Antimicrobial Use in the Emergency Department – Pearls and Pitfalls

Authors: Kayvan Moussavi, PharmD, BCCCP (Assistant Professor, Department of Pharmacy Practice, Marshall B. Ketchum University College of Pharmacy) and Joshua Garcia, PharmD, BCPS (Assistant Professor, Department of Pharmacy Practice, Marshall B. Ketchum University College of Pharmacy) // Reviewed by: Alex Koyfman, MD (@EMHighAK); Tim Montrief, MD (@EMinMiami); Brit Long, MD (@long_brit); Manpreet Singh, MD (@MprizzleEM)

Case:

A 65-year-old, 80 kg male presents to your ED with signs and symptoms of sepsis (febrile, altered mental status, hypotensive). He has a history of hypertension and hyperlipidemia and a listed allergy to penicillin (diarrhea).  The patient’s wife states he started feeling ill yesterday and was complaining of a sore neck and fatigue.  You suspect that the patient has bacterial meningitis.  You order 2 L of 0.9% NaCl, blood cultures, and plan to perform a lumbar puncture (LP) as soon as possible; however, you are very busy today and need to see several other sick patients before you will have time for the LP. You think it might be better to administer antimicrobials after blood cultures but before the LP, so you order Zosyn® 4.5 g and vancomycin 1 g IV. 

A few minutes later, the ED pharmacist approaches you and asks, “Are you considering meningitis in that patient (the one needing the LP)?”  You state that the patient is septic likely due to bacterial meningitis.  The pharmacist asks, “Would you be okay with changing to vancomycin, ampicillin, ceftriaxone, and dexamethasone instead of vanco and Zosyn®?”  You respond with, “Doesn’t vanco and Zosyn® cover everything?”               

Introduction:

Infectious diseases are frequent in patients presenting to the ED, and these conditions can be complicated as they are caused by different types of organisms (e.g. bacteria, viruses, fungi, etc.), affect patients of all ages, can cause variable degrees of disease severity (e.g. minor, moderate, life threatening), and can affect nearly all organ systems. This topic becomes even more complex when medication allergies, resistance patterns, antimicrobial optimization (e.g. dosing, tissue penetration), medication shortages, costs, and institutional formularies are considered.  Additionally, there is growing pressure on ED providers to deliver appropriate antimicrobial therapy almost immediately after arrival of patients meeting diagnostic criteria for sepsis.^1,2  This limits the time to decide if antimicrobials are indicated and, if they are indicated, choose the best therapy for your patients.

This article is designed to guide ED providers towards selecting the best empiric antimicrobial regimen for infections commonly treated in the ED.  Each type of infection will be addressed by stating the most common pathogens, options for antimicrobial therapy, and pearls/pitfalls related to antimicrobial use in those infection types.  Because vancomycin and piperacillin-tazobactam (Zosyn®) are often considered for empiric therapy (especially in patients with sepsis), we will also address if this combination is appropriate for each type of infection.  Please note that these recommendations are based on national or international guidelines, so they may not apply to every patient, clinical scenario, or geographic location.  Consult your institutional or regional antibiograms (if available).

