#284 An Antibiotics Primer, with @IDdocAdi

July 12, 2021 | By Nora Taranto

This antibiotics primer will break down the (cell) walls of antibiotic knowledge. Stop feeling silly when you deal with penicillins! We discuss antibiotic classes, common uses, the pathophysiology behind antibiotic mechanisms, and so much more with infectious disease expert, Dr. Adi Shah MBBS (@IDdocAdi)! 

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Credits

• Producer, Script and Show Notes: Nora Taranto MD
• Infographic, Cover Art, Show Notes: Beth Garbitelli
• Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP   
• Editor: Matthew Watto (written materials): Clair Morgan of nodderly.com
• Reviewer: Victor Kovac MD
• Guest: Adi Shah MBBS

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Show Segments

• Intro, disclaimer, guest bio
• Guest one-liner
• Picks of the Week*
• How to approach antibiotics
• Choosing antibiotics / Framework
• Dr. Shah’s favorite antibiotics
• Pneumonia
• Diabetic Foot Infections
• Take-home points
• Outro

Antibiotics Pearls

1. Use Dr. Shah’s broad questions to guide your cognitive framing of antibiotic use and stewardship (see graphic). 
2. Antibiotic stewardship is not just about stopping antibiotics. It is about making the right antibiotic choice, at the right dose, for the right duration, for the right patient.  Always look at your patient before starting your antibiotic. 
3. Whether you are treating a patient with advanced dementia or advanced cancer,  remember that medications have adverse effects and side effects: Remember this, before empirically treating everyone with Vanc-o-Pime (Vanc and Cefepime). 
4. Look for the antibiogram at your local institution, to identify drugs that might not be so good to use in your area. 

Antibiotics Primer  

The Framework 

Dr. Shah recommends thinking about why you are choosing a specific antibiotic. He has a few questions he asks himself: 

1. Do we suspect an infectious process or non-infectious process?
2. Do I have time to see if the patient responds to the current regimen, or do I need to cover broadly, immediately? (aka Just how sick is the patient?) 
3. In deciding on empiric coverage, what are previous antimicrobial exposures, and what side effects has the patient experienced?
4. What is the suspected site of infection? 
5. Any tests to order before starting antibiotics? (Think blood cultures!) 
6. Is source control needed?
7. What am I trying to cover with the antibiotic regimen?

Think critically about the patient’s presentation, per Dr. Shah (e.g. with a swollen extremity for several months, does it make sense to classify that as cellulitis that requires broad spectrum antibiotics?). Don’t be afraid to stop antibiotics. 

Some Helpful Tidbits, to Start

Resources, when you don’t know what to pick: A couple of suggestions: Johns Hopkins Antibiotics Guide, Mayo Clinic Antimicrobial Therapy Quick Guide, Sanford Guide, and (as always) UpToDate 

Dr. Shah’s Favorite Antibiotic: Doxycycline. Works against Cellulitis, Bartonella, Ticks, COPD exacerbations, atypical pneumonia, CAPs, *some STIs, penicillin-resistant syphilis, and Acne. And it’s Oral! What more could you ask for?!  He also likes Quinolones (for some situations), and TMP-SMX for others, given both have good oral bioavailability. 

Common Antibiotic Pearls and Pitfalls: 

1. Pip-Tazo covers anaerobes (So no need to empirically add metronidazole) 
2. Daptomycin does not work for pneumonia (it is sequestered by surfactant)  (Silverman 2005).  
3. You do NOT need metronidazole for aspiration pneumonia coverage, unless you are treating an empyema or lung abscess.  (Watto’s advice: please do not use clindamycin for ‘aspiration pneumonia’ either! (ATS 2019)
4. When using azithromycin or levofloxacin, check the QT interval.
5. Just because patients are in the hospital does not mean they need to be on IV Antibiotics the entire time. Check out Brad Spellburg’s IV to PO comparison charts. 

Short Courses!

More  evidence is emerging for the efficacy and safety of shorter courses of antibiotics (Lee 2021).  You can discontinue abx in community acquired pneumonia after 5 days, as long as you see improvement and clinical stability (Lee 2021). For more best practices, check out the ACP’s June 2021 recommendations on short courses for common infections.  

Who is at-risk for MDRO? For MRSA? 

If patients have been recently exposed to a healthcare setting, if they are on dialysis, or if they are coming from an assisted living/nursing home, you may want broader coverage for drug resistant organisms. If there is a clear abscess on imaging, you should cover for MRSA as well. For more on MRSA risk factors, check out this 2020 StatPearls Article. 

