Antibiotics – Part 1: Spectrum

Table of Contents

Table of Contents

Updated April 2022

Authors: Brandon Fainstad, MD¹, Yilin Zhang, MD²

1 Assistant Professor, Department of Medicine, University of Colorado

2 Assistant Professor, Department of Medicine, University of Washington

Both authors were equal contributors to this talk. 

Objectives

  1. Identify the spectrum of coverage for the most commonly used inpatient antibiotics
  2. Recognize antibiotics that specifically cover MRSA (optional objective in the Additional Learning Section)

Teaching Instructions

Plan to spend 60 minutes preparing for this talk by using the Interactive Board and clicking through the graphics animations to become familiar with the flow and content of the talk. Print out copies of the Learner’s Handout so learners can fill in the antibiogram as you walk through every antibiotic class. All clickable elements are indicated by a shaded shape and mouse cursor. Each button will be clickable until the mouse cursor disappears.

The anticipated time to deliver the entire talk is about 20-25 min without cases and 30-35 min with cases. This talk covers only Spectrum of Activity (Part 1). A second part of this talk is on Sites of Infection

The talk can be presented in 2 ways:

  1. Project the “Interactive Board” OR
  2. Reproduce your own drawing of the presentation on a whiteboard OR
  1. Project the Interactive Board for Presentation OR
  2. Reproduce a drawing of the differential diagnosis figure and timeline on a whiteboard.   

This talk assumes that learners have a basic working knowledge of different types of bacteria.

Basic Questions: In evaluating an antibiotic's spectrum of activity, ask the following 4 questions. Click on each button 

  1. Does it cover gram positive organisms (GP), namely Staph and Strep?
    • Does it cover MRSA?
    • Does it cover Enterococcus? (higher-level question)
  2. Does it cover gram negative (GN) organisms?
    • Does it cover Pseudomonas (PsA)?
    • Does it cover ESBLs? (higher-level question, resistance to 3rd generation cephalosporins) 
  3. Does it cover atypical organisms (Mycoplasma, Chlamydophila, Legionella)?
  4. Does it cover anaerobes?
    • Does it cover B. fragilis (gut anaerobes)? 

Antibiogram: Click on each class of antibiotics to learn more. 

PencillinsPencillins are broadly separated into 4 classes – natural pencillins, anti-staphylococcal penicillins, broad spectrum pencillins which include aminopencillins and anti-pseudomonal penicillins. 

General rules for penicillins – there is no MRSA coverage, no atypical coverage, and there is generally increasing gram negative (GN) with later generations/classes.

  • Penicillin – natural pencillins are Pen G (IM, IV) or Pen VK (PO). These have good Strep coverage. Notably, Pen G is 1st line for many Strep infections (Group A Strep, S. pneumoniae) and is active against many oral anaerobes.
    • There is high Staph resistance to penicillins and should not be used to empirically cover Staph infections.  
    • Of note, pencillin does have some activity against gram negative organisms, notably Treponema pallidum (syphilis), Neisseria, Pasteurella
    • It also has activity against some Enterococcus (namely E. faecalis). 
  • Anti-staphylococcal pencillins – namely nafcillin (IV), dicloxacillin (PO), methicillin (PO), oxacillin (PO). The antistaphylococcal pencillins are first line therapy for MSSA and CoNS.  It has activity against Strep species as well. 
  • Aminopencillins – ampicillin (IV) and amoxicillin (PO) are aminopencillins that are often given with a beta-lactamase (sulbactum or clavulanate which expands activity against Staph, many gram negative rods (E. coli, H. flu, M. catarrhalis), and gut anaerobes. Coverage is shown for aminopenicillin + beta-lactamase inhibitor.
    • First line for for Enterococcus faecalis infections. Variable activity against E. faecium.
    • Bonus: Fun Mneumonic for Enterococcus spp.
      • Enterococcus faecaLESS is LESS resistant (~90% ampicillin sensitive) and only rarely are Vancomycin resistant (aka VRE)
      • Enterococcus faecium is more resistant (~10% ampicillin sensitive) and more frequently is VRE
  • Antipseudomonal – namely piperacillin (IV), which is typically given with a beta-lactamase inhibitor tazobactam. This is the broadest spectrum penicillin and has broad coverage against GPs, enteric GNRs, gut anaerobes, and Pseudomonas. The major difference between ampicillin-sulbactam and piperacillin-tazobactam is the addition of Pseudomonas coverage.

Cephalosporins: Cephalosporins are classified into 5 generations.

General rules for cephalosporins– there is no Enterococcus coverage, no atypical coverage. Generally, increasing generations provide additional GN coverage (with the exception of 5th generation).

