What We Mean By ‘Antibiotic Resistance’: The Ciprofloxacin-Shigella Alert Edition

While the problem of antibiotic resistance is a common topic (and not just on this blog!), there is little discussion of how we actually measure it–and those details do matter. So before we get to a recent CDC alert–one all doctors, and not just infectious disease specialists, should be aware of–let’s review some stuff.

A common method to figure out if a bacterial isolate is resistant to a given antibiotic is to determine its minimal inhibitory concentration breakpoint, or ‘MIC.’ The bacterium is grown in a liquid broth, and then a small amount of this bacteria-laden broth is added to different sterile liquid broths, each of which contains a certain concentration of the antibiotic. The MIC is the lowest concentration that inhibits growth and is usually expressed in units of micrograms/milliliter (or grams/liter*). Obviously, I’m glossing over many technical details, but this is the basic idea.

So how do we know what MIC breakpoint to use? Well, we do TEH SCIENTISMZ! We correlate outcomes of infections with various strains’ MICs as well as use animal models and do a whole lot of pharmacokinetics. And MIC breakpoints are changed if we see treatment failures**.

Finally, one other thing before we get to the CDC alert, which is some bacterial taxonomy. As we’ve mentioned before, Shigella are really just a subset of E. coli***, which cause a lot of urinary tract infections.

So onto the CDC alert (I’ll translate into English; boldface mine):

This Health Advisory describes the identification of emerging Shigella strains with elevated minimum inhibitory concentration values for ciprofloxacin and outlines new recommendations for clinical diagnosis, management, and reporting, as well as new recommendations for laboratories and public health officials. Current interpretive criteria provided by the Clinical and Laboratory Standards Institute (CLSI) categorize these strains as susceptible to ciprofloxacin, which is a fluoroquinolone antibiotic and a key agent in the management of Shigella infections.

However, recent data from the Centers for Disease Control and Prevention (CDC) and state and local public health partners show that these strains often have a quinolone resistance gene that may lead to clinically significant reduced susceptibility to fluoroquinolone antibiotics. Clinicians treating patients with multidrug-resistant shigellosis for whom antibiotic treatment is indicated should avoid prescribing fluoroquinolones if the ciprofloxacin MIC is 0.12 μg/mL or higher even if the laboratory report identifies the isolate as susceptible, and should work closely with their clinical microbiology laboratory and infectious disease specialists to determine appropriate antimicrobial therapy….

CDC has identified an increase in Shigella isolates in the United States with minimum inhibitory concentration (MIC) values of 0.12–1 μg/mL for the fluoroquinolone antibiotic ciprofloxacin. Preliminary data suggest that all Shigella isolates with ciprofloxacin MICs in this range for which results are available harbor at least one quinolone resistance gene known to confer reduced susceptibility in enteric bacteria. Shigella isolates without a quinolone resistance gene typically have a ciprofloxacin MIC of ≤0.015 μg/mL. Current CLSI criteria categorize Shigella isolates with a ciprofloxacin MIC of ≤1 μg/mL as susceptible to ciprofloxacin.

CDC does not yet know whether fluoroquinolone treatment of a Shigella infection with a ciprofloxacin MIC of 0.12–1 μg/mL is associated with a worse clinical outcome for the patient or if such treatment increases the risk of transmission to other individuals. In Salmonella isolates, ciprofloxacin MICs of 0.12–1 μg/mL have been associated with reduced susceptibility, prolonged clinical illness, and treatment failures and are now categorized by CLSI as intermediate or resistant to ciprofloxacin in Salmonella species.

Fluoroquinolone resistance is of particular concern given that data from the National Antimicrobial Resistance Monitoring System indicate that many Shigella isolates with a quinolone resistance gene also are resistant to many other commonly used treatment agents, such as azithromycin, trimethoprim-sulfamethoxazole, amoxicillin-clavulanic acid, and ampicillin. This susceptibility profile may encourage clinicians to prescribe fluoroquinolone antibiotics to patients who require treatment.

Several points:

  1. A strain can be called susceptible (sensitive), yet still have a resistance gene. This can either be a misunderstanding of what sensitivity is (i.e., the strain isn’t sensitive), or a potential problem in that the strain is one step closer to clinical resistance.
  2. We don’t know if Shigella isolates with reduced susceptibility to ciprofloxacin (i.e., the presence of a quinolone resistance gene and an MIC of 0.12–1 μg/mL) will respond differently than highly susceptible Shigella isolates (MIC =< 0.1 μg/mL). But in Salmonella, a relative of Shigella/E. coli this reduced susceptibility did lead to treatment failure (the patient was still sick after treatment). It’s worth noting that EUCAST, which determines breakpoints used in Europe, doesn’t bother to distinguish between E. coli/Shigella and Salmonella; they use the same breakpoints.
  3. Shigella that are resistant to ciprofloxacin are often resistant to other first-line antibiotics.

The CDC recommends that when confronted with Shigella infections, doctors should “not routinely prescribe antibiotic therapy for Shigella infection. Instead, reserve antibiotic therapy for patients for whom it is clinically indicated or when public health officials advise treatment in an outbreak setting.”

The CDC also advises that “[w]hen antibiotic treatment is indicated, tailor antibiotic choice to antimicrobial susceptibility results as soon as possible with special attention given to the MIC for fluoroquinolone antibiotics.”

You can read the full CDC report here.

By the way, maybe we should reconsider Il Trumpe’s proposal to cut CDC funding by twelve percent? Just saying.

*The use of grams/liter, “g/L”, is becoming more common place, as many ‘smart’ word processors and the like will autocorrect the mu symbol to “u.” Progress, or something.

**Oddly, though, it’s easier to get breakpoints changed for something not on patent.

***For the biologists, Shigella is both polyphyletic and paraphyletic. Because it’s an asshole.

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