When to double-cover for Pseudomonas?  

If you have a patient heavily exposed to health care settings–especially if they have high-risk features such as recent chemotherapy, bone marrow transplant, solid organ transplant, or are in the ICU on several pressors–it is reasonable to use two antipseudomonal agents upfront.  Options include pip-tazo + levofloxacin or tobramycin, pip-tazo + amikacin, cefepime + tobramycin or amikacin or levo.  But, if stable, double coverage may not be necessary. 

How to choose: Breaking it down by Class 

There are several groups of antibiotics: beta-lactams (which include penicillins, cephalosporins, and carbapenems),  tetracyclines, quinolones, and others (such as aminoglycosides).  You can also think about antibiotics in terms of coverage realms (ie: agents that cover MRSA vs. those that do not). 

β-Lactams

This family includes penicillins, cephalosporins, and carbapenems, which all act via bactericidal mechanisms by inhibiting peptidoglycan synthesis in the bacterial cell wall (Lima 2020).  Mechanisms of resistance vary among the subclasses. Resistance to penicillins occurs via primarily β-lactamases (eg: penicillinase) which are enzymes produced by the bacteria that break down the beta-lactam ring, rendering them less effective (Lima 2020).  Resistance to cephalosporins occurs primarily when bacteria reduce binding-protein affinity for cephalosporins (Lima 2020, Livermore 1987).  

The Golden Moldies: Penicillins (the -Cillins) 

penicillin, amoxicillin, ampicillin, oxacillin, methicillin, nafcillin

Penicillin works well for streptococcal skin infection (Stevens 2016, IDSA SSTI 2014), strep throat (Chahine 2013), and of course, syphilis (CDC 2015). Amoxicillin-clavulanic acid and ampicillin-sulbactam work great for oropharyngeal infections because they cover oral species and streptococcus.  A common side effect is diarrhea, which can settle down after a few days of use, per Dr. Shah.  Ampicillin is indicated for enterococcal endocarditis with ceftriaxone (Shah 2020), with the so-called synergy effect (Thieme 2018).  Methicillin, naficillin, and oxacillin act against MSSA (Johns Hopkins Antibiotic Guide). 

Big Picture: Great for a variety of skin and soft tissue infections, upper and lower respiratory tract infections, and other gram positive infections, with some added gram negative and anaerobic coverage as you add the beta lactamase inhibitors (as in Amox-Clav). 

The Coverage Gaps: MRSA, Gram Negatives, and Anaerobes

Amoxicillin-clavulanic acid provides solid anaerobic and gram negative coverage; given this and its strep coverage, it can be used for simple soft tissue infections as well (IDSA SSTI 2014, Huttner 2019) but it does not cover pseudomonas or MRSA. 

Generational Saga of the Cephalosporins (The -Cefs)

cefadroxil, cefuroxime, ceftriaxone, cefepime, ceftaroline

There are at least 5 generations of cephalosporins, or the “workhorse” of the beta lactams. 

Cefadroxil is a 1st generation cephalosporin great for uncomplicated soft tissue infections, specifically MSSA (methicillin-sensitive staphylococcus aureus)  and streptococcus (John Hopkins Antibiotic Guide), and has twice-daily (instead of four times daily) dosing.  1st generation cephalosporins have limited gram negative and no MRSA (methicillin-resistant staphylococcus aureus) coverage per Dr. Shah.  Cefuroxime is an effective 2nd generation cephalosporin (Scott 2001).  Ceftriaxone is a favorite in the 3rd generation for bacteremia, pneumonia, deep soft tissue infections, abscesses (Richards 1984).  4th generation cefepime has excellent pseudomonas (Chapman 2003), broad gram negative (including gut anaerobes), and gram positive coverage, but does not cover MRSA or oral anaerobes per Dr. Shah (although some resistance arising, per Endimiani 2009). Ceftaroline is a 5th generation cephalosporin which *does* cover MRSA (Zanel 2009).  Ceftazidime-avibactam, ceftolozane-tazobactam (van Duin 2016), and Cefiderocol are cephalosporins that work against pseudomonas, but consult ID when using. When you combine ceftriaxone with ampicillin, for enterococcal endocarditis, you rely on different binding affinities for the PBPs, which leads to better inhibition of wall synthesis and bactericidal properties (Wert 2015).

