Restriction of quinolones: A step-by-step guide for Hospitals and Nursing Homes

Have you thought of restriction of Quinolones at your workplace?

I was able to persuade my physician colleagues by sound reasoning and some resolve.

The reasoning I used is outlined below with articles and synopses-these can be adapted to your needs into slides, papers, emails and proposals for committees like pharmacy and therapeutics or medical administration.

For those that like bullets:

RESISTANCE: Organisms are becoming resistant to quinolones
COLLATERAL DAMAGE: Quinolones seem to enhance development and propogation of resistance, and harm the biome
TOXICITY: Quinolones seem to harm patients in other subtle ways
ANECDOTES

RISING RESISTANCE

Over the past several years both nationally throughout the US, and likely locally within your region there have been emerging multi-drug resistant organisms (MDROs). This include many organisms showing resistance not only to quinolones but with emergence of carbapenemase producing pseudomonal isolates, Gram negatives with Extended Spectrum beta-lactamases (ESBLs) and pan-resistant Acinetobacter.

Quinolones are mentioned in some guidelines as possible choices for empiric treatment of MSSA and Pseudomonas; however, our regional and national antibiograms dictate against use in such cases. Current clinical guidelines recently released by Infectious Disease Society/American Thoracic Society for Hospital and Ventilator associated pneumonia strongly recommend using local antibiograms for choosing empiric antibiotics for management of Hospital and ventilator associated pneumonia:

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): e61-e111. http://cid.oxfordjournals.org/content/63/5/e61.long

COLLATERAL DAMAGE

Recent literature warns of Collateral Damage effects of quinolones: ‘Collateral damage is a term used to refer to ecological adverse effects of antibiotic therapy; namely, the selection of druresistant organisms and the unwanted development of colonization or infection with multidrug-resistant organisms-

Quinolone use has been linked to infection with methicillin-resistant staphylococcus aureus and with increasing quinolone resistance in gram-negative bacilli, such as Pseudomonas aeruginosa.”

Paterson DL. “Collateral Damage” from Cephalosporin or Quinolone Antibiotic Therapy. Clin Infect Dis. (2004) 38 (Supplement 4): S341-S345. http://cid.oxfordjournals.org/content/38/Supplement_4/S341.full.pdf+html

Quinolone use apparently leads to systematic trends towards MRSA based on studies done by Weber et al. Weber SG, Gold HS, Hooper DC, Archer AW, Carmeli Y. Fluoroquinolones and the Risk for Methicillin-resistant Staphylococcus aureus in Hospitalized Patients. Emerging Infectious Diseases. 2003; 9(11):1415-1422. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035560/

Another study by Zervos M et al “observed that susceptibility decreases occur not only in difficult-to-treat organisms, such as P. aeruginosa, but also in more common organisms, such as E. coli. These findings have important implications for the treatment of bacterial infections. If the use of fluoroquinolones continues to increase, both the prevalence and degree of reduced susceptibility to these agents can be expected to increase as well.

(Zervos M, Hershberger E, Nicola DP, et al. Relationship between fluoroquinolone use and changes in susceptibility to Fluoroquinolones of selected pathogens in 10 United States teaching hospitals, 1991–2000. Clin Infect Dis 2003;37:1643-8. http://cid.oxfordjournals.org/content/37/12/1643.long)

"Rapid emergence of quinolone resistance may occur over several weeks and during long-term therapy in individual patients with Staphylococcus aureus."

Blumberg HM et al. Rapid Development of Ciprofloxacin Resistance in Methicillin-Susceptible and -Resistant Staphylococcus aureus. J Infect Dis. (1991) 163 (6): 1279-1285. http://jid.oxfordjournals.org/content/163/6/1279.abstract

TOXICITY

The FDA in 2016 issued yet another warning, strengthening the Black Box language:

FDA Black Box Warning Change:

“While these drugs are effective in treating serious bacterial infections, an FDA safety review found that both oral and injectable fluoroquinolones are associated with disabling side effects involving tendons, muscles, joints, nerves and the central nervous system. These side effects can occur hours to weeks after exposure to fluoroquinolones and may potentially be permanent.”

These side effects can affect any and all demographics, but the most susceptible individuals are often the elderly.

The aging population also has a higher propensity to suffer side effects such as confusion and change in mental status and higher risk of Clostridium difficile.

RESTRICTING QUINOLONES MAY REVERSE THESE EFFECTS

Quinolone restriction has been shown to restore sensitivities and reverse the trend towards the emergence of ESBL producing organisms and MRSA. There are many studies, which support such systematic restriction of quinolones both as an independent pharmacy intervention or and as part of an antibiotic stewardship program. Restriction under an Antibiotic Stewardship program has been shown to result in reemergence of sensitivity to these quinolones as well as other antibiotics after a period of time; thereby, preserving and making these agents more useful in the future.

Optimization of the formulary antibiotics may not only preserve coverage, but protect patient population for years to come.

“…reducing quinolone consumption can lead to an immediate increase in the susceptibility of E. coli urine isolates to quinolones.” Gottesman BS et al. Impact of quinolone restriction on resistance patterns of Escherichia coli isolated from urine by culture in a community setting. Clin Infect Dis. 2009 Sep 15;49(6):869-75. http://cid.oxfordjournals.org/content/49/6/869.full.pdf+html

Per Lewis et al. restriction of quinolone use was correlated to decreased quinolone and carbapenem resistance in Pseudomonas aeruginosa isolates within their critical care areas. Lewis GJ1, Fang X, Gooch M, Cook PP. Decreased resistance of Pseudomonas aeruginosa with restriction of ciprofloