Multi-drug Resistant Organisms "BAD BUGS"

What is Dalbavancin (Dalvance)?

A medication used to treat MRSA> Similar to vancomycin, but has an additional lipophilic tail that gets into the cell membrane. Very long-acting.

How did VRSA develop?

A patient had recurrent MRSA and concurrent VRE. VRSA strain acquired the vancomycin resistance gene cluster vanA from VRE.

Avycaz is a new product for MDR gram-negatives. What is active against and what is it NOT active against?

Active against AmpC, ESBL, and KPC-producing Enterobacteriaceae Less effective for MDR pseudomonas FDA approved February 2015 for cUTIs and cIAIs

Zerbaxa is a new product for MDR gram-negatives. What is active against and what is it NOT active against?

Active against MDR Pseudomonas and ESBL-producing Enterobacteriaceae NOT active against KPC FDA approved December 2014 for cUTIs and cIAIs

Gram-negative MDRO treatment. Name advantage(s) and disadvantages of aminoglycosides.

Advantage: Broad gram-negative spectrum Disadvantage: Associated with toxicities Not recommended as monotherapy for treatment of Pseudomonas

Gram-negative MDRO treatment. Name advantage(s) and disadvantages of Carbapenems?

Advantage: DOC for ESBL-producing organisms Can be used in combination Disadvantage: Increasing rate of resistance

VRE treatment options: What are some advantages and disadvantages of Tigecycline? NOTE: THIS IS USUALLY LAST-LINE BECAUSE OF THE BLACK BOX WARNING of increasing mortality.

Advantage: Good tissue penetration, and activity against anaerobes Disadvantage: Nausea = VERY COMMON Low serum, urine concentrations Black box warning - worsened mortality (in patients with pneumonia especially)

VRE treatment options: What are some advantages and disadvantages of Fosfomycin?

Advantage: Narrow spectrum, and option for VRE cystitis Disadvantage: Not for systemic infections.

VRE treatment options: What are some advantages and disadvantages of Quinopristin-dalfopristin? NOTE: This is ALSO a last-line option

Advantage: There is an FDA indication Disadvantage: Only active against E. faecium Phlebitis, arthralgias, myalgias *vein irritation = has to be given through a central line. Flush line after administered.

VRE treatment options: What are some advantages and disadvantages of Linezolid?

Advantages: Available in IV and PO. FDA indication for VRE Disadvantage: Myelosuppression and serotonin-syndrome

Gram-negative MDRO treatment. Name advantage(s) and disadvantages of Zerbaxa.

Advantages: Activity against MDR-Pseudomonas and ESBL-producing organisms Disadvantages: Only approved for IAIs and UTIs; limited data for other infections

Gram-negative MDRO treatment. Name advantage(s) and disadvantages of Avycaz.

Advantages: Activity against ESBL, AmpC, KPC-producing organisms Disadvantages: Only approved for IAIs and UTIs; limited data for other infections

Gram-negative MDRO treatment. Name advantage(s) and disadvantages of Polymyxins.

Advantages: Limited resistance Broad Gram-negative spectrum Disadvantages: Associated with toxicities Difficult to dose

VRE treatment options: What are some advantages and disadvantages of Nitrofurantoin? NOTE: This is only for bladder infections, not for systemic infections.

Advantages: Narrow spectrum, option for VRE cystitis Disadvantage: NOT for systemic infections. Not recommended for CrCl < 40 mL

VRE treatment options: What are some advantages and disadvantages of Daptomycin?

Advantages: Once daily dosing and well tolerated. Disadvantages: CANNOT USE FOR PNEUMONIA. Need to monitor for myopathy

Gram-negative MDRO treatment. Name advantage(s) and disadvantages of Unasyn.

Advantages: Sulbactam has intrinsic activity against acinetobacter. Disadvantages: Increasing rates of resistance Optimal dose unknown

Gram-negative MDRO treatment options: what are the six drugs that treat?

Aminoglycosides Unasyn (ampicillin-sulbactam) Avycaz Carbapenems Polymyxins Zerbaxa

Acinetobacter baumanni is associated with HA infections. Most commonly pneumonia, bloodstream infections, UTIs, surgical site infections. MDR-acinetobacter has various mechanisms of resistance. What are the treatment options?