Community Acquired Pneumonia (CAP):^3-6

• Common Organisms
  • Adult
    • Outpatient: S. pneumoniae, M. pneumoniae, H. influenzae,C. pneumoniae, viruses (e.g. influenza, adenovirus, respiratory syncytial virus, parainfluenza)
    • Inpatient (Non-ICU): same as outpatient plus Legionella, aspiration
    • Inpatient (ICU): S. pneumoniae, S. aureus, Legionella, gram-negative bacilli, H. influenzae
    • Risk factors for multidrug-resistance (e.g. microbiology history, recent use of antimicrobials (within 90 days), recent hospitalization for 5 or more days): S. aureus, P. aeruginosa, gram-negative bacilli
  • Pediatrics (3 months of age and older)
    • Outpatient: S. pneumoniae, M. pneumoniae, viruses (e.g. influenza)
    • Inpatient: S. pneumoniae, M. pneumoniae, C. pneumoniae, S. aureus
• Therapy
  •  Adults
    • Outpatient
      • Macrolides (e.g. azithromycin/clarithromycin) now have poor activity against S. pneumoniae in many regions.⁶  Consider alternative regimens if appropriate (e.g. amoxicillin or cefdinir + azithromycin).
        • 1^st line: Agent covering S. pneumoniae plus azithromycin/clarithromycin
        • Alternative: Doxycycline
      • Chronic heart, lung, liver, kidney disease, diabetes, cancer, asplenia, immunosuppression, antimicrobials within 90 days:
        • If patient elderly or has multiple comorbidities, consider using beta-lactam based combination instead of fluoroquinolones (see Pearls/Pitfalls below)
        • 1^stline: Beta-lactam plus atypical coverage
        • Alternative: levofloxacin/moxifloxacin/gemifloxacin
        • Alternative: [amoxicillin/amoxicillin-clavulanate] + [azithromycin/clarithromycin]
      • High S. pneumoniae resistance to azithromycin/clarithromycin:
        • Levofloxacin/moxifloxacin
        • [Amoxicillin/amoxicillin-clavulanate/cefdinir/cefpodoxime/cefprozil] + [azithromycin/clarithromycin]
    • Inpatient (Non-ICU)
      • 1^stline: Beta lactam with atypical coverage is recommended.
        • [Cefotaxime/ceftriaxone/ceftaroline/ampicillin/ertapenem] + [azithromycin/clarithromycin]
        • [Cefotaxime/ceftriaxone/ceftaroline/ampicillin/ertapenem] + doxycycline
      • Alternative: levofloxacin/moxifloxacin/gemifloxacin
      • Note: if patient elderly or has multiple comorbidities, consider using beta-lactam based combination instead of fluoroquinolones (see Pearls/Pitfalls below).
    • Inpatient (ICU)
      • 1^st line: [cefotaxime/ceftriaxone/ceftaroline/ampicillin-sulbactam] + azithromycin
      •  Alternative:
        • [Cefotaxime/ceftriaxone/ampicillin-sulbactam] + [levofloxacin/moxifloxacin/gemifloxacin]
        • Aztreonam + [levofloxacin/moxifloxacin/gemifloxacin]
        • Pseudomonas concern (e.g. bronchiectasis, COPD requiring steroids/antimicrobials, recent antimicrobials): [piperacillin-tazobactam/cefepime/imipenem/meropenem] + [azithromycin/levofloxacin/ciprofloxacin] +/- [gentamicin/tobramycin/amikacin]
        • MRSA concern (e.g. ESRD, IV drug abuse, prior influenza, recent antimicrobials): add vancomycin/linezolid
          • If possible, use linezolid due to better lung penetration
  • Pediatrics
    •  Outpatient
      • 1^st line: amoxicillin/amoxicillin-clavulanate
      • Alternative:
        • Cefpodoxime
        • Levofloxacin
        • Clindamycin
      • Atypical pathogen concern (e.g. S. pneumoniae): azithromycin/erythromycin/clarithromycin/doxycycline/ levofloxacin/moxifloxacin
      • Note: Viral pathogens cause majority of CAP in preschool aged children (i.e. antibacterials rarely indicated for these patients)⁶
    • Inpatient
      • 1^st line: ampicillin/penicillin G/ceftriaxone/cefotaxime
      •  Alternative
        • Levofloxacin
        • Clindamycin
      • Atypical pathogen concern: azithromycin/erythromycin/ clarithromycin/doxycycline/ levofloxacin/moxifloxacin
      • MRSA concern: vancomycin/linezolid/clindamycin
• Pearls/Pitfalls
  • Most recent CAP guidelines were published in 2007.³
    • Macrolides (e.g. azithromycin/clarithromycin) now have poor activity against S. pneumoniae in many regions.⁶ Consider alternative regimens mentioned above.
    • Growing evidence that fluoroquinolones (e.g. levofloxacin, moxifloxacin) can cause serious adverse effects (e.g. arrhythmias, aortic aneurysm and dissection, peripheral neuropathy, tendon rupture, etc.), especially in the elderly or in those with comorbidities.⁶ Consider alternatives if possible (e.g. beta-lactams).
  • Antibacterials do not cover viruses (e.g. influenza).
    • • Influenza A/B: use oseltamavir or zanamivir when indicated^5,6
  • Double coverage for gram negatives (e.g. beta-lactam + fluoroquinolone/aminoglycoside for P. aeruginosa) is controversial.
    • • Pros
        • Recommended by guidelines^3,4
        • Theoretical increased likelihood of appropriate empiric coverage^7,8
        • In vitro synergy (e.g. beta-lactam + fluoroquinolone/aminoglycoside)^7-9
        • Theoretical reduction in emergence of resistant organisms⁸
      • Cons
        • Increased toxicity (e.g. nephrotoxicity, ototoxicity)^7,8,10
        • Risk of superinfection (e.g. C. difficile)^7,8
        • Increased costs⁷
        • Does not reduce mortality¹⁰
• Vancomycin + piperacillin-tazobactam?
  • Yes; however, no atypical organism or viral coverage

