Antibiotics: Selected Topics Steven Park, MD/PhD Director, Antimicrobial Stewardship Program Division of Infectious Diseases UCI Medical Center

Case 1 60 yo healthy female admitted for fevers and dysuria. No history of previous pyelonephritis. On admission, temperature 102. BP stable. Pulse 105 but after a liter of fluid comes down to 84. WBC 20 with left shift; creatinine 1.0; UA with 140 wbc. Urine sent for culture. Blood cultures drawn. Patient started on ceftriaxone. Patient does not look ill. Complaining of dysuria.

Case 1 continued Laboratory calls you the next day and tells you both urine and blood are growing gram negative rods Patient feels better. No more fevers. CBC 14 Blood pressure and pulse ok

Next step? a. Continue ceftriaxone b. Start Zosyn since gram negative may be pseudomonas c. Start cefepime since it has better pseudomonal coverage than Zosyn d. Start ciprofloxacin in preparation for discharge with oral ciprofloxacin

Case 2 60 yo male transferred from SNF for fever Long time resident of SNF due to multiple medical conditions Has foley catheter Febrile with leukocytosis. BP 85/40; P130; R26 Patient looks ill Chest xray clear. UA with pyuria and looks cloudy Creatinine 0.8

Case 2 continued Patient s blood pressure drops and patient intubated Levophed and ADH required to maintain BP Nurse about to start phenylephrine SNF calls and states that blood from yesterday is growing gram negative rods which are lactose negative and look like pseudomonas. Urine also with gram negative rods.

Next step? a. Start Zosyn b. Start cefepime c. Start meropenem d. Start cefepime and amikacin

Lactose fermenters Characteristic of gram negative organisms Ability of organism to use lactose as food source Fermenters: E. coli, Enterobacter, Klebsiella Non-fermenters: Pseudomonas, Acinetobacter, Stenotrophomonas

Gram negative agents Penicillins Cephalosporins Carbapenems Fluoroquinolones Aminoglycosides Polymixins Aztreonam New agents

Penicillins Penicillin, oxacillin, nafcillin, dicloxacillin really no gram negative coverage Amoxicillin/clavulanate (Augmentin) and ampicillin/sulbactam (Unasyn) has some gram negative coverage including anaerobes (not reliable for E. coli so do not use for abdominal infections). Can use for aspiration pneumonia Piperacillin/tazobactam (Zosyn) broadest coverage including pseudomonas and anaerobes Zosyn sometimes active against ESBL and can use in urine infections due to ESBL

Cephalosporins Gram negative coverage increases as you go from 1 st to 3 rd generation and gram positive coverage decreases Only ceftazidime and cefepime will cover pseudomonas Ceftazidime has no gram positive coverage Limited anaerobic coverage except cefoxitin and cefotetan Cefepime sometimes active against ESBL and can use in urine infections due to ESBL No enterococcal coverage

Carbapenems Ertapenem, imipenem, and meropenem Most reliable agents against ESBL Meropenem and imipenem will cover pseudomonas Ertapenem will not reliably cover pseudomonas and enterococcus and penicillin resistant S. pneumoniae Meropenem considered better than imipenem for gram negatives Imipenem considered better than meropenem for gram positives Some concern with imipenem and seizure threshold

Fluoroquinolones Levofloxacin, ciprofloxacin, moxifloxacin Broad gram negative coverage including pseudomonas (not moxifloxacin) Pretty good gram positive coverage (levofloxacin, moxifloxacin better than ciprofloxacin) Moxifloxacin has better anaerobic coverage and can use for abdominal infection Need to add Flagyl to levofloxacin and ciprofloxacin for colonic infections to cover anaerobes Watch out for QT prolongation and tendinitis and tendon rupture

Aminoglycosides Amikacin, gentamicin, tobramycin Excellent gram negative coverage including pseudomonas No gram positive coverage Very little tissue penetration Good for bacteremia, endovascular infections, and urine infections Nephrotoxic and ototoxic Need to measure levels

Polymixins Polymixin E (Colistin), polymixin B Stopped using decades ago. Started using again 10 years ago due to MDR gram negative infections Excellent gram negative coverage including pseudomonas, acinetobacter, ESBL, carbapenem resistant enterobacteriaceae (CRE) No gram positive coverage Limited tissue penetration Good for bacteremia, endovascular infections Doesn t concentrate in urine like aminoglycosides but still nephrotoxic