Ampicillin/sulbactam (Unasyn) *generally narrow spectrum* Carbapenems Tigecycline Polymyxins Aminoglycosides Rifampin in combination *only in combination with other antibiotics

What is the downside to polymyxins?

Because they are old, the PK/PD isn't really available - hard to dose

Extended Spectrum β-Lactamases [ESBL] are encoded by genes located on plasmids. What is the definition of ESBLs? Which is it inhibited by?

Beta-lactamases capable of conferring bacterial resistance to the penicillins, 1st, 2nd, and 3rd generation cephalosporins, and aztreonam [but not the cephamycins or carbapenems] Inhibited by clavulanic acid

Amp C Beta-lactamases hydrolyze most ______ _____.

Beta-lactams

What is the treatment to "SPACE" organisms? Once induced, AmpC β-lactamases confer resistance to almost all beta-lactams If a 3rd generation cephalosporin is used, there is a 20 - 25% likelihood resistance will develop on therapy What are the treatment options?

Beta-lactams: cefepime, carbapenems Non beta-lactams

CA-MRSA is typically associated with ______ and ______ _____ _____. Provide an example.

CA-MRSA is typically associated with skin and soft tissue infections. SPIDER-BITE, for example

What are the treatment options for CRE? What should be noted with each? NOTE: You must consider susceptibility profile of organism, site of infection, and patient specific factors.

COMBINATION THERAPY IS A MUST! Agents: Polymyxins (Poly E - Colisin, or Poly B) - Electrostatic interaction disrupts cell membrane Dosing confusion Nephrotoxicity and neurotoxicity Aminoglycosides: Nephrotoxicity and ototoxicity Tigecycline: Inhibits protein synthesis Extensive tissue penetration Associated with increased mortality Carbapenems: High dose, prolonged infusion regimens

What is CRE?

Carbapenem-resistant Enterobacteriaceae [CRE] Associated with high mortality rates THE MOST RESISTANT BACTERIAAAAAAAA OFTEN carry genes that confer high levels of resistance to antimicrobials

What are two new medications available for MDR gram-negatives?

Ceftolozane/tazobactam (Zerbaxa) Ceftazidime/avibactam (Avycaz)

Anti-microbial stewardship: Implement policies that support optimal antibiotic use Document dose, duration, and indication Develop and implement facility specific treatment recommendations Interventions to improve antibiotic use Antibiotic "time outs" Pharmacy-driven Interventions Dose adjustments and optimization Review of drug-drug interactions, IV to PO conversions FLIP

Changes in antimicrobial use Formulary restrictions Example: Minimized inappropriate use of 3rd generation cephalosporins Resulted in: 22% decrease in broad spectrum antibiotic use Decreased CDI rates Decreased rates of resistant Enterobacteriaceae

What is the treatment option for CA-MRSA pneumonia?

Clindamycin

Which drug for CRE treatment is formulated as its inactive prodrug?

Colistin (poly E) Formulated as its inactive prodrug colistin methanesulfonate [CMS] Unstable compound that converts to colistin via hydrolysis Colistimethate - renal excreted - if they have good kidney function they might excrete it before it is able to turn into the active drug

What is the most common combination therapy for CRE?

Colistin + tigecycline +/- meropenem

Pseudomonas aeruginosa is associated with both CA and HA acquired infections. Such as, UTIs, bloodstream infections, pneumonia, surgical site infections. MDR-pseudomonas is increasing in ICU patients (variety of mechanisms of resistance). What are the treatment options?

Combination therapy (beta-lactam plus aminoglycoside) Polymyxins New agents (Zerbaxa or Avycaz *usually a little less active versus zerbaxa*)

Which medication is inactivated by lung surfactants?

Daptomycin

VRE treatment options: Name six options.

Daptomycin Linezolid Tigecycline Quinopristin/dalfopristin Nitrofurantoin Fosfomycin

What is the name of the new fluoroquinolone approved in June 2017 and what is it indicated for?

