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3/17/19 Super Bugs Need Super Drugs, or Do They? George Dresden, MSN, ACNP, DNP Objectives ØDetermine which antibiotic to use based on pharmacodynamic category: time dependent, concentration dependent, time dependent/concentration enhanced ØImprove your prescribing of antibiotics for bacteria with resistance to beta lactams, including penicillin. ØAssess for all gram negative and positive bacteria, as well as viral etiologies with secondary bacterial infections. Recognize, isolate, and treat the superbugs early. ØIn immunocompromised patients test for fungal etiologies, and be prepared to treat them. Differentiate between opportunistic and non-opportunistic systemic infections. Antibiotic/Antimicrobial Resistance Biggest Threats in 2013 Urgent Threats Ø Drug-resistant Shigella Ø Carbapenem-resistant Enterobacteriaeae (CRE) Ø Methicillin-resistant Staphyococcus aureus (MRSA) Ø Drug-resistant Neisseria Gonorrhoeae Ø Drug-resistant Streptococcus pneumoniae Ø Clostridiodes Difficile Ø Drug-resistant Tuberculosis Serious Threats Ø Multidrug-resistant Acinetobacter Concerning Threats Ø Drug-resistant Campylobacter Ø Vancomycin-resistant Staphylocccus aureus (VRSA) Ø Fluconazole-resistant Candida Ø Erythromycin-Resistant Group A Streptococcus Ø Extended-spectrum Beta-lactamase producing Ø Clindamycin-resistant Group B Streptococcus Enterobacteriaceae Ø Vancomycin-resistant Enterococcus (VRE) Ø Multidrug-resistant Pseudomonas aerginosa CDC is working toward releasing an updated Threats Ø Drug-resistant non-typhoidal Salmonella Report in the Fall of 2019. 1 3/17/19 World Health Organization’s Top 12 Priority Pathogens Priority 1: CRITICAL Priority 2: HIGH › Acintobacter baumannii, carbapenem-resistant › Enterococcus faecium, vancomycin-resistant › Pseudomonas aeruginosa, carbapenem-resistant › Staphylococcus, methicillin-resistant, vancomycim- intermediate and resistant › Enterobacteriaceae, carbapenem-resistant, ESBL- producing › Helicobacter pylori, clarithromycin-resistant – Klebseilla pneumonia › Campylobacter spp., fluroquinolone-resistant – Escherichia coli – Enterobacter spp. › Salmonellae, fluroquinolone-resistant – Serratia spp. › Neisseria gonorrhoeae, third generation – Proteus sp. cephalosporin-resistant, fluroquinolone-resistant – Providencia spp – Morganella spp. Priority 3: MEDIUM › Streptococus pneumoniae, penicillin-non-susceptible › Haemophilus influenzae, ampicillin-resistant › Shigella spp., fluroquinolone-resistant So, How Did We Get Here? Quick Terminology Review-Take a Nap if this is Old Hat for you › Bacteriostatic-inhibition of bacterial growth › Bactericidal-killing of bacteria › Minimum inhibitory concentration (MIC)-the lowest concentration of antibiotic that completely inhibits growth of the specific organism being tested › Minimum bactericidal concentration (MBC)- the lowest concentration of antibiotic at which bacteria are killed Evidence supports killing when treating endocarditis, meningitis and osteomyelitis, otherwise, inhibition of growth is generally sufficient. So How Did We Get Here? › Overuse or misuse of antibiotics, i.e. giving antibiotics for a viral infection (#1 misuse) › Patients not completing courses of antibiotics when they start feeling better, so they get re-infected › Saving antibiotics and sharing them with others or taking them later for a different illness 2 3/17/19 Concentration vs Time-Dependent Killing For an antibiotic to eradicate an organism: – It must bind to its target site(s) in the bacterium – It must occupy an adequate number of binding sites (concentration) Pharmacokinetic/Pharmacodynamic Parameters Affecting Antibiotic Potency – To work effectively, it must remain there long enough for the metabolic processes of the bacteria to be sufficiently inhibited (Time-Dependent) Concentration vs Time-Dependent Killing Antibiotic Pharmacodynamic Categories Time –Dependent Concentration-Dependent Time-Dependent-Concentration (T> MIC) Cmax/MIC or AUC/MIC Enhanced No post-antibiotic effect Strong post-antibiotic effect AUC 24/MIC (for gram-) Moderate post-antibiotic effect Penicillins Aminoglycosides Macrolides (Azithromycin) Cephalosporins Fluroquinolones Clindamycin Erythromycin Metronidazole Vancomycin Amphotericin B Tetracyclines Aztreonam Carbapenems Azole antifungals >MIC for 40-50% of dosing AUC/MIC >125 for gram- interval-max killing seen when bacteria, > 25-50 for gram+ time above MIC is at least 70% cocci Cmax/MIC >10. of dosing interval. DOUBLE COVERAGE Based on the assumptions Ø The combination provides a broad spectrum of coverage for empiric treatment before knowing the ID and susceptibility of offending pathogen Ø The combination may provide additive or synergistic effects against the pathogen Ø The combination of antibiotics may decrease or