Aztreonam Purely gram negative agent including coverage for pseudomonas Not active against ESBL or CRE Can use in penicillin allergic patients Can not use it for patients allergic to ceftazidime

New gram negative agents Ceftolozane/Tazobactam (ZERBAXA) Recently FDA approved Has in vitro activity against gram negative pathogens including Pseudomonas and most ESBL enterobacteriaceae Limited CRE coverage Limited activity against gram positive pathogens Equally effective as Levaquin for complicated urinary tract infections Equally effective as Meropenem for complicated intra-abdominal infections (included ESBL) when combined with Flagyl Limited activity against Acinetobacter Ceftazidime/Avibactam (AVYCAZ) Recently FDA approved Has in vitro activity against gram negative pathogens including Pseudomonas and most ESBL enterobacteriaceae Some CRE activity (KPC) Limited activity against gram positive pathogens Equally effective as Imipenem for complicated urinary tract infections Equally effective as Meropenem for complicated intra-abdominal infections when combined with Flaygl Limited activity against Acinetobacter

Empiric treatment of gram negative bacteremia Before you have sensitivities Really depends on how sick the patient is and how much you need to be right initially One end of the spectrum is patient from community and stable (case 1) The other end of the spectrum is patient in hospital or from SNF and in septic shock (case 2) Unfortunately a lot of patients fall in between these 2 spectrums and in the end it s clinical judgement

Case 1 From the community Probably going to be regular E. coli (non-esbl) Low likelihood of resistant gram negative organism Willing to take small chance of being wrong because patient is stable

Case 2 From SNF (they have the highest rates of resistant organisms) Need to cover pseudomonas completely 2 antibiotics might increase the chance of appropriate empirical therapy Can t be wrong as patient critically ill Need to save life before kidneys

UCI Antibiogram 2016

Empiric treatment of gram negative bacteremia Most patients fall in between 2 ends of spectrum Even with scenario 2, the answer is controversial No evidence that 2 gram negative agents better than 1 in septic shock Both monotherapy and combination therapy are endorsed by Surviving Sepsis Campaign (grade 1b) In the end, it s clinical judgement Call ID fellow or me Why not put everyone with gram negative bacteremia on meropenem?

Carbapenem resistant enterobacteriaceae (CRE) at UCI 2011: 2 cases 2016: 50 cases

Case 3 70 yo male with Parkinson s disease admitted for frequent falls Fell today and hit head. CT with small subdural hematoma and patient admitted Denies fevers, chills, sob, cough, dysuria. Complaining of fatigue more than usual. He thinks he needs his Parkinson medications adjusted On admission, afebrile, blood pressure stable. Looks tired but not ill WBC 14 with 85% neutrophils but no left shift UA negative Blood cultures drawn

Case 3 continued Next day lab informs you that ¼ blood culture bottles with Staphylococcus aureus, sensitivities pending Patient doing well. Wants to go home. Afebrile. WBC 15.

Next step? a. Start vancomycin b. Start daptomycin c. Start linezolid d. Start Bactrim e. No antibiotics since it is probably contaminant given only ¼ bottles and patient with no signs of infection

Case 3 continued Next day the other 3 bottles are positive and organism identified as MRSA with vancomycin MIC<0.5; sensitive to daptomycin, linezolid, synercid, gentamicin, rifampin, Bactrim TTE shows 0.5 cm vegetation of native mitral valve Vancomycin continued with good trough levels 5 days later, patient doing well but blood still growing MRSA. Vancomycin MIC still <0.5

Next step? In addition to looking for another source of infection: a. Keep vancomycin b. Start daptomycin c. Add gentamicin to vancomycin d. Add rifampin to vancomycin e. Start linezolid

Staphylococcus aureus Staphylococcus aureus should not be treated as a contaminant Vancomycin is still the mainstay of therapy Combination therapy only for prosthetic valve endocarditis (gentamicin, rifampin) and hardware associated osteomyelitis with retention of hardware (rifampin) Think about failure after 7 days of persistent cultures IDSA guidelines high dose daptomycin with another agent recommended if true failure (B-III)

Antimicrobial failure is rare Usually due to lack of source control Abscess Natural course of disease rather than antimicrobial failure Aspiration pneumonia Endovascular infections Other staphylococcus aureus infections