Big Picture: Good Gram positive coverage. With increasing generation, you get increased gram negative coverage.  

The Coverage Gaps: Think LAME. Cephalosporins do not have activity against listeria, atypicals (mycoplasma, chlamydia), MRSA, and enterococci (Shrestha 2014, accessed June 23 2021).  

Carbaloading the Carbapenems (the -Penems) 

Imipenem, Meropenem, Ertapenem 

Matt quotes an ID colleague, on the use of penems: “It’s like mowing your lawn with napalm.”  They destroy the good flora in your body (Bhalodi 2019).  And they broadly cover gram positives, gram negatives, and anaerobes (Papp-Wallace 2011).  

Meropenem has excellent broad activity against pseudomonas and extended spectrum beta-lactamase (ESBL) producing organisms (Fish 2006). Imipenem and Meropenem are equivalents, but Imipenem also covers enterococcus and nocardia, even with intracranial and lung involvement (Wilson 2012). Ertapenem covers everything else including gram negative and anaerobic coverage, except for pseudomonas, MRSA, and atypicals (Zanel 2006, Goswami 2011). Great for bacteremia. And it’s once daily! 

Big Picture:  Think BIG coverage. Covers gram positives, gram negatives, and anaerobes. 

The Gaps: MRSA (And sometimes pseudomonas, for ertapenem).  

The Worry: Bacterial resistance to carbapenems is a rare but growing public health concern and mechanism occurs primarily in gram-negative pathogens (enterobacteria, klebsiella, pseudomonas, acinetobacter) via proposed mechanisms of carbapenemases, target site mutations, and efflux pumps (Lima 2020). 

Classifying Antibiotics: Tetracyclines

One of Dr. Shah’s favorite antibiotics is doxycycline. It works against acne, cellulitis, bartonella from animal bites, tick-borne illness, atypical pneumonia, COPD exacerbations (that anti-inflammatory effect!), CAP, sexually transmitted infections, and penicillin-resistant syphilis (Cross 2016).  It can be taken orally, twice daily.  Important to remember the photosensitivity and esophagitis as possible adverse effects, so should be taken with lots of water (and sun hats)! 

Classifying Antibiotics: Quinolones

Fluoroquinolones–despite associations with C. difficile infections (McCusker 2003), tendinopathy (Lewis 2014), aneurysms (Rawla 2019), and neuropsychiatric side effects (Sellick 2018)–have good utility, good oral bioavailability, and are the only oral option for Pseudomonas (HIV and ID Observations, Dr. Paul Sax, 2013).  

Classifying Antibiotics: Others!

TMP-SMX, metronidazole, clindamycin, rifampin, and linezolid (as well as doxycycline, and fluoroquinolones) are all antibiotics with good oral bioavailability (HIV and ID Observations, Dr. Paul Sax, 2013).

TMP-SMX is useful for PJP, Nocardia, toxoplasmosis, UTI (Kemnic 2020)  and works decently in osteomyelitis (Kim 2014). Adverse effects for TMP-SMX include blood dyscrasias (Parajuli 2019), G6PD-mediated hemolytic anemia (Williams 2016), and can raise serum creatinine via pseudo-elevation or true nephrotoxicity (Fraser 2012; Urakami 2021).  Get a CBC and CMP at least once during treatment. 

Targeted Coverage: Activity Against MRSA?  

vancomycin, daptomycin, ceftaroline, linezolid, clindamycin, doxycycline, TMP-SMX 

For those hospitalized, sick patients, while blood cultures are pending, or if MRSA bacteremia, or Enterococcal infection: Think Vancomycin, Daptomycin (and Ceftaroline, though we use it less for this specific reason), which have bactericidal properties (Brauers 2007).  Linezolid is bacteriostatic (Brauers 2007), and should ideally be used alongside another MRSA agent for bacteremia (you want bactericidal effect for Bacteremia, in general, per Dr. Shah).  Daptomycin will not work in lung infections, because it is inactivated by surfactant (Silverman 2005). 

For Community-Acquired MRSA, e.g. skin and soft tissue infections, sometimes Doxycycline is sufficient. Refer to your local antibiogram for better coverage guidance. 

“Clindamycin is most ID docs least favorite antibiotic,” says Dr. Shah. It’s C.Diff-ogenic, along with quinolones. The only place to use it is in early necrotizing fasciitis (ie: within 48 hr of onset) for its antitoxin effect (Smieja 1998). 