Abdominal:^6,11

• Organisms
  • Community acquired: enteric gram-negative and gram-positive organisms
    • Distal small bowel, appendix, colon, proximal GI perforations: anaerobes
    • High risk (e.g. elderly, immunocompromised) or severe infection: resistant gram-negative organisms
    • Biliary tract and immunosuppression (e.g. liver transplant): enterococcus
  • Health care-associated: resistant gram-negative and gram-positive organisms (e.g. P. aeruginosa, MRSA, enterococcus), anaerobes
• Therapy
  • Adults
    • Extra-biliary
      • 1^st line:
        • Mild-moderate: cefoxitin/ertapenem/moxifloxacin/tigecycline/ticarcillin-clavulanic acid
        • Severe or high risk (e.g. severe physiologic disturbance, elderly, immunocompromised): imipenem-cilastatin/meropenem/doripenem/ piperacillin-tazobactam
      • Next line:
        • Mild-moderate: [cefazolin/cefuroxime/ceftriaxone/cefotaxime/ciprofloxacin/ levofloxacin] + metronidazole
        • Severe: [cefepime/ceftazidime/ciprofloxacin/levofloxacin] + metronidazole
      • Health care-associated: [imipenem-cilastatin/meropenem/doripenem/piperacillin-tazobactam] OR [[ceftazidime/cefepime] + metronidazole]] +/- [aminoglycosides/colistin] +/- vancomycin
      • Note: if antibiogram resistance patterns allow, consider single agent instead of combination therapy (see Pearls/Pitfalls below).
    • Biliary
      • Community acquired acute cholecystitis of mild-moderate severity:
        • Cefazolin/cefuroxime/ceftriaxone
      • Community acquired acute cholecystitis of high severity, advanced age, or immunocompromised:
        • [Imipenem-cilastatin/meropenem/doripenem/piperacillin-tazobactam]
        • [Ciprofloxacin/levofloxacin/cefepime] + metronidazole
      • Acute cholangitis following bilio-enteric anastomosis of any severity:
        • [Imipenem-cilastatin/meropenem/doripenem/piperacillin-tazobactam]
        • [Ciprofloxacin/levofloxacin/cefepime] + metronidazole
      • Health care-associated biliary infection of any severity:
        • [Imipenem-cilastatin/meropenem/doripenem/piperacillin-tazobactam] + vancomycin
        • [Ciprofloxacin/levofloxacin/cefepime] + metronidazole + vancomycin
      • Note: if antibiogram resistance patterns allow, consider single agent instead of combination therapy (see Pearls/Pitfalls below).
  • Pediatrics
    •  Extra-biliary
      • 1^st line: [ertapenem/meropenem/imipenem-cilastatin/ticarcillin-clavulanic acid/piperacillin-tazobactam]
      • Next line:
        • [Ceftriaxone/cefotaxime/cefepime/ceftazidime] + metronidazole
        • [Gentamicin/tobramycin] + [metronidazole/clindamycin] +/- ampicillin
      • Note: if antibiogram resistance patterns allow, consider single agent instead of combination therapy (see Pearls/Pitfalls below).
    • Biliary⁶
      • 1^st line: [Imipenem-cilastatin/meropenem/doripenem/ampicillin-sulbactam/piperacillin-tazobactam]
      • Next line:
        • [Ceftriaxone/cefotaxime/cefepime/ceftazidime] + metronidazole
        • Aztreonam + metronidazole
        • Ciprofloxacin + metronidazole
        • Moxifloxacin
        • Add vancomycin to above regimens if enterococcus concern (e.g. health care-associated)
      • Notes:
        • Not discussed in intra-abdominal IDSA 2010 guidelines. Recommendations based on regimens recommended for adults⁶
        • If antibiogram resistance patterns allow, consider single agent instead of combination therapy (see Pearls/Pitfalls below).
    • Necrotizing enterocolitis (NEC)
      • 1^st line: ampicillin + gentamicin + metronidazole
      • Next line:
        • Ampicillin + cefotaxime + metronidazole
        • Meropenem
        • • MRSA or ampicillin-resistant enterococcus concern: add vancomycin
          • Fungal concern: fluconazole/amphotericin B
  • If Candida detected: fluconazole/caspofungin/micafungin/anidulafungin
  • If C. difficile colitis: oral or rectal vancomycin/oral fidaxomicin/oral or IV metronidazole
• Pearls/Pitfalls
  • Use of fewer antimicrobials will generally reduce risk of adverse drug effects (e.g. single agent vs. combination therapy).¹¹ If possible (i.e. if resistance patterns allow), consider single agent regimens.
  • Cephalosporins and fluoroquinolones have minimal anaerobic coverage. Can combine these agents with metronidazole to provide anaerobic coverage.⁶
  • If C. difficile colitis, IV vancomycin and piperacillin-tazobactam are inappropriate (i.e. they do not cover this type of infection). Oral/rectal vancomycin, fidaxomicin, or metronidazole should be used for these patients.¹²
  • Patients with liver cirrhosis and upper gastrointestinal bleed are at high risk of spontaneous bacterial peritonitis. Short-term use (7 days) of prophylactic antimicrobials can increase survival.^6,13-15
    • Options: ceftriaxone / norfloxacin / ciprofloxacin
• Vancomycin + piperacillin-tazobactam?
  • Yes, especially for higher severity of illness and health care-associated infections. However, IV vancomycin and piperacillin-tazobactam do not adequately cover C. difficile infections.