Vancomycin Still the mainstay therapy Indicated for all infections Be careful with acute kidney injury Some concern over efficacy recently but this is debatable (MIC creep) Only 14 cases of vancomycin resistant staphylococcus aureus in US total

Daptomycin FDA approved for right sided endocarditis and skin/soft tissue infection Can t use for pneumonia Can increase CPK Can become resistant during treatment Reports of eosinophilic pneumonia

Clindamycin FDA approved for serious S. aureus (not MRSA) infections Used in children with MRSA infections causing septic arthritis, osteomyelitis, pneumonia, and lymphadenitis Excellent tissue penetration except brain Inducible resistance can be present so lab needs to D zone test Used mainly for skin/soft tissue infections in adults But based on pediatric data, probably can use in pneumonia, osteomyelitis, septic arthritis Excellent bioavailability

Linezolid FDA approved for skin/soft tissue infection and pneumonia Can cause serotonin syndrome in patients taking SSRI s Myelosuppression (reversible), neuropathy side effects (not reversible) Less resistance reported than daptomycin No clear evidence that linezolid better than vancomycin for nosocomial pneumonia Not recommended for bacteremia (bacteriostatic) and failures reported

Tetracyclines Doxycycline FDA approved for skin/soft tissue infection due to S. aureus Data lacking for more invasive infections Minocycline may still work if resistant to doxycycline Tygacil also improved for intra-abdominal infections. Don t use for bacteremia.

Bactrim Not FDA approved for any S. aureus infection Still used quite a bit for skin/soft tissue infection Not a lot o f data for invasive infection Recent open label randomized trial failed to show non-inferiority of Bactrim versus vancomycin (OR 1.4)

Synercid FDA approved for skin/soft tissue infections Rarely used these days Usually now for VRE resistant to daptomycin and linezolid High incidence of arthralgias

Ceftaroline 5 th generation cephalosporin FDA approved for community acquired pneumonia and skin/soft tissue infection Has gram negative coverage in addition to MRSA coverage $400 per day

MRSA: Treatment of serious infections For endocarditis, bacteremia, pneumonia, osteomyelitis, necrotizing fasciitis, vancomycin is still first line Daptomycin for bacteremia, endocarditis, osteomyelitis, necrotizing fasciitis Linezolid for pneumonia Clindamycin for pneumonia (based on data on pediatrics) and skin/soft tissue infections, osteomyelitis, septic arthritis Bactrim and doxycycline for skin/soft tissue infections

Case 4 45 yo female is admitted with C. difficile colitis C. difficile PCR positive with NAP1 strain Multiple episodes of diarrhea per day Patient febrile with WBC 22K Creatinine 1.8 (previously normal) Tachycardic which responds to 1 liter NS Abdomen mildly distended and tender CT scan with colitis in descending colon but no ileus

Next step? a. Start po Flagyl b. Start po vancomycin c. Start fidaxomicin d. Start po vancomycin and IV Flagyl

Case 4 continued Patient starts to get hypotensive requiring levophed 10 mcg Transferred to unit WBC increases to 38K Still having profuse diarrhea No ileus on imaging

Next step? a. Add po Flagyl b. Add IV Flagyl c. Add fidaxomicin d. Add IV Flagyl and rectal vancomycin

Treatment of C. difficile colitis Mild (leukocytosis<15k; creatinine<1.5 times baseline): use po Flagyl Severe (leukocytosis>15; creatinine>1.5 times baseline): use po vancomycin Severe, complicated (critically ill, hypotension, megacolon, ileus): use po vancomycin, IV Flagyl, rectal vancomycin (if you suspect ileus) Do not add IV Flagyl unless it is severe and complicated No evidence that increased doses of vancomycin better but most physicians would do it Can get high serum levels of po vancomycin with prolonged therapy in patients with renal failure New guidelines coming soon

C. Difficile testing at UCI Can only be ordered on non-formed stool Can not have other causes of diarrhea (laxatives, tube feeds) Both PCR and toxin EIA reported PCR too sensitive Some data that toxin EIA correlates better with C. difficile colitis JAMA study that showed for PCR+/toxinpatients, treatment had no effect on outcome

C. Difficile testing at UCI PCR-/toxin- PCR+/toxin+ PCR-/toxin+ PCR+/toxin- Do not treat for C. difficile colitis Treat for C. difficile colitis Treat for C. difficile colitis Do not treat unless signs of toxicity present (patient sick) Formal UCI guidelines coming soon

Case 5 You get called by lab on MICU patient with positive cultures for yeast. Patient hospitalized with severe MI and heart failure. Underwent CABG and prolonged hospital course complicated by nosocomial pneumonia requiring Zosyn. Blood cultures drawn 2 days ago for fevers. Blood positive only from IJ. Peripheral negative. Still febrile but stable.