  • 1st generation – cefazolin (IV) and cephalexin (PO) has good gram positive coverage and can be used for MSSA, some CoNS species, and Strep species. There is very limited GN coverage.
    • There is high Staph resistance to penicillins and should not be used to empirically cover Staph infections.  
  • 2nd generation – cefuroxime (PO, IV), cefaclor (PO), cefofetan (IV), cefoxitin (IV) add additional GN coverage (H. flu, Klebsiella, Moraxella).
    • Bonus: the cephamycins (cefoxitin, cefofetan) do have some activity against anaerobes including Bacteroides
  • 3rd generation – 3rd G cephalosporins have expanded coverage against GNRs (namely Enterobacteriaceae). They are generally split into two categories.
    • Ceftriaxone (IV), cefotaxime (IV), cefdinir (PO) , cefpodoxime (PO) – Good Strep and GNR coverage. No anaerobic coverage. 
    • Ceftazidime (IV) – Limited GP coverage (no Staph), however, has added activity against PsA. It has poor CNS penetration and should not be used for meningitis. No oral cephalosporins cover PsA.
  • 4th generation – cefepime (IV) has activity against PsA and AmpC producing organisms. 
  • Advanced generations – these should only ever be ordered in consultation with an ID specialist. These advanced generations have additional coverage against multidrug resistant organisms (MDROs)
    • Ceftaroline – sometimes called a 5th generation cephalopsorin (though this is not universal). This has activity against MRSA. 
    • Ceftolozone-tazobactam (not shown) – has activity against PsA, ESBL, and AmpC
    • Ceftazidime-avibactam (not shown) – beta-lactamase inhibitor has some activity against ESBL, AmpC, and some carbapenemase producing species.

Carbapenems: They are the broadest antibiotic class with GP, GN, and anaerobic coverage. 

General rules for cephalosporins– They are the most reliable ESBL coverage. But they have no activity against MRSA, atypicals, and generally have poor Enterococcus coverage.

  • Ertapenem – No PsA coverge and has the benefit of being dosed once daily. First line agent for Bfragilis infections and ESBL E. coli infection.
  • Meropenem/ imipenem/ doripenem – all have similar spectrum of activity. Similar spectrum of activity as ertapenem but has additional PsA coverage.
    • Generally, poor/variable Enterococcus coverage, but some may have activity against E. faecalis when used with a beta-lactamase inhibitor (e.g., imipenem-cilastin)

Fluoroquinolones (FQ)The authors of this talk like to divide them into “respiratory” and “urinary” fluoroquinolones. They have broad spectrum coverage, excellent bioavailability, convenient dosing schedule, good tissue penetration and are generally well tolerated. However, overuse has led to increasing resistance and raised concerns about potentially harmful side effects (QT prolongation, increased risk of aortic aneurysms and dissections, tendon rupture, encephalopathy, C. diff).

General rules – Good GNR coverage, good atypical coverage, good bioavailability

  • Ciprofloxacin (urinary) – good GNR coverage in GU and GI tract. However, there is increasing E. coli resistance. There is none to minimal Staph coverage and poor Strep coverage. Because of this poor Strep coverage, it is not used as empiric coverage for respiratory infections. It can be used as a second anti-Pseudomonal agent in respiratory failure or as atypical coverage.
  • Levofloxacin (urinary/respiratory) – Improved GP coverage compared to ciprofloxacin (notably, MSSA, some CoNS species, and S. pneumoniae, S. viridans, and E. faecalis). Good empiric coverage for low risk respiratory and GU infections. It also covers some oral anaerobes such as Peptostreptococcus
  • Moxifloxacin  (respiratory) – Limited anti-PsA activity and poor renal penetration. However, it is the FQ with the broadest anaerobic coverage, making it the most reliable FQ for GI infections or aspiration pneumonia. 

Anti-Pseudomonal agentsAdditional anti-PsA and GN covergae for patients who are allergic or have an adverse drug reaction to to beta-lactam antibiotics. 

  • Aminoglycosides – amikacin (IV, IM), gentamicin (IV), plazomicin (IV), tobramycin (IV) can be used to treat infections caused by aerobic GNRs and PsA. No anaerobic or atypical coverage. All aminoglycosides can cause oto- and nephrotoxicity.
    • Gentamicin is the only aminoglycoside that has some activity against GP organisms and is used to synergistically with other antibiotics to treat Enterococcal endocarditis (this is not shown in the antibiogram). 
    • Plazomicin is a new aminoglycoside that has some activity against ESBL GNRs.
  • Aztreonam – monobactam that covers aerobic GNs and PsA. No GP, anaerobic or atypical coverage. There is very little cross-reactivity with beta-lactams, with a notable exception of ceftazidime. The side chain on aztreonam is similar to ceftazidime side chain and should be avoided in patients with known allergy to ceftazidime.  