Genitourinary:^6,16-19

• Organisms
  • Gram negatives: E. coli, Klebsiella spp., Proteus spp., other enteric gram negative rods, P. aeruginosa (hospital related)
  • Gram positives: Staphylococcus saprophyticus, Enterococcus spp. (often contaminant in catheter-related infections)
• Therapy
  • Adults
    • Uncomplicated cystitis (pre-menopausal, non-pregnant females with no underlying urologic abnormalities, immunocompromising conditions, or poorly controlled diabetes):
      • 1^stline: Nitrofurantoin/TMP-SMX (if local TMP-SMX resistance < 20% and not used for UTI in last 3 months)
      • Next line:
        • Fosfomycin
        • Ciprofloxacin/levofloxacin
        • Amoxicillin-clavulanic acid/cephalexin/other oral cephalosporins
    • Complicated cystitis:
      • 1^st line:
        • Ciprofloxacin/levofloxacin
      • Next line:
        • Nitrofurantoin/TMP-SMX
        • If high risk for drug-resistance (i.e. prior resistant isolate, recent exposure to healthcare facility, recent fluoroquinolone or beta-lactam use): Ertapenem/ piperacillin-tazobactam/cefepime
    • Uncomplicated pyelonephritis:
      • 1^st line:
        • Ciprofloxacin/levofloxacin (if local fluoroquinolone resistance <10%)
        • Ceftriaxone
        • May transition to oral cephalosporin or TMP/SMX
      • Next line:
        • Aminoglycosides
    • Complicated pyelonephritis:
      • 1^st line:
        • Ceftriaxone/ertapenem/cefepime/piperacillin-tazobactam
  • Pediatrics
    • IV therapy may be preferred for critically ill children that cannot take oral options
      • IV options: Ceftriaxone/ceftazidime/cefotaxime
      • PO options: Amoxicillin-clavulanate/cephalexin/TMP-SMX/ cefixime/cefpodoxime
• Pearls/Pitfalls
  • Catheterization greatly increases the risk of genitourinary infections. Try to remove the need of catheters or reduce the duration of catheterization, if possible.¹⁸
  • Caution should be taken with patients that present with positive urine cultures, positive urinalysis, but no genitourinary or systemic symptoms of infection. This suggests asymptomatic bacteriuria (ASB), which should not be treated with antibiotics in most circumstances.¹⁶
    • ASB patients that should be screened for and treated in: pregnant women and patients undergoing endoscopic urologic procedures associated with mucosal trauma.¹⁶
    • Notably the IDSA guidelines have recommended against the screening and treatment of ASB in solid organ transplant patients (including renal) >1 month post-transplantation. The guidelines had insufficient evidence for solid organ transplant patient <1 month post-transplantation and neutropenic patients.¹⁶
  • S. aureus is an uncommon urinary pathogen. It’s presence in the urine accompanied with signs and symptoms of infection may indicate a descending urinary tract infection, potentially originating from an endocarditis infection. Screening for endocarditis should be added in these scenarios.
• Vancomycin + piperacillin-tazobactam?
  • Yes, but vancomycin less likely to be useful as overwhelming genitourinary tract infections are gram-negative. Consider piperacillin-tazobactam alone.

Skin and Soft Tissue:^20,21

• Organisms
  • Cellulitis/purulent abscesses: S. aureus, Beta-hemolytic streptococcus (Streptococcus pyogenes, Streptococcus agalactiae, etc.)
    • Purulent abscess with focalization: S. aureus >>> Beta-hemolytic streptococcus
    • Cellulitis without focal abscess: Beta-hemolytic streptococcus >>> S. aureus
  • Necrotizing infections:
    • Monomicrobial or Polymicrobial
    • Gram positives (Staphylococcus spp., Streptococcus spp., Enterococcus spp., Clostridium spp.), gram negatives (Vibrio vulnificus,Aeromonas hydrophila, coli, Klebsiella spp., Proteus spp., P. aeruginosa), and anerobes (B. fragilis, Peptostreptococcus spp., Peptococcus spp.)
  • Diabetic foot infections:
    • Polymicrobial
    • Gram positives (Staphylococcus spp., Streptococcus spp., Enterococcus spp.), gram negatives (E. coli, Klebsiella spp., Proteus spp., Pseudomonas aeruginosa), and anaerobes (B. fragilis, Peptostreptococcus spp., Peptococcus spp.)
  • Impetigo and ecthyma (pediatrics)
    • Staphylococcus aureus, Beta-hemolytic streptococcus (Streptococcus pyogenes, Streptococcus agalactiae, etc.)
  • Dog/Cat Bites:
    • Staphylococcus spp., Streptococcus spp., Enterobacteriacaea, anaerobes, Pasteurella spp.
  • Human Bites:
    • Staphylococcus spp., Streptococcus spp., Enterobacteriacaea, anaerobes, Eikenella corrodens
• Therapy
  •  Adults
    • Cellulitis/purulent abscesses:
      • Mild:
        • No antibiotics, incision and drainage only
      • Moderate:
        • Incision and drainage + doxycycline or TMP-SMX
      • Severe:
        • Incision and drainage + [vancomcyin/daptomycin/linezolid/tedizolid/ceftaroline]
    • Cellulitis without focal abscess:
      •  Mild:
        • 1^st line: Penicillin VK/cephalexin/dicloxacillin
        • Alternative: Clindamycin
        • If concerned for MRSA: Doxycycline/TMP-SMX
      • Moderate:
        • 1^st line: Penicillin/ceftriaxone/cefazolin
        • Alternative: Clindamycin
        • If concerned for MRSA: Doxycycline/TMP-SMX
      • Severe:
        • Vancomcyin + piperacillin-tazobactam
    • Necrotizing infections:
      • Immediate surgical debridement + [vancomycin/linezolid] + [piperacillin-tazobactam/meropenem/ertapenem/imipenem-cilistatin] + clindamycin
    • Diabetic foot infections
      •  Mild-moderate:
        • MRSA risk factors: TMP-SMX/doxycycline/clindamycin
        • No MRSA risk factors: Cephalexin/cefpodoxime/levofloxacin/amoxicillin-clavulanate
      • Severe:
        • 1^st line: Vancomycin + [piperacillin-tazobactam/meropenem/imipenem-cilistatin]
        •  Alternatives:
          • Daptomycin/linezolid/tedizolid for gram positive coverage
    • Bites:
      • 1^st line: Amoxicillin-clavulanic acid or ampicillin-sulbactam
      •  Alternatives:
        • Ertapenem (serious infections)
        • [Levofloxacin/ciprofloxacin] + metronidazole
        • Moxifloxacin
  • Pediatrics
    •  Impetigo
      • Topical mupirocin/topical retapamulin/cephalexin/amoxicillin-clavulanate/dicloxacillin
      • If MRSA coverage needed or PCN allergic: Doxycycline/TMP-SMX/clindamycin
    • Ecthyma
      • Cephalexin/amoxicillin-clavulanate/dicloxacillin
      • If MRSA coverage needed or PCN allergic: Doxycycline/TMP-SMX/clindamycin
• Pearls/Pitfalls
  • Cephalosporins and narrower penicillins have minimal anaerobic coverage. Can combine these agents with metronidazole to provide anaerobic coverage.⁶
  • Adequate source control is paramount in purulent infections via incision and drainage. Antibiotics may not be necessary in mild infections that can be managed by incision and drainage alone.²¹
  • Necrotizing infections are frequently caused by monomicrobial Streptococcus speciesthat are susceptible to penicillin. However, until surgical cultures return confirming the infecting organism, initiate broad empiric coverage.²¹
  • Clindamycin can be added to necrotizing fasciitis infections to neutralize the toxins produced by streptococcus.^6,21
  • Impetigo can be highly contagious among children. Be sure to limit physical contact during breakout period.²¹
• Vancomycin + piperacillin-tazobactam?
  • Yes, however non-necrotizing infections are largely gram positive and vancomycin alone may be adequate. Necrotizing and severe diabetic foot infections require broad spectrum coverage.

