opportunity ‐UTIs
• Much of the antibiotic use here is not appropriate and avoidable.
• Wrong treatment, Wrong Drug, Wrong Duration are common
• Resistance to Fluoroquinolones Trimethoprim‐Sulfa
• Ensure the patient has a UTI not an alternate diagnosis
• When catheters in place ‐ all are bacteriuric• The reservoir for MDROs
What Causes the Pain in UTI
• Visceral pain is usually projected over the dermatome that shares common spinal innervation
• In murine models – strains which cause ASB elicit different responses than symptomatic UPEC strains – It is LPS which induces the pain through TLR4
• Inflammatory cells in urine are not the cause of pain and do not correlate with UTI in ASB
• New therapeutic approach? Probiotics with LPS
Rudick CN J Infect Dis 2010:201:1240
Biotherapeutics in UTI
• Vaginal application of L. crispatus reduces UTI
• ASB E. coli – bacterial interference
• Strain 83972 of E coli
• Use of these strains in mice prevents symptomatic infection
• Reduces pain more than ciprofloxacin
• Promotes clearance
Rudick CN PLOS One 2014;9:e109321
A Challenging UTI
• A 53 year old man with Parkinson’s disease and a seizure disorder presents with his 4th urinary tract infection in the past year.
• He has back pain and dysuria. His current urinalysis shows pyuriaand bacteriuria
• Urine culture is growing Klebsiella pneumoniaeResistant to: Ciprofloxacin, Gentamicin, Trimethoprim‐Sulfa, Pip‐Tazo, Cefepime, Ertapenem, Imipenem, Meropenem
• What antibiotic is most likely to be effective for treatment of his Klebsiella pneumoniae infection?
Management of Carbapenem‐resistant Enterobacteriaceae (CRE)
• Any Enterobacteriaceae isolate non‐susceptible to all 3rd generation Cephs and Imipenem, Doripenem or Meropenem
• CALL FOR BACK‐UP!!
New Drugs for MDROsCeftazidime‐Avibactam (Avycaz)
• New non‐beta‐lactam beta‐lactamase inhibitor added to Ceftazidime which enhances activity against some MDR GNRs including CRE
• Most KPCs, ESBL, AmpC
• NOT Metallo‐beta lactamases!
• 2.5 g IV q 8h (over 2h)
– 2 g Taz plus 500 mg Avibactam
Epidemiology of Carbapenem‐Resistant Enterobacteriaceae in 7 US Communities,
2012‐2013
• 87% from urine; 11% blood
• Device associated or hospitalized
• Fatal in 9%
• Higher rates in GA, MD, NY vs CO, NM, OR lower
• Median age 66
• Incidence 2.93/100k vs MRSA 25, CDI 147
Guh AY et al JAMA Oct 5, 2015;doi10.10001/jama2015.12480
New Cephalosporins for Resistant Gram Negatives
• Ceftolozane/tazobactam (Zerbaxa)
– Similar to ceftazidime w/modified sidechain at position 3 ‐ antiPseudomonal
– Tazo protects the ceph from ESBLs
– Better than Ceftaz vs P. aeruginosa
– Not active vs KPCs or MBLs
– Approved for IAI, UTI
Latest Addition vs CREMeropenem‐Vaborbactam (Vabomere)
– 4g IV q8h over 3 hrs (CCl>50)
– 2g Mero + 2 g Vaborbactam
– Targets KPC producers
– cUTI, recent data on other severe infections
– Active vs Enterobacteracae
– Active vs KPC producing strains not VIM, NDM
– Side effects – HA, infusion site, diarrhea
STDs
• Neisseria Gonorrhea – increasing resistance– Ceftriaxone
• Chlamydia trachomatis– Doxycycline or Azithromycin
• Mycoplasma genitalum– Moxifloxacin
• Syphilis – no resistance– Primary/Secondary – Benzathine Penicillin 2.4 mU x 1– Latent – Benzathine PCN 2.4 mU weekly x 3– Neurosyphilis – IV Pen G 24 mU/d x 10‐14 days– Severe Beta lactam allergy (1, 2ndary only)‐ Doxy
Slowly Resolving C difficile Infection
• A 74 year old man developed CDI after receiving clindamycin for a dental cleaning prophylaxis in the setting of a prosthetic hip replacement performed in 1992.
• He has been on oral vancomycin for 6 days and continues to have 2‐3 pudding texture stools/d
• Which of the following should you do next?
A. Check the Cdiff toxin test
B. Provide Imodium and Citrucel
C. Increase the vancomycin dose
D. Add metronidazole
Clostridium difficile infection
• A consequence of antimicrobial overuse and poor environmental hygiene
• Recent problem is OVER – diagnosis with PCR
• Only test when diarrhea is persistent in absence of other causes
• Vancomycin and Fidaxomicin are preferred
• New monoclonal Ab ‐ Bezlotuxumab
• Refer recurrent cases for clinical trials
Testing for the diagnosis of CDI
Martin, J. S. H. et al. (2016) Clostridium difficile infection: epidemiology, diagnosis and understanding transmissionNat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2016.25
Over diagnosis of C. difficile
• Treated pts may shed for 6 weeks
• After treatment tests can remain + for months
• Repeat testing is discouraged
• Up to 1/3 pts have post CDI IBS (mixed or d)
– Longer CDI duration, current anxiety and higher BMI
• Review all meds, laxatives etc
Wadgwa A et al Aliment Pharmacol Ther 2016;44:576‐82
Al Nassir WN et al. 2008 Clinical Infectious Diseases 47(1):56–62..