Macrolides: Azithromycin (PO, IV), erythromycin (PO, IV), and clarithromycin (PO) are the most commonly used macrolides. They ahve good atypical coverage but increasing Strep resistance limits utility in CAP. Risks includes QTc prolongation. 

  • A new macrolide, fidaxomicin, is particularly effective against C. diff infections. 

Anti-MRSA antibiotics: Antibiotics with activity against MRSA can be split into options for the community acquired MRSA (CA-MRSA) and those for hospital acquired MRSA (HA-MRSA). Click on “Community” and Hospital” to reveal classes of antibiotics that can be used in each setting. 

CA-MRSA: There is variation in the resistance of community acquired MRSA isolates to each of the following antibiotics. Choice of therapy should be based on local antibiotic resistance patterns. 

  • Clindamycin (PO, IV) – has activity against oral anaerobes, good GP (Staph, Strep, Clostridium) coverage, and minimal GN coverage. There is high resistance of B. fragilis so it is not recommended for intraabdominal infections. Also has anti-toxin activity and is used for toxic-shock syndrome.
    • Major drug side effects/ adverse reactions include C. diff infections. 
  • Trimethoprim- Sulfamethoxazole (TMP-SMX, Bactrim) (PO, IV) – has broad spectrum of coverage to GN's, Staph. There is variable Strep coverage and no Enterococcal or anaerobic coverage. First line therapy for Nocardia, Stenotrophomonas, and  Pneumocystis.
    • There are many drug side effects including drug rash (Stevens-Johnson Syndrome), hyperkalemia/ hyponatremia, nephrotoxicity. 
    • Because of variable Strep coverage, in the treatment of purulent cellulitis, a cephalosporin or beta-lactam is often used in conjunction with TMP-SMX to “double cover” for Strep
  • Tetracyclines – Doxycycline (PO, IV) and tetracycline (PO) are the most commonly used tetracyclines. Tetracyclines generally have strong atypical and oral anaerobic coverage, good Staph coverage, and some Enterococcal coverage, and some GN coverage (non-Enterobacteraceae). There is minimal Strep coverage. It is the antibiotic of choice for rickettsial infections. 
    • The primary side effects are photosensitivity and teratogenicity.  
    • Because of minimal Strep coverage, in the treatment of purulent cellulitis, a cephalosporin or beta-lactam is often used in conjunction with a tetracycline to cover for Strep

Hospital Treatment of MRSA: For nosocomial infections (HA-MRSA) or in hospital treatment of MRSA, IV agents should be used. The most commonly used agents are vancomycin (IV only), daptomycin, and linezolid.

  • Vancomycin (IV only) – pure GP coverage. 1st line therapy for MRSA, Enterococcal infections (though there is some resistance (Vancomycin Resistant Enterococcus, VRE) among Enterococcus species). Also used for empiric coverage of CoNS infections (variable beta-lactam sensitivity). 
    • Primary side effects include red man syndrome, nephrotoxicity. 
  • Daptomycin (IV) – pure GP coverage. Should not be used for MRSA pneumonia because it is deactivated by surfactant in the lungs. 
    • Primary side effect is rhabdomyolysis. 
  • Linezolid (IV/PO) – pure GP coverage. First line agent for VRE. Costly, but available both IV and PO. 
    • Primary side effects are myelosuppression with prolonged used and risk of serotonin syndrome when used with other serotonergic agents. 

Printouts

Presentation Board

Take Home Points

When selecting an antibiotic, ask:

  1. Which group of bugs do you want to cover (GPCs, GNRs, anaerobes and/or atypical)?
  2. For GPCs, if there is a risk for MRSA or enterococcus: escalate to vanco -> dapto -> linezolid -> cefteroline
  3. For GNRs, with increasing concern for pseudamonas or ESBLs: escalate to lefovloxacin -> ceftazidime -> cefepime -> piperacillin/tazobactam -> meropenem, using aminoglycosides or aztremonam for severe PCN allergy

References

Gilbert, DN, et al. (2017). Sanford guide to antimicrobial therapy 2017. Retrieved from: http://webedition.sanfordguide.com

Metlay, JP, et al. American Journal of Respiratory and Critical Care Medicine, Volume 200, Issue 7, 1 October 2019, Pages e45-e67, https://www.atsjournals.org/doi/full/10.1164/rccm.201908-1581ST

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