Delafloxacin (Baxdela) Indicated for the management of SSTIs

What is the drug of choice for ESBL? What are others?

Drug of CHOICE: CARBAPENEMS Other treatment options (non-beta-lactams): Aminoglycosides Fluoroquinolones Cephamycins Beta-lactam/beta-lactamase inhibitor combinations? Cefepime? Need to consider site and severity of infection

Quinopristin-dalfopristin is ONLY active against ____ ______.

E. Faecium

What are some gram-negative MDROs

ESBL, AmpC, CRE, MDR-Acinetobacter, MDR-Pseudomonas

Name some gram-negative MDROs and their subtypes if they are known.

Enterobacteriaceae (AmpC, ESBL, CRE) Acinetobacter baumannii Pseudomonas aeruginosa

Name the "ESCAPE" bacteria. Remember that these are the bacteria that are able to "escape" the antibiotic.

Enterococcus faecium Staphylococcus aureus Clostridium difficile Acinetobacter baumannii Pseudomonas aeruginosa Enterobacteriaceae

Of the nosocomial enterococcus species, which is the more resistant to antibiotics?

Enterococcus faecium is more resistant to antibiotics Enterococcus faecalis - more "friendly" Emergence in the past two decades is attributable to their resistance

Name six populations of people that are at risk for CA-MRSA

Extremes of age (children <2 years old; adults >65 years old) Situations that promote transmission (athletes, MSM men- who have sex with men) Residence in close quarters (prisons, residential homes) Military personnel IV drug users History of colonization or recurrent infection with CA-MRSA

T/F Mechanisms of resistance for hVISA and VISA includes possessing vancomycin resistant genes found in enterococcus.

FALSE They do no possess vancomycin resistant genes found in

T/F Dalbavancin is active against VRE.

False It is not

T/F Linezolid has less risk of serotonin syndrome than tedizolid.

False MORE RISK

T/F Vancomycin is more nephrotoxic than telavancin.

False Other way around.

Where are enterococcus species normally found?

Found in normal flora of GI tract and adult feces.

Dalbavancin and Oritavancin are both good for what type patients?

Good for patients who are non-adherent. Also good for SEVERE SSTIs but do not require hospitalization (outpatient or ED settings).

What are some risk factors for colonization and infection of VRE?

Heavy use of antimicrobial agents (Especially vancomycin and third-generation cephalosporins *more at risk for VRE* ) Increased length of hospital stay Older age Immunosuppression [transplant, malignancy]

____ ____ and ____ _____ are important for the treatment for CRE.

High doses, extended infusions

Infections with MDROs are associated with what three things?

Higher rates of hospitalization Greater length of hospital stay Higher rates of illness and death

Persons who have had frequent or recent contact with hospitals or healthcare facilities [i.e. nursing homes, dialysis centers] within the previous year, have recently undergone an invasive medical procedure, or are immunosuppressed are at risk for what?

Hospital-acquired MRSA These patients are generally resistant to multiple classes of antibiotics.

Penicillinases inactivate which antibiotics?

Hydrolyze early penicillins

Extended-spectrum Beta-lactamases (ESBL) inactivates which antibiotics?

Hydrolyze most beta lactams except carbapenems

Amp C-type cephaosporinases inactivate which antibiotics?

Hydrolyze most beta lactams except cefepime and carbapenems

Carbapenemases inactivate which antibiotics?

Hydrolyze most beta-lactams including carbapenems

Broad spectrum Beta-lactamases inactivate which antibiotics?

Hydrolyze penicillins and first generation cephalosporins

How is delafloxacin available?

IV and PO

What are the treatment options for skin and soft tissue infections HA-MRSA?

Incision and drainage is the primary treatment Hospitalized patients: Vancomycin Linezolid Daptomycin

What are the treatment options for skin and soft tissue infections CA-MRSA?

Incision and drainage is the primary treatment. Outpatients: Clindamycin *remember need a D-test* Bactrim Doxycycline Minocycline

Ceftaroline (a newer anti-MRSA treatment option) is indicated for what (name two)? What is an advantage and disadvantage?