Central Nervous System:²²

• Organisms
  • Neonates (< 1 month): Streptococcus agalactiae, Listeria monocytogenes, enteric gram negative rods ( coli, Klebsiella spp., etc.), viruses (RSV, HSV, etc.)
  • Infants (1 – 23 months): Streptococcus pneumoniae, Neisseria meningitidis, Streptococcus agalactiae, Haemophilus influenza, E. coli, viruses (RSV, HSV, etc.)
  • Age 2 – 50 years: Streptococcus pneumoniae, Neisseria meningitidis,viruses (RSV, HSV, etc.)
  • Age > 50 years: Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, aerobic gram negative rods ( coli, Klebsiella spp., etc.), viruses (RSV, HSV, etc.)
  • Penetrating head trauma: Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes
  • Post-neurosurgery: Staphylococcus aureus, coagulase negative Staphylococcus aureus, aerobic gram negative rods (including Pseudomonas aeruginosa)
  • CSF shunt or hardware in place: Staphylococcus aureus, coagulase negative Staphylococcus aureus, aerobic gram negative rods (including Pseudomonas aeruginosa), Propionibacterium acnes
• Therapy
  • Neonates (< 1 month): Ampicillin + [cefotaxime/aminoglycoside] + acyclovir
  • Infants (1 – 23 months): [Cefotaxime/ceftriaxone] + vancomycin + acyclovir
  • Age 2 – 50 years: [Cefotaxime/ceftriaxone] + vancomycin + acyclovir
  • Age > 50 years: [Cefotaxime/ceftriaxone] + vancomycin + ampicillin + acyclovir
  • Penetrating head trauma: Vancomycin + [cefepime/ceftazidime/meropenem]
  • Post-neurosurgery: Vancomycin + [cefepime/ceftazidime/meropenem]
  • CSF shunt or hardware in place: Vancomycin + [cefepime/ceftazidime/meropenem]
  • If penicillin allergy (see section below on cross-reactivity)
    • S. pneumoniae: meropenem/moxifloxacin
    • N. meningitidis: meropenem/moxifloxacin/chloramphenicol
    • L. monocytogenes: TMP-SMX/meropenem
    • H. influenzae, enterics: meropenem/aztreonam/chloramphenicol
    • P. aeruginosa: aztreonam/ciprofloxacin/meropenem
• Pearls/Pitfalls
  • Piperacillin-tazobactam does not achieve adequate concentrations in the CSF. Use of other beta-lactams with CSF penetration (e.g. ceftriaxone, cefotaxime) is recommended.^6,22  Cefepime or carbapenems can be used if P. aeruginosa or resistant organisms are a concern.⁶
  • L. monocytogenes is a common pathogen that affects both the very young (< 1 month) and elderly (> 50 years) and is not adequately covered by vancomycin or cephalosporins. Ampicillin is added for coverage of the L. monocytogenes, and clinicians do not need to be concerned with double beta-lactam therapy.^6,22
  • If adding IV acyclovir for viral coverage, ensure that patients receive adequate IV hydration to prevent crystallization(~1L/gram of acyclovir/24hours).
  • Adjunctive dexamethasone (0.15mg/kg Q6h for 2-4 days) can be added 10-20 mins before, or concomitantly with, the first dose of antibiotics to reduce the risk of neurological sequelae.^6,22
• Vancomycin + piperacillin-tazobactam?
  • No, since piperacillin-tazobactam does not achieve adequate concentrations in the CSF. Choose ceftriaxone instead, add vancomycin for any potential resistant S. pneumoniae, and add ampicillin for Listeria monocytogenes in the appropriate age groups.