Time to ImprovementVancomycin versus Metronidazole
The Vulnerability Zone• Vancomycin maintains inhibitory activity 4‐5 days after completed
• Metronidazole – no late activity• 14‐21 days after treatment stools support CD growth
• 21‐28 days after – most inhibit• 3 phyla are associated with intact colonization resistance– Actinobacteria– Firmicutes– Tenericutes
©2011 MFMER | slide‐59Abujamel T Plos One Oct 2013;8
AntiBx Prophylaxis to prevent rCDI
MTN 1‐3 days prior – retrospective cohort– The rate of C. difficile infection was 1.4% in the patients who received
metronidazole and 6.5% in those who did not (P<0.001). In a multivariable analysis accounting for age, sex, and comorbidities, patients receiving metronidazole had an 80% reduced risk for
developing C. difficile infection.Rodriguez S et al Clin Gastroenterol Hepatol 2014
Oral Vancomycin prophylaxis vs SOC– 4.2% vs 26.6%
– 125 or 250 mg BID
– Recur defined by PCR+, diarrhea <4 weeksVan Hise Clin Infect Dis 2016
How to avoid C. diff when treating common infections
• A 77 year old woman with COPD and recurrent C.diff presents to your office with purulent cough, mild dyspnea and T 99F.
• Her Chest X‐ray is unremarkable, her peak flow is markedly reduced.
• In addition to a short course of corticosteroids and her MDI, which of the following would you recommend?
A. Amoxicillin‐clavulanate 500 mg BID
B. Levofloxacin 500 mg daily
C. Doxycyline 100 mg BID
D. Clarithromycin 500 mg BID
Doxycycline/Tetracyclines associated with lower risk of CDI
• 4 case control and 2 cohort studies bet 1993‐2012 show 0.62 OR vs other antibiotics
• In a subgroup analysis, Doxycycline OR 0.55
Tariq R, Cho J, Kapoor S, Orenstein R, Singh S, Pardi DS, Khanna S. ID Week 2018
Options for when you need antibiotics in patients at risk or with CDI
• At risk
– Doxycyline – RTI, SSTI (Staph)
– Penicillin VK – Strep throat, dental, SSTI
– Fosfomycin, Nitrofurantoin, Gentamicin – UTI
– Probiotics plus Abx
• With Concurrent CDI
– Oral Vancomycin low dose plus Abx
– Bezlotuxumab infusion plus CDI Rx plus Abx
Fluoroquinolone Antibacterial Drugs: Drug Safety Communication ‐ FDA Advises Restricting Use for Certain Uncomplicated Infections
UPDATED 07/26/2016. FDA revised the Boxed Warning, Warnings and Precautions and Medication Guide sections. These medicines are associated with disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient.FDA has determined that fluoroquinolones should be reserved for use in patients who have no other treatment options for acute bacterial sinusitis, acute exacerbation of chronic bronchitis, and uncomplicated urinary tract infections because the risk of these serious side effects generally outweighs the benefits in these patients
FDA Restrictions
Treatment DurationsShort course = long course
Illness
• CAP
• HAP
• Pyelonephritis
• Intra‐abdominal infection
• AECOPD
• ABRS
• Cellulitis
• Chronic osteomyelitis (v)
Treatment days (short/long)
• 3‐5 7‐10
• <8 10‐15
• 5‐7 10‐14
• 4 10
• <5 >7
• 5 10
• 5‐6 10
• 42 84
B. Spellberg JAMA Intern Med 2016;176:1254‐1255
Which Bugs are resistant?
• Outpatient
– ESBL E. coli
– MRSA
• Inpatient
– VRE
– MDR – Gram Negatives
– Candida – non‐albicans
Once daily Aminoglycosides
• Gentamicin/Tobra 5‐7 mg/kd (Creat Cl >40)
– Q24 >60; Q36 40‐59
• Amikacin 15‐20 mg/kg
• ClCr calculation: Males: (140 ‐ age [y]) x (weight [kg]) SCr [mg/dL] x 72
Females: 0.85 x (140 ‐ age [y]) x (weight [kg]) SCr [mg/dL] x 72 For obese patients (>20% IBW), use DW rather than actual body weight for calculating mg/kg dosing.
Dosing weight = IBW + 0.4 (actual body weight ‐ IBW):
Ertapenem (Invanz)
• Intravenous – once daily
• Active against ESBLs
• No activity
– Enterococcus sp
– Pseudomonas
– Acinetobacter
Fosfomycin (Monorul)
• Oral powder‐ 3g
• Active in urinary tract
• Need a Creatinine Clearance of at least 40
• Enterococcus, MDR – E. coli
• Get susceptibilities
Linezolid (Zyvox )
• Oral, 100% bioavailable
• Now generic
• Excellent for complicated SSTI – MRSA
• Interactions – SSRIs – relative
• Long term use issues
When all else fails, what tools are left?
• Get an ID Consult• Revival of the old guard
– Colistin, Aminoglycosides
• New antimicrobials– Gram Negatives – Avycaz (ceftazidime‐avibactam), Zerbaxa(ceftolozane‐tazobactam)
– Gram positives ‐ Baxdela (delafloxacin), Sivextro(tedizolid), Orbactiv (oritavancin), Dalvance (dalbavancin), Vibativ(telavancin)
• Coming attractions– Plazomicin ‐ IV neoglycoside (synergy vs MRSA, PA, CRA)– Eravacycline – fluorocycline – GPC/GNRs not PA; mcr‐1
Tips to prevent resistance
• Infection prevention starts in your hands
• Eliminate devices
• Clean the patient
• Clean the environment
• Vaccinate
• Practice good stewardship
SummaryTo Control Antimicrobial Resistance
AntimicrobialStewardship
Develop NewDrugs andVaccines
Improved Diagnostics
InfectionPrevention
ReduceResistanceReservoirs
Research &Public Policy
Education