prevent the emergence of resistant bacteria 3 3/17/19 Beta Lactams Development of Beta Lactam Resistance › Decreased penetration to the target site – Permeability of the outer membrane no longer allows the antibiotic through such as with Pseudomonas aeruginosa › Alteration of the target site – Penicillin binding proteins (PBPs) may be changed so that they no longer have an affinity for the beta-lactam antibiotics so that the bacterial cell is no longer inhibited. Examples are pneumococci, methicillin resistance in staphylococci, and Haemophilus influenzae. › Inactivation by a bacterial enzyme (ESBL) – Chromosomal beta-lactamases – Plasmid-mediated beta-lactamases How to Use Beta Lactams Effectively Anti-Staphylococcal Penicillin Natural Penicillin › Methcillin › Pen V – Gm+, very narrow spectrum, should be given IV, – Gm+, less effective against gm -, narrow may cause interstitial nephritis spectrum, PO, prone to ß-lactamase (tonsillitis, anthrax, rheumatic fever, › Oxacillin streptococcal skin infections) – Gm+, treatment for PCN-resistant Staphyloocus Amino-Penicillin aureus, very narrow spectrum, should be given IV › › Nafcillin Ampicillin – Gm+, treatment for staphylococcal infections, very – Gm+ & gm -, broad spectrum PO and IV, narrow spectrum, should be given IV prone to ß-lactamase (ear infections, sinusitis, UTI, menigitis) › Cloxacillin › – Effective against staphylococci that produce ß- Amoxicillin lactamase, very narrow spectrum, should be given – Gm+ & gm -, broad spectrum PO and IV, PO prone to ß-lactamase (skin infection, sinusitis, UTI, streptococcal pharyngitis) › Dicloxacillin and Flucloxacillin – Gm+, and Staphyococci that produce ß- lactamase, very narrow spectrum, should be given PO 4 3/17/19 How to Use Beta Lactams Effectively Anti-Pseudomonal Penicillin Cephalosporin › Pipercillin › 1st generation predominantly active – Gm+ & Gm-, extended spectrum, against Gm+ Bacteria, the 3 successive should Be given IV or IM if given with generations have increased activity tazoBactam a ß-lactamase inhibitor, against Gm- bacteria, reducing Gm+ further strengthens its effectiveness activity. › CarBenicillin › 1st generation: cefalothin, cefalexin, – Gm- & limited Gm+, mainly useful for cefadroxil, & cefazolin UTI › 2nd generation: cefuroxime (PO), & › Ticarcillin cefotetan – Mainly Gm-, particularly Pseudomonas aeruginosa, also stenotrophomonas › 3rd generation: cefotaxime, ceftriaxone, maltophilia infections & ceftazidime › 4th generation: cefepime › 5th generation: ceftaroline How to Use Beta Lactams Effectively Carbapenems Monobactam › Broad spectrum beta-lactam › Aztreonam antibiotics. They are highly – Gm+ and Gm- & anaerobic bacteria, resistant to ß-lactamases. broad spectrum, IV, NOT active against MRSA › Imipenem – Aerobic and anaerobic, Gm+ and ß-lactamase Inhibitors Gm- (including ESBL-producing strains), and Pseudomonas, IV, can › Resemble ß-lactam antibiotic produce seizures at high doses structure, so bind to the ß- lactamase and protect the › Meropenem antibiotic from destruction – Aerobic and anaerobic, Gm+ and Gm-, ultra broad spectrum, IV › They are most successful when the binding is irreversible › Ertapenem – Gm+ and Gm-, broad spectrum, IV, › 3 Most Important: Clavulanic NOT effective against MRSA acid, Sulbactam, & Tazobactam Beta-Lactamase Enzyme 5 3/17/19 Why Is It Important To Detect ESBL’s? › The presence of an ESBL-producing organism in a clinical infection can result in treatment failure if the wrong antibiotic is used. › ESBL’s can be difficult to detect because they have varying levels of activity against the cephalosporins. It is crucial to choose wisely which antibiotics to test against. For example, one enzyme may have a minimum inhibitory concentration (MIC) of 4 μg/ml on ceftazidime but have poor activity on cefotaxime with a MIC of 256 μg/ml. › If an ESBL is detected, ALL PENICILLIN’S, CEPHALOSPORINS, AND AZTREONAM SHOULD BE REPORTED AS RESISTANT, even if in vitro test results indicate they have susceptibility. Metallo Beta-Lacamase › Resistant against a broad spectrum of beta-lactam antibiotics. › This includes those in the carbapenem family. › This particular class is characterized by its ability to hydrolyze carbapenems and by their resistance to available ß-lactamase inhibitors (tazobactam, sulbactam, clavulanic acid) but susceptibility by metal ion chelators (vitamin B12, ascorbic acid). › The most common bacteria that are responsible for this enzyme are Gm- such as Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Penicillin-under or over utilized? › Penicillin allergy is the most common, reported by up to 15% of hospitalized patients › Clinically-can they be safely given structurally related cephalosporins or carbapenems › Do they need allergy consultation
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