Endocarditis:²³

• Organisms:
  • Gram positives: Staphylococcus aureus, Staphylococcus epidermidis, Viridans Group Streptococci, Streptococcus gallolyticus, Streptococcus pneumoniae, Streptococcus pyogenes, Nutritionally variant Streptococcus
  • Gram negatives: (HACEK organisms): Haemophilus spp., Aggregatibacter spp., Cardiobacterium hominis, Eikenella corrodens, Kingella kingae
  • Fungus (immunocompromised patients): Candida spp.
• Therapy
  • Adults:
    • Acute presentation (days) with native-valve: Cover aureus, beta-hemolytic Streptococci, aerobic gram negative bacilli
      • Vancomycin + cefepime
    • Subacute presentation (weeks) with native-valve: Cover aureus, Viridans Group Streptococci, HACEK organisms, and enterococci
      • Vancomycin + ampicillin-sulbactam
    • Prosthetic-valve and onset of symptoms within 1 year of valve replacement: Cover Staphylococci spp., Enterococci spp.,and aerobic gram negative bacilli
      • Vancomycin + rifampin + gentamicin + cefepime
    • Prosthetic-valve and onset of symptoms >1 year of valve replacement: Cover Staphylococci spp., Viridans group Streptococci, Enterococcus spp.
      • Vancomycin + ceftriaxone
• Pearls/Pitfalls
  • Infectious disease consultation should be obtained to define an optimal empiric regimen at the time of initiation of antimicrobial therapy.
  • Make sure to obtain blood cultures BEFORE initiating antibiotics if possible. Failure to do so may result in a lower yield of organisms from the blood and difficulty in later narrowing therapy.
    • If using ceftriaxone for empiric therapy, use maximum dosing of 2g Q24h rather than standard 1g Q24h.
• Vancomycin + piperacillin-tazobactam?
  • Yes in most cases, but obtain an infectious disease consultation before initiating therapy.

Septic Arthritis:^6,24-26

• Organisms:
  • Direct inoculation: Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus spp., E.coli, Pasturella(bites), Eikenella(bites)
  • Contiguous spread: Staphylococcus aureus, Streptococcus spp., Enterococcus spp., E. coli (diabetic foot), Bacteroides fragilis (diabetic foot), Pseudomonas aeruginosa
  • Hematogenous: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, E.coli (nosocomial), Pseudomonas aeruginosa (IVDU)
  • Prosthetic joint: Staphylococcus epidermidis, Propionibacterium acnes, Corynebacterium spp.
• Therapy
  • Adults:
    • Direct inoculation:
      • 1^st line: Vancomycin + ceftriaxone
      • Alternatives: Daptomycin or linezolid in place of vancomycin
    • Contiguous spread:
      • Vancomycin+ceftriaxone or piperacillin/tazobactam (if risk of Pseudomonas aeruginosa and Bacteroides fragilis)
      • Alternatives: Daptomycin or linezolid in place of vancomycin
    • Hematogenous:
      • Vancomycin+piperacillin/tazobactam (if IVDU or nosocomial)
      • Alternatives: Daptomycin or linezolid in place of vancomycin
    • Prosthetic joint:
      • Vancomycin + rifampin
      • Alternatives: Daptomycin or linezolid in place of vancomycin
  • Pediatrics:
    • 1^st line: Vancomycin +[ceftriaxone/cefotaxime/ceftazidime/cefepime]
    • Alternatives: Clindamycin, daptomycin, or linezolid in place of vancomycin
• Pearls/Pitfalls
  • Surgical debridement / source control is paramount in management.^24,25
  • If adding rifampin, be aware of drug-drug interactions with other medications such as warfarin, anticonvulsants, etc. as rifampin may lower concentrations of these medications to subtherapeutic levels.
• Vancomycin + piperacillin-tazobactam?
  • Yes, although vancomycin is staple of empiric therapy in most cases. Consider using narrow gram-negative agent or no gram-negative agent if the bacterial etiology and clinical scenario are not indicative of such.