Indicated for CAP and SSTIs Advantages: Well tolerated Disadvantages: Limited literature on dosing/use in more serious/complicated infections

Telavancin (a newer anti-MRSA treatment option) is indicated for what (name two)? What are some advantages and disadvantages?

Indicated for: HAP/VAP/SSTIs Advantage: Once daily dosing Disadvantages: Nephrotoxic, teratogenic REMS program Higher rate of mortality in patients with renal impairment

Oritavancin (a newer anti-MRSA treatment option) is indicated for what? What are some advantages and disadvantages?

Indicated for: SSTIs Advantages: Long half-life (one dose). Ease of use outpatient. Activity against VISA, VRSA, VRE Disadvantages: Only approved for SSTIs Interactions with warfarin and heparin monitoring *prolongs PTT, and causes increased warfarin concentrations

Dalbavancin (a newer anti-MRSA treatment option) is indicated for what? What are some advantages and disadvantages?

Indicated for: SSTIs Advantages: Long half-life; only 1 dose Ease of use outpatient Data for use in CRBSIs Disadvantages: Only approved for SSTIs No activity against VRE

Tedizolid (a newer anti-MRSA treatment option) is indicated for what (name two)? What are some advantages and disadvantages?

Indicated for:SSTIs Advantages: Available IV and PO. It is once daily dosing, may not interact with MAO-Is and SSRIs. No significant thrombocytopenia. Disadvantages: Only approved for SSTIs

Amp C Beta-lactamases may show ______ ______ in the presence of beta-lactams. This is why beta-lactams should be avoided, EXCEPT for ______ or ______.

Inducible Resistance Cefepime or Carbapenems

What is the clinical significance of hVISA?

It is associated with vancomycin treatment failures Lack of uniform and reliable testing methods. Serves as a precursor for VISA (especially if vancomycin is under-dosed)

What CRE pathogen is predominant type in the US?

Klebsiella pneumoniae carbapenemase [KPC]

Name three organisms that are ESBL producers.

Klebsiella pneumoniae, E. coli, Proteus mirabilis

THE POLYMYXINS NOTES: Came to the market before establishment of the present day drug approval process - limited PK/PD data available Discovered in the 1950s and widely used until the 1970s (when the Ags came out) Cationic polypeptides Originally shelved due to toxicity concerns Making a comeback Increasingly the only remaining antibiotics with activity against MDR _____-_____ ______.

MDR gram-negative bacilli

What are two pathogens covered by Delafloxacin?

MRSA Pseudomonas THE ONLY FQ with coverage for both! Also: MSSA, Streptococcus species, Enterococcus faecalis, E. coli, Enterobacter, Klebsiella pneumonia

Oritavancin covers _____ and ______.

MRSA VRE

What is the definition of multi-drug resistant organisms?

Microorganisms, predominantly bacteria, that are resistant to more than one class of antimicrobial agents

Enterococci are intrinsically resistant to most ____-_____ antibiotics, including _______.

Most beta-lactam antibiotics [cephalosporins!]

What is the CRE definition?

Nonsusceptible to one of the following carbapenems Doripenem, Meropenem, Imipenem Resistant to all of the following 3rd generation cephalosporins Ceftriaxone, cefotaxime, ceftazidime

Enterococcus has shown acquired resistance to what medications (name three)? Why (name three reasons)?

Penicillin and ampicillin - beta-lactamase production, alteration of PBPs. High level resistance to aminoglycosides - resistant to synergism Vancomycin resistant - more common in E. faecium, vanA, vanB.

What predisposes a patient to VRSA infection?

Prior MRSA and VRE infections or colonization. Or previous extensive treatment with vancomycin.

What are some risk factors for acquisition of ESBL?

Prolonged ICU/hospital stay Nursing home residency Invasive procedures Exposure to certain antibiotics and total antibiotic use 3rd generation cephalosporins, fluoroquinolones Plasmids that carry ESBL genes often carry other multi-resistance genes

CA-MRSA strains carry _______ - which confers resistance to methicillin but are generally susceptible to non-beta-lactam antibiotics.

SCCmecIV

What is Tedizolid (Sivextro)?

