As an internal medicine resident and pulmonary/critical care fellow, I loved fluoroquinolones.  They were effective, easy to prescribe, and had 100% oral bioavailability (disclosure:  I was gifted a pair of Avelox trauma shears during that time)(1).  However, working full-time in the ICU has forced me to realize that these drugs aren't so wonderful for the critically ill.

Reason #1:  Increasing resistance limits use of fluoroquinolones as monotherapy in sepsis

Ironically, the advantages of fluoroquinolones have also been their Achilles' heel (no pun intended).  Fluoroquinolones are the #1 most commonly used antibiotics among outpatient prescribers, administered broadly for anything from diverticulitis to the common cold (Douros 2015).  This success has fueled the rapid emergence of antibiotic resistance (Asenio 2011):

Once upon a time, fluoroquinolones could be used as monotherapy for urosepsis.  Ciprofloxacin plus metronidazole (“Cipro-Flagyl”) was used for abdominal sepsis.  However, most antibiograms now show that fluoroquinolone cover only ~75% of E. Coli (the most common gram-negative pathogen; Rotschafer 2011).  Thus, fluoroquinolones can no longer be relied upon for gram-negative coverage.

Empirical therapy with the fluoroquinolones as the primary or sole agent should be extremely limited –Rotschafer 2011 Critical Care Clinics

Reason #2:  Fluoroquinolones add little to beta-lactam antibiotics when used for double-coverage of pseudomonas

Very well, perhaps we can't use fluoroquinolones as monotherapy.  But we could still combine them with a beta-lactam to double-cover pseudomonas, right?  For example, suppose that piperacillin-tazobactam covers 90% of pseudomonas and ciprofloxacin covers 70% of pseudomonas.  Then, the combination of ciprofloxacin and piperacillin-tazobactam should cover 97%!

Wrong.  Unfortunately, the bacteria that are resistant to piperacillin-tazobactam aren't 70% likely to respond to ciprofloxacin.  These are often multi-drug resistant organisms, so their sensitivity to ciprofloxacin is much lower, perhaps ~20%.  Thus, adding ciprofloxacin to piperacillin-tazobactam doesn't increase your coverage rate from 90% to 97%, but rather only increases it marginally (e.g. from 90% to 92%).

A post further discussing the fallacy of double-coverage with a fluoroquinolone is located here.  Over time, as fluoroquinolone resistance continues to rise, any marginal benefit from double-coverage will continue to dwindle.

Reason #3:  Fluoroquinolones induce the emergence of multi-drug resistant bacteria

Most antibiotics select for resistance against themselves (e.g. vancomycin selects for vancomycin-resistant enterococci).  No surprise there.  However, fluoroquinolones also have a particular tendency to generate bacteria that are resistant to other antibiotics.  For example, fluoroquinolones select for MRSA, extended-spectrum beta-lactamase producing gram-negative bacilli, and carbapenem-resistant enterobacteriaceae (CRE, a widely feared “superbug”)(Falagas 2007, Charbonneau 2006).  I've seen this happen:  a patient admitted from the community developed CRE after extensive antibiotic therapy including fluoroquinolones, in a hospital which was previously free of CRE.

Fluoroquinolones are well known to precipitate clostridium difficile infection, with some epidemics attributed to them (Pepin 2005).  A highly virulent NAP-1 strain of clostridium difficile has been specifically linked to fluoroquinolone use (Vardakas 2012).  However, the risk of clostridium difficile from fluoroquinolones may be lower than the risk from clindamycin or cephalosporins (Slimings 2014).

due to adverse events, emergence of antimicrobial resistance, and selection of potential pathogens, quinolones do not appear to be suitable for sustained use in hospitals as “workhorse” antibiotic therapy –Paiva 2015 Critical Care Medicine

Reason #4:  There are often better approaches to “penicillin allergy”

Traditionally, a major driver for using fluoroquinones was “penicillin allergy.”  For example, any patient being admitted with pneumonia with a penicillin allergy would be automatically treated with levofloxacin.  Over the last several years, there has been increasing recognition that there is little cross-reaction between penicillin and third or fourth-generation cephalosporins (Campagna 2012).  This often eliminates the rationale for using a fluoroquinolone.

Reason #5:  Delirium

Fluoroquinolones have long been recognized to cause delirium.  They directly antagonize inhibitory GABA receptors and stimulate excitatory NMDA receptors, activating the brain.  This may cause insomnia, agitated delirium, and seizures (Chowdhry 2015).  Although reported in only ~1% of patients, this could be more problematic among critically ill patients who are at high risk of delirium (Douros 2015).

Reason #6:  New black box warning for persistent neurological abnormalities

Fluoroquinolones rarely can cause a syndrome involving persistent peripheral neuropathy, sometimes associated with weakness and delirium (Cohen 2001).  This may cause debility lasting months to years.  The FDA recently issued a black box warning regarding this complication, stating:

FDA has determined that fluoroquinolones should be reserved for use in patients who have no other treatment options for acute bacterial sinusitis, acute exacerbation of chronic bronchitis, and uncomplicated urinary tract infections because the risk of these serious side effects generally outweighs the benefits in these patients.  For some serious bacterial infections the benefits of fluoroquinolones outweigh the risks, and it is appropriate for them to remain available as a therapeutic option.

This could be especially problematic in the ICU for two reasons:

1. In an intubated and sedated patient, it would be impossible to promptly diagnose a patient with fluoroquinolone toxicity.  This would prevent rapid discontinuation if toxicity should occur.
2. Critically ill patients are at increased risk of critical illness neuropathy, a multifactorial process which may be severe.  It is possible that fluoroquinolone-induced neurotoxicity could be more problematic in this context.

This hasn't gone unnoticed by medical malpractice lawyers:

However, fluoroquinolones aren't that bad

In fairness, fluoroquinolones are generally very effective and toxicity is uncommon.  In situations where fluoroquinolones are the best antibiotic choice, they should certainly be used.  My objection to fluoroquinolones isn't that they are evil, but rather that better alternatives usually exist in the ICU.  The utility of fluoroquinolones is probably greater among outpatients, among whom many of the above considerations are less pertinent.

Fluoroquinolones generally aren't very useful among critically ill patients for several reasons:

1. Resistance impairs the ability to use fluoroquinolones as monotherapy for sepsis.
2. Fluoroquinolones add very little to beta-lactams, making “double-coverage” with a fluoroquinolone ineffective.
3. Fluoroquinolones are notable for their ability to breed multi-drug resistant organisms and clostridium difficile.
4. Most patients with a “penicillin allergy” can be safely treated with a third- or fourth-generation cephalosporin, rather than fluoroquinolone.
5. Fluoroquinolones block GABA receptors and stimulate NMDA receptors, which may cause delirium and seizure.
6. The FDA recently released a boxed warning that fluoroquinolones can cause a persistent, debilitating peripheral neuropathy.

More information:

• FDA Drug Safety Communication 7/26/2016
• Double-coverage of gram negatives with a fluoroquinolone? (PulmCrit)

Notes

1. This occurred over five years ago. Currently I have no conflicts of interest and haven't accepted anything from pharma in years.

Image credits:  Insect image from Wikipedia here, dinosaur image here.

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Josh Farkas

Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.

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