Bacteremia with Unclear Source:

• Organisms: Almost any organism. Consider nosocomial pathogens (e.g. P. aeruginosa and MRSA) if significant exposure to healthcare system. Atypicals and anaerobics are less common in bacteremia but prudent to keep on differential diagnosis.
• Therapy
  • Adults: Broad-spectrum antimicrobials covering resistant gram positives, resistant gram negatives. Atypicals and anaerobic coverage not normally needed unless high suspicion
    • Gram negative options: Piperacillin-tazobactam/cefepime/ceftazidime,
      • If concerned for ESBLs or resistant organisms: Ertapenem/imipenem-cilistatin/meropenem
    • Gram positive options: Vancomycin/linezolid/daptomycin
  • Pediatrics: Broad-spectrum antimicrobials covering resistant gram positives, resistant gram negatives. Atypicals and anaerobic coverage not normally needed unless high suspicion
    • Gram negative options: Piperacillin-tazobactam/cefepime/ceftazidime
      • If concerned for ESBLs or resistant organisms: Ertapenem/imipenem-cilistatin/meropenem
    • Gram positive options: Vancomycin/linezolid/daptomycin
• Pearls/Pitfalls
  • Make sure to obtain echocardiogram if inciting organism is one of concern for endocarditis (i.e. S. aureus, beta-hemolytic streptococcus, etc.).
• Vancomycin + piperacillin-tazobactam?
  • Yes

Other Important Information:

• Vancomycin + piperacillin-tazobactam and kidney injury
  • There is a growing body of evidence that the combination of vancomycin and piperacillin-tazobactam increases the risk of acute kidney injury (AKI) compared to: vancomycin alone, piperacillin-tazobactam alone, vancomycin and meropenem, or vancomycin and cefepime.^27-31
  • If clinically appropriate (e.g. similar sensitivity of suspected organism to cefepime), consider using alternative therapy (e.g. vancomycin and cefepime).
• Penicillin allergies and beta-lactam cross-reactivity
  • Recent estimates of cross-reactivity rates for patients with allergies to penicillins and other beta-lactams are extremely low^32-34
    • Penicillin and cephalosporins: ~2%
    • Penicillin and carbapenems: <1%
    • Penicillin and aztreonam: ~0%
  • If a patient has reported history of non-allergic symptoms after penicillin exposure (e.g. nausea, headache, diarrhea) or symptoms based on family history only, use of all beta-lactams (including penicillins) is likely safe.^32-34
  • If a patient has reported history of penicillin allergy resulting in IgE-mediated symptoms (e.g. anaphylaxis) or other severe reactions (e.g. Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TENS]), consider non-beta-lactam alternatives.^32-34
• Useful guides
  • Because it is easy to forget important information related to infectious diseases (e.g. pathogens, options for therapy, dosing, etc.), antimicrobial therapy references can be extremely useful to ED clinicians. One of our favorites is “The Sanford Guide to Antimicrobial Therapy.”  This guide discusses antibacterial, antifungal, antiviral, antiparasitic, and other antimicrobial treatment options in a concise, convenient manner (available in electronic and print forms).  We highly recommend this reference for all ED providers.
  • If available at your institution, pharmacists and infectious disease specialists can assist with therapy selection, dosing, and administration-related issues (e.g. IV compatibility). Do not hesitate to use your resources.

Case Resolution:

After reviewing your infectious disease reference of choice, you recall the patient is 65-years-old and at risk of bacterial meningitis caused by S. pneumo, Listeria, meningococcus, or gram-negative bacilli.  An antimicrobial regimen of choice could include ceftriaxone, vancomycin, and ampicillin.  Because diarrhea alone does not suggest history of an allergic reaction, you feel comfortable with ordering ampicillin (a member of the penicillin family) and ceftriaxone (a member of the cephalosporin family).  Your ED pharmacist recommended ceftriaxone 2000 mg, vancomycin 1500 mg, ampicillin 2000 mg, and dexamethasone 10 mg IV.  You agree with these doses and leave a note for the nurse to administer dexamethasone just before the first antimicrobial.  If the patient remains hypotensive after the fluid bolus, you plan to start a norepinephrine infusion.  One of your ED physician colleagues just arrived for her shift, so she can attend to the other sick patients while you perform the LP.  The patient’s nurse says she already brought the supplies you requested to bedside, so everything is ready for you.

Take Home Points:

• Knowledge of the best options for empiric antimicrobial therapy is essential for ED clinicians to prevent delays and avoid inappropriate therapy.
• Vancomycin and piperacillin-tazobactam (Zosyn®) will cover most infections; however, there are specific infections that would be inadequately treated with this regimen (e.g. C. difficile colitis, CNS infections, VISA/VRSA/ESBL/CRE infections).
• In patients with allergies to penicillin, cross-reactivity is generally low to nonexistent for cephalosporins (~2%), carbapenems (<1%), and aztreonam (~0%).
• References like “The Sanford Guide to Antimicrobial Therapy” can help ensure your patients receive the most appropriate therapy.
• Ask for help if needed (e.g. pharmacists, infectious disease specialists, etc.).