Second-generation oxazolidinone approved for anti-MRSA (skin and skin structure infections)

What is the proposed mechanisms of resistance for hVISA and VISA?

Sequential mutations resulting in cell wall modifications [thicker cell wall] Synthesis of excess amounts of D-ala-D-ala In a nut shell: Has a thickened cell wall - more binding sites for vancomycin to bind too (makes it less effective because it doesn't bind where cell wall synthesis is occurring).

Name the "SPACE" organisms that might display AmpC Beta-lactamase. Which two are the most common.

Serratia Providencia, Proteus [indole positive], Pseudomonas Acinetobacter Citrobacter Enterobacter Most common: citrobacter and Enterobacter

What are some advantages of Dalbanvin or Oritavancin? Name four.

Similar spectrums of activity Improved activity against some vancomycin-resistant strains Ease of use Can possibly treat patients with complicated SSTIs on an outpatient basis

Name some gram-positive MDROs and their subtypes.

Staph aureus (MRSA, hVISA, VISA, VRSA) Enterococcus (VRE)

Intrinsic resistance enterococci: They have low affinity penicillin binding proteins that results in ______ to most beta-lactams. Aminoglycosides also have low uptake as _______.

TOLERANCE Monotherapy

T/F There are specific guidelines for MRSA.

TRUE

T/F Delafloxacin is not associated with QT prolongation.

TRUE! Most FQs are, so this is good news :) Other adverse effects are similar to the other FQs

What is unique about Ampicillin/sulbactam used in the treatment for acinetobacter baumannii?

The SULBACTAM is actually what has the action against this pathogen. It binds to PBP2 MUST USE HIGHER DOSES Optimal dose unknown - most recommend at least 6g per day for serious infections

T/F Enterococci is intrinsically resistant to bactrim.

True

T/F Oritavacin is active against VRE.

True

T/F Vancomycin breakpoints for MRSA are created by the Clinical Laboratory Standards Institute and are updated periodically.

True

Rates of colonization for staphylococcus aereus are high among what populations?

Type 1 diabetes Intravenous drug users [IVDU] Patients requiring hemodialysis Surgical patients HIV patients

What are some advantages of Tedizolid? Name three.

Unlikely to interact with MAO-Is and SSRIs Unlikely to cause significant thrombocytopenia Compared to linezolid, can be used to treat skin and skin structure infections for 6 days (versus 10 days for linezolid)

__________ survives for long periods of time on dry surfaces - environment contaminant able to cause outbreaks

VRE

When ____ and _____ are present, you get a change in the amino acids of D-la D-la and the binding is much reduced leading to a resistance to vancomycin.

VanA and VanB

What are the treatment options for HA-MRSA pneumonia?

Vancomycin Linezolid

What is hVISA?

Vancomycin Heteroresistance. Phenotypically susceptible using broth microdilution (BMD). Testing in greater detail reveals subpopulations of cells with reduced susceptibility. FURTHER NOTES: hVISA: vancomycin heteroresistance - still in the susceptible range; however, if you were to perform an E-test you can see some of the subs are resistant. The closer the vancomycin gets to the MIC gets to the break point, even tho it is in the susceptible range, you are more at risk of having sub-population resistance.

What is VRSA?

Vancomycin Resistant

What is VISA?

Vancomycin intermediate resistance

HA-MRSA Who is affected, and what areas are typically affected?

WHO: Immunocompromised Long term care facility residents Recent hospitalization Dialysis patients Recent surgery AREAS: Bloodstream Surgical Site Lungs

CA-MRSA Who is affected? What sites are affected?

WHO: Young, otherwise healthy patients No recent hospitalizations Areas: Skin and soft tissues LUNGS

MRSA Methicillin resistance is conferred by the ______ gene. It encodes a ______-_____ ______ with decreased affinity for beta-lactam antibiotics. Part of a mobile genetic element called the "staphylococcal cassette chromosome mec"

mecA Penicillin-binding proteins

Optimizing PK-PD. Beta-lactams are ____ ____ and it is pertinent to optimize and extend the time for the concentration above the MIC for pseudomonas aeruginosa.

time dependent