Next step? a. Start fluconazole b. Start fluconazole and pull IJ c. Start micafungin and pull IJ d. Pull IJ only since yeast likely colonizer

Candidemia Candidemia is never treated as contaminant Potential for bad complications, endophthalmitis and endocarditis If suspect line, needs to come out Get ophthalmologic consult for exam Get echocardiogram if endocarditis suspected Empiric therapy with micafungin in case non-albicans candida (glabrata only 50% sensitive to fluconazole) Candida glabrata identified 39/57 cases at UCI last year

Case 6 72 yo diabetic male admitted for infected foot ulcer Ulcer present for months but has been draining for last month and more last couple of days Exam shows 3 cm deep ulcer (but not to bone) with some erythema. Some drainage but not purulent Afebrile WBC 14 Patient looks good ER has sent superficial swab of ulcer to microbiology MRI with acute osteomyelitis

Next step? a. Start vancomycin and Zosyn and follow up swab cultures. b. No antibiotics for now. Start antibiotics after microbiology results back. c. Hold antibiotics. Consult orthopedics. d. Start vancomycin and Zosyn. Consult orthopedics.

Case 6 continued Orthopedic services states no surgical intervention required

Next step? a. Start vancomycin and Zosyn and treat for 6 weeks b. Await swab cultures results and then direct therapy based on results c. Get ID consult d. Ask orthopedic service for bone biopsy for culture or deep specimen for culture before starting antibiotics

IDSA Practice Guideline on Diabetic Foot Infections When and how should I obtain specimen(s) for culture from a patient with a diabetic foot wound? Recommendations For clinically uninfected wounds, we recommend not collecting a specimen for culture (strong, low). For infected wounds, we recommend that clinicians send appropriately obtained specimens for culture prior to starting empiric antibiotic therapy, if possible. Cultures may be unnecessary for a mild infection in a patient who has not recently received antibiotic therapy (strong, low). We recommend sending a specimen for culture that is from deep tissue, obtained by biopsy or curettage and after the wound has been cleansed and debrided. We suggest avoiding swab specimens, especially of inadequately debrided wounds, as they provide less accurate results (strong, moderate).

Bone Biopsy ID physicians want it Surgeons say it is not necessary. Reasoning is that bone cultures are unreliable and you are going to treat with broad spectrum antibiotics anyway since diabetic foot osteomyelitis is usually polymicrobial ID physicians will point out cultures positive in 87% cases and still benefit in narrowing antibiotics Swabs unreliable. Concordance with bone cultures only 50% What do the guidelines say?

Bone Biopsy Uptodate: Bone biopsy (open or percutaneous) should be obtained for pathogen identification and to obtain susceptibility data when this is feasible IDSA Practice Guideline Diabetic Foot Osteomyelitis: Obtaining a bone specimen for culture (and histology, when available), is most likely to be justified when there is: Uncertainty regarding the diagnosis of osteomyelitis despite clinical and imaging evaluations An absence (or confusing mix) of culture data from soft tissue specimens Failure of the patient to respond to empiric antibiotic therapy A desire to use antibiotic agents that may be especially effective for osteomyelitis but have a high potential for selecting resistant organisms (eg, rifampin, fluoroquinolones)

Bone Biopsy: How do you put it together? IDSA Practice Guideline does not give FIRM recommmendation to obtain bone biopsy in all cases of diabetic foot osteomyelitis If you can avoid vancomycin or broad spectrum abx, you should Retrospective study showed better outcomes with bone culture guided therapy versus none (56% vs 22%) Nevertheless reports of 76% success rates with empiric therapy alone

When do you have to start antibiotics right away? And when should you wait until you can get proper cultures? Make every attempt to get cultures if you know that treatment will be prolonged Hardware associated osteomyelitis Diabetic foot infections Endovascular infections Decision to start antibiotics right away depends on the infection and how the sick the patient is Septic shock: Start right away Meningitis: Start right away Bad pneumonia: Start right away Endocarditis: Depends If symptoms have been going on for a while, safe to wait If unsure, call ID fellow or Antimicrobial Stewardship Program attending (me)

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