Related emDOCs Posts:

• UTI Empiric Antibiotics: http://www.emdocs.net/uti-empiric-antibiotics/
• Diabetic Foot Infection: http://www.emdocs.net/diabetic-foot-infection-types-antibiotics-warranted/
• Antibiotic Medication Errors: http://www.emdocs.net/common-ed-medication-errors-antibiotics/
• Cellulitis: http://www.emdocs.net/cellulitis-antibiotic-selection-management-updates/
• Antibiotic Timing in Sepsis: http://www.emdocs.net/r-e-b-e-l-em-time-to-antibiotics-in-sepsis/
• Lactate, Antibiotics, Procalcitonin in Sepsis: http://www.emdocs.net/sepsis-update/
• Bacterial Endocarditis: http://www.emdocs.net/r-e-b-e-l-em-bacterial-endocarditis/

From Dr. Katy Hanson at Hanson’s Anatomy:

References/Further Reading:

1. Dellinger, R.P., et al., Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med, 2013. 41(2): p. 580-637.
2. Rhodes, A., et al., Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med, 2017. 45(3): p. 486-552.
3. Mandell, L.A., et al., Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis, 2007. 44 Suppl 2: p. S27-72.
4. Kalil, A.C., et al., Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis, 2016. 63(5): p. e61-e111.
5. Bradley, J.S., et al., The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis, 2011. 53(7): p. e25-76.
6. Gilbert, D.N., et al., The Sanford Guide to Antimicrobial Therapy: 2018, ed. J.C. Sanford. Vol. 48. 2018, Sperryville, VA: Antimicrobial Therapy, Inc. 262.
7. Johnson, S.J., E.J. Ernst, and K.G. Moores, Is double coverage of gram-negative organisms necessary? Am J Health Syst Pharm, 2011. 68(2): p. 119-24.
8. Tamma, P.D., S.E. Cosgrove, and L.L. Maragakis, Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev, 2012. 25(3): p. 450-70.
9. Song, M., et al., Results of a local combination therapy antibiogram for Pseudomonas aeruginosa isolates: is double worth the trouble? Ther Adv Infect Dis, 2017. 4(6): p. 165-170.
10. Paul, M., et al., Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev, 2014(1): p. CD003344.
11. Solomkin, J.S., et al., Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis, 2010. 50(2): p. 133-64.
12. McDonald, L.C., et al., Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis, 2018. 66(7): p. e1-e48.
13. Garcia-Tsao, G., et al., Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology, 2007. 46(3): p. 922-38.
14. Bernard, B., et al., Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology, 1999. 29: p. 1655-1661.
15. Lam, K.L., J.C. Wong, and J.Y. Lau, Pharmacological Treatment in Upper Gastrointestinal Bleeding. Curr Treat Options Gastroenterol, 2015. 13(4): p. 369-76.
16. Nicolle, L.E., et al., Clinical practice guideline for the management of asymtomatic bacteriuria: 2019 update by the Infectious Disease Society of America. Clinical Infectious Diseases, 2019. XX(XX): p. 1-28.
17. Gupta, K., et al., International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis, 2011. 52(5): p. e103-20.
18. Hooton, T.M., et al., Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clinical Infectious Diseases, 2009. 50: p. 625-663.
19. Huttner, A., et al., Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial. JAMA, 2018. 319(17): p. 1781-1789.
20. Lipsky, B.A., et al., 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis, 2012. 54(12): p. e132-73.
21. Stevens, D.L., et al., Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clin Infect Dis, 2014. 59(2): p. 147-59.
22. Tunkel, A.R., et al., Practice Guidelines for the Management of Bacterial Meningitis. Clinical Infectious Diseases, 2004. 39: p. 1267-84.
23. Baddour, L.M., et al., Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation, 2015. 132(15): p. 1435-86.
24. Berbari, E.F., et al., 2015 Infectious Disease Society of Amerida (IDSA) clinical practice guidelines for the diagnosis and treatment of native vertebral osteomyelitis in adults. Clinical Infectious Diseases, 2015. 61(6): p. e26-46.
25. Osmon, D.R., et al., Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases, 2013. 56(1): p. e1-25.
26. Rybak, M., et al., Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm, 2009. 66(1): p. 82-98.
27. Robertson, A.D., et al., Incidence of Acute Kidney Injury Among Patients Receiving the Combination of Vancomycin with Piperacillin-Tazobactam or Meropenem. Pharmacotherapy, 2018. 38(12): p. 1184-1193.
28. Gomes, D.M., et al., Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime. Pharmacotherapy, 2014. 34(7): p. 662-9.
29. Luther, M.K., et al., Vancomycin Plus Piperacillin-Tazobactam and Acute Kidney Injury in Adults: A Systematic Review and Meta-Analysis. Crit Care Med, 2018. 46(1): p. 12-20.
30. Navalkele, B., et al., Risk of Acute Kidney Injury in Patients on Concomitant Vancomycin and Piperacillin-Tazobactam Compared to Those on Vancomycin and Cefepime. Clin Infect Dis, 2017. 64(2): p. 116-123.
31. Mullins, B.P., et al., Comparison of the Nephrotoxicity of Vancomycin in Combination With Cefepime, Meropenem, or Piperacillin/Tazobactam: A Prospective, Multicenter Study. Ann Pharmacother, 2018. 52(7): p. 639-644.
32. Blumenthal, K.G., et al., Antibiotic allergy. The Lancet, 2019. 393(10167): p. 183-198.
33. Shenoy, E.S., et al., Evaluation and Management of Penicillin Allergy: A Review. JAMA, 2019. 321(2): p. 188-199.
34. Sakoulas, G., M. Geriak, and V. Nizet, Is a Reported Penicillin Allergy Sufficient Grounds to Forgo the Multidimensional Antimicrobial Benefits of beta-Lactam Antibiotics? Clin Infect Dis, 2019. 68(1): p. 157-164.