A Few Clinical Cases: 

Pneumonia:

If Inpatient (assess for fever, increased age, high respiratory rate, lab abnormalities)Generally, choose a combination of a Cephalosporin (ceftriaxone is great!) and something for atypical coverage (azithromycin, doxycycline, or less commonly levofloxacin). Think about MRDO risk factors (recent hospitalization, recent antibiotic exposure, h/o MDRO) and add MRSA or Pseudomonal coverage as needed. Get a MRSA swab to help pull off Vanc sooner rather than later if negative.   

If a patient has been treated recently for multiple COPD exacerbations, and or they look peri-septic, you may want to expand coverage.  Think about covering for MRSA with vancomycin, and also for pseudomonas with an agent such as cefepime, or pip-tazo.  If you cover for MRSA, always get a MRSA nasal swab so that you can narrow.   Important to remember that kidney dysfunction with pip-tazo + vancomycin can occur (Blair 2021). Dr. Shah also recommends a sputum culture and, for select ICU patients, bronchoscopy for deeper samples. 

The Diabetic Foot: 

Differentiate between deep (abscess, fluctuant, induration, pus) versus more superficial Streptococcal cellulitis.  In simple/superficial cellulitis, you do not need MRSA coverage. With fluctuance, pus, or evidence of abscess, cover MRSA (and perhaps perform an I&D as well). 

Also important to rule out osteomyelitis.  Plain films are okay to start with, sometimes they can show osteomyelitis.  If you don’t see anything, you may need an MRI which has better sensitivity (Hatzenbuehler 2011). Gold standard is a bone biopsy (Hatzenbuehler 2011). 

If you are admitting a septic patient or one who has clear signs of infection, start antibiotics without delay (Surviving Sepsis Campaign Guidelines Update 2016).  If they have antimicrobial exposures and uncontrolled diabetes, cover for MRSA, anaerobes, and Pseudomonas (Surviving Sepsis Campaign Guidelines Update 2016).  If there is clear necrosis, start with vancomycin + cefepime +metronidazole.  It’s important to obtain a bone biopsy, and consider source control, sooner rather than later.   If they have negative margins from an amputation, they will require only a short course of cellulitis coverage (Rossel 2019).  N.b. There is some evidence for equivalence of long-term oral versus IV antibiotics in these types of smoldering bone infections (Spellberg 2012). 

Take Home Points

1. Antibiotic stewardship is not just about stopping antibiotics. It is about making the right antibiotic choice, in the right dose, for the right amount of time, for the right patient. 
2. Always look at your patient before starting your antibiotic. Guidelines are meant to guide, you still have to tailor your recommendations based on the patients.  
3. Multi Drug Resistant Organisms do not care about your feelings or emotions. 
4. If you are treating a patient with advanced dementia or advanced cancer,  remember that these drugs [antibiotics] can cause harm so always consider these factors before empirically treating all patients with vanc and pip-tazo. 

Links*

1. The Cubs Tickets,  Go! Cubs! Go!
2. Unwinding Anxiety by Judson Brewer
3. Why We’re Polarized by Ezra Klein
4. Paul’s Pick of the Week: New Skin by CRX 
5. Matt’s Pick of the Week: Apple Pencil 
6. Johns Hopkins Antibiotic Guide (behind paywall, so check institutional access)
7. Mayo Clinic Antimicrobial Therapy Quick Guide by John W. Wilson and  Lynn L. Estes 
8. The Sanford Guide to Antimicrobial Therapy 2021
9. Brad Spellburg’s Oral Antibiotic Comparison Charts
10. How to Figure Out the Length of Antibiotic Therapy by Paul E. Sax 

*The Curbsiders participates in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising commissions by linking to Amazon. Simply put, if you click on our Amazon.com links and buy something we earn a (very) small commission, yet you don’t pay any extra.

Goal

Listeners will understand basics about the pathophysiology of antibiotics, better choose antibiotics based on spectrum of activity and determine choice/course of antibiotics for common infections. 

Learning objectives

After listening to this episode listeners will…

1. Understand good first line agents for common bacterial infections
2. Identify the spectrum of activity of common antibiotics 
3. List common side effects for commonly used antibiotics 
4. Define antimicrobial stewardship, and understand how to use their own institutional antibiograms   

Disclosures

Dr. Shah reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Taranto N, Shah A, Garbitelli B, Williams PN, Watto MF. “#284 An Antibiotics Primer, with @IDdocAdi”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list Final publishing date July 12, 2021.