Antibiotics II Glycopeptides Aminoglycosides Macrolides “The Mycins” Margaret K. Hostetter, M.D.

St. epi St. aureus Pneumo Grp A strepGrp B strep Enterococcus Meningococcus Listeria H. flu E. coli Klebsiella Enterobacter Serratia Ps.aerug Pseud spp B. fragilis Mouth Gut GRAM POSITIVES GRAM NEGATIVES ANAEROBES THE GLYCOPEPTIDES Vancomycin + + requires addition of an aminoglycoside

St. epi St. aureus Pneumo Grp A strepGrp B strep Enterococcus Meningococcus Listeria H. flu E. coli Klebsiella Enterobacter Serratia Ps.aerug Pseud spp B. fragilis Mouth Gut GRAM POSITIVES GRAM NEGATIVES ANAEROBES SIDE EFFECTS of VANCOMYCIN HISTAMINE-RELEASE Infusion in < 1 hour flushed skin angioneurotic edema hypotension NEPHROTOXICITY or OTOTOXICITY RARE VANCOMYCIN-RESISTANT ENTEROCOCCI

Risk Factors for Health Care Acquired MRSA MRSA252 Hospitalized on antibiotics or frequently hospitalized (e.g. cystic fibrosis) Previous colonization - patient or family Long-term care facility - patient or family Respiratory therapy - patient or family Dialysis - patient or family Serious infections susceptible only to Vancomycin, Daptomycin, Linezolid Emerg Infect Dis 11(6) 2005

Risk Factors for Community Acquired MRSA (CA-MRSA) USA300 >> USA400 ~5% of children are carriers NO RISK FACTORS Crowding, sharing of personal items: sports teams, military facilities, correctional facilities, child care Skin condition (e.g. eczema) Differing susceptibilities: TMP-SMX, clindamycin, doxycycline

D-Test for Inducible Clindamycin Resistance E E C C

Resistant Organisms in YNHH

Treatment of MRSA DrugCSFBloodLungsBones/ Joints Nafcillin Cephs Vanco√ at 60/kg√+ Clinda Bactrim If susceptible but not ABE, SBE If susceptible Linezolid√√ but not ABE, SBE √√ Daptomycin√√√

Penicillin Resistance in Pneumococci DrugSusceptible µg/ml Intermediate µg/ml Resistant µg/ml PO penicillin< >2.0 IV penicillin non-meningeal <2.04.0>8.0 IV penicillin meningeal <0.06None>0.12 3˚ cephs non-meningeal <1.02.0>4.0 3˚ cephs meningeal <0.51.0>2.0

Treatment of Penicillin Resistant Pneumococci DrugCSFBlood LungsPO PCN (all) √ Immunocompetent √ Immunocompetent Amox Ceph 2˚, 3˚ √ Immunocompetent √ Immunocompetent Ceftin Clinda√ Except endocarditis √Clinda Vanco√ + rifampin √± √ Increase dose to 60 mg/kg/day

Case Study A 60-day-old female infant presents with temperature to 39.5˚ C rectally, poor feeding, and lethargy. Physical exam is normal except for lethargy and fever. Blood culture is drawn. Urinalysis and CXR are normal. CSF shows 100 WBC’s (90% PMN’s, 10% lymphs), glucose 40/90, protein 175. Differential diagnosis? Possible causative organisms? Antibiotic regimens?

Antibiogram for Meningitis in Infants mos Possible Cause PenicillinCephalo- sporin Amino- glycoside Other Group B strep PCN, ampicillin 3˚---Vanco Strep pneumoniae All unless resist. 3˚ unless resist. ---Vanco H. influenzae type b Ampicillin (only ~75%) 3˚--- Meningo- coccus PCN, ampicillin 3˚---

Therefore, the regimen for meningitis in any child 2 months of age or older is Vancomycin PLUS Cefotaxime or Ceftriaxone

Vancomycin Levels Not generally indicated ( Clin ID 1994;18: ) Used for patients with fluctuating renal function or chronic renal failure PEAK µg/ml; now shoot for 40µg/ml TROUGH µg/ml

Vancomycin: Not a Wonder Drug Very confined spectrum Poorer anti-staphylococcal activity than Nafcillin in endocarditis ( AAC 1990; 33: ) Very poor penetration into lung and bone ( AAC 1988; 32: ) Advantages –Staphylococcus epidermidis or MRSA –Penicillin-allergic patients –Acceptable penetration into CSF (shunts, meningitis 2˚ penicillin resistant pneumococci) but at higher dosage (60 mg/kg/day)

Administration of IV Vancomycin (plus other agents where necessary) is required for which of the following scenarios? antibiotic-associated colitis that has failed to respond to metronidazole initial therapy of meningitis in a 10-year-old routine surgical prophylaxis for line insertion prophylaxis for urethral dilatation in a 13 month-old infant with corrected tetralogy of Fallot initial therapy of pneumococcal otitis media in a vomiting patient initial therapy of a respiratory decompensation in a 6 month- old tracheotomized child known to carry MRSA Case Study √ √ √

A 6-year old boy who did not receive varicella vaccine is hospitalized with an area of erythema and induration extending for a diameter of 5 cm. around a pox. Aspirate of the advancing border grows group A streptococci and Staph aureus. The empiric therapy of choice is aqueous penicillin G aqueous penicillin G plus Vancomycin Vancomycin Clindamycin Imipenem √

Case Study A 6-year old boy who did not receive varicella vaccine is hospitalized with an area of erythema and induration extending for a diameter of 5 cm. around a pox. Aspirate of the advancing border grows group A streptococci and Staph epidermidis. The therapy of choice is aqueous penicillin G alone aqueous penicillin G plus Vancomycin Vancomycin alone Imipenem √

When Is Staph epi a Pathogen? Blood cultures of neonates with lines in place - Confirm with culture of peripheral blood before Abx Blood cultures of other patients with lines in place - Confirm with culture of peripheral blood before Abx Blood cultures of patients with prosthetic valves or patches in the heart Cultures of CSF in symptomatic patients with ventricular shunts Cultures of implants in patients with prosthetic joints

The Aminoglycosides Gentamicin Tobramycin Amikacin

St. epi St. aureus Pneumo Grp A strepGrp B strep Enterococcus Meningococcus Listeria H. flu E. coli Klebsiella Enterobacter Serratia Ps.aerug Pseud spp B. fragilis Mouth Gut GRAM POSITIVES GRAM NEGATIVES ANAEROBES requires addition of a peniclllin + Tobramycin Amikacin Gentamicin

St. epi St. aureus Pneumo Grp A strepGrp B strep Enterococcus Meningococcus Listeria H. flu E. coli Klebsiella Enterobacter Serratia Ps.aerug Pseud spp B. fragilis Mouth Gut GRAM POSITIVES GRAM NEGATIVES ANAEROBES SIDE EFFECTS of the AMINOGLYCOSIDES TRUE ALLERGY RARE NEPHROTOXICITY Associated with Hypotension Loop diuretics Vancomycin Liver disease OTOTOXICITY High-tone frequencies Vestibular RESPIRATORY Curare-like effects with IV push Treat with calcium HIGH TROUGH HIGH PEAK

Aminoglycoside Levels Gentamicin/Tobramycin –PEAK 5-10 µg/ml –TROUGH < 2 µg/ml Amikacin –PEAK µg/ml –TROUGH <10 µg/ml

Aminoglycoside Levels Patients at risk for nephrotoxicity –Fluctuating renal function, usually 2˚ BP instability –Other nephrotoxic agents -e.g. Vancomycin –Liver disease When to do trough: just before third dose When to do peak: 1 hour after third dose PEAK - correlates with efficacy, ototoxicity TROUGH - correlates with nephrotoxicity

How to Adjust Adjust the dosage interval, not the individual dose, in order to retain the peak Rough rule of thumb –If pt’s creatinine is 2X normal, increase the dosing interval 2-fold (e.g. from 8 to 16 hours) –If pt’s creatinine is 3X normal, increase the dosing interval 3-fold (e.g. from 8 to 24 hours)

Case Study A three-year old girl with a neurogenic bladder has a history of recurrent urinary tract infections. Six weeks ago she was treated with Cefotaxime for a resistant E. coli. She now presents with fever and blood and urine cultures growing Pseudomonas aeruginosa, sensitive to Ticarcillin and Gentamicin. On a dose of Ticarcillin of 300 mg/kg/day and Tobramycin, 2.5 mg/kg/dose, her Tobramycin levels are as follows: Tobra peak of 8.0 and trough of 3.0 Tobra peak of 3.0 and trough of 0.4 Tobra peak of 13.0 and trough of 1.0 Discuss the implications of each of these levels in terms of adequacy of treatment, risk for nephrotoxity or ototoxicity, and changes in management.

Case Study A 16-year-old boy under treatment for ALL presents to the ED with 6 hours of fever, onset about 7 days after his last chemotherapy. Physical exam shows a Broviac catheter and an enlarging black lesion on his thigh. His WBC count is 2,000 with <10% PMN’s. Possible causative organisms? Antibiotic regimens?

Antibiogram for Sepsis in the Immunocompromised Host Possible CausesPenicillinsCephalosporinsPenicillin Allergy Gram + St epi/aureus, GAS, oral strep, Enterococci Nafcillin1˚, 2˚, 3˚ except Ceftaz Bactrim? Clindamycin Vancomycin Gram – E. coli, Klebsiella Enterobacter, Ps aeruginosa Ticar/clav (Timentin) Pip/tazo (Zosyn) 1˚, 2˚, 3˚Aminoglycoside Fungi---

When Do You Need “Double Coverage” for Gram Negatives? When treating Pseudomonas aeruginosa with Ticarcillin or Piperacillin---requires Gent or Tobra for synergy When choosing empiric therapy for a patient with fever and neutropenia/neutrophil dysfunction and shock As an empiric regimen for an immunocompromised patient possibly infected with GNR (CSF, blood, lungs, urine, other sterile sites)

When Don’t You Need “Double Coverage” for Gram Negatives? When treating an uncomplicated non- pseudomonal infection in a normal host (e.g. UTI, pyelo, osteo, cellulitis) –Cefotaxime –Ceftazidime –Aminoglycoside –Fluoroquinolone N.B. When treating Pseudomonas aeruginosa with Ticarcillin or Piperacillin in a normal host, it’s advisable to add an aminoglycoside

St. epi St. aureus Pneumo Grp A strepGrp B strep Enterococcus Meningococcus Listeria H. flu E. coli Klebsiella Enterobacter Serratia Ps.aerug Pseud spp B. fragilis Mouth Gut GRAM POSITIVES GRAM NEGATIVES ANAEROBES Azithromycin Mycoplasma, Chlamydia Clinda C. difficile

Case Study An 18-month-old unvaccinated male infant presents with two days of fever, cough, and increasing work of breathing. CBC shows a WBC count of 35,000 with 80% PMN’s. CXR shows a lobar infiltrate in the left lower lobe. A blood culture is drawn and the child is admitted. Possible causative organisms? Antibiotic regimens? Antibiotic regimens if he has anaphylaxis to penicillin?

Antibiogram for Community Pneumonia in Child < 6 years OrganismPenicillinsCephalosporinsAminoglyco side Other MSSANafcillin1˚, 2˚, 3˚ except Ceftaz ---Clindamycin Linezolid Vancomycin MRSA--- Bactrim Clindamycin Linezolid Vancomycin Strep pneumoniae Penicillin, Ampicillin, Nafcillin 1˚, 2˚, 3˚ except Ceftaz ---Linezolid Vancomycin Azithromycin Group A strepAll PCN1˚, 2˚, 3˚ except Ceftaz ---Clindamycin Linezolid H flu type BAmpicillin 2˚, 3˚ except Ceftaz ---Aztreonam

Case Study A 10-year-old girl presents with two days of fever, cough, and increased work of breathing. CBC shows a WBC count of 35,000 with 80% PMN’s. CXR shows a segmental infiltrate in the left lower lobe. A blood culture is drawn and the child is admitted. Possible causative organisms? Antibiotic regimens? Antibiotic regimens if she has anaphylaxis to penicillin?

Antibiogram fro Community Pneumonia in a Child > 6 years Possible Cause PenicillinCephalo- sporin Amino- glycoside Other Strep pneumoniae All even if resist. 1˚, 2˚, 3˚---Clinda,Eryth, Azithro Mycoplasma pneumoniae --- Eryth, Azithro

Case Study An 11-day-old female infant presents with temperature to 39.5˚ C rectally, poor feeding, and lethargy. No source for the fever is found on physical exam. Blood culture is drawn. Urinalysis and CXR are normal. CSF shows 400 WBC’s (90% PMN’s), glucose 25/90, protein 175. Differential diagnosis? Possible causative organisms? Antibiotic regimens?

Antibiogram for Late Onset Neonatal Meningitis Possible Cause PenicillinCephalo- sporin Amino- glycoside Other [St. aureus]Vanco ListeriaAmpicillin or other PCN Gent, Tobra as adjunct --- Group B strep Ampicillin or other PCN 1˚, 2˚, 3˚Gent, Tobra as adjunct --- GNRAmpicillin (only ~50%) 1˚, 2˚, 3˚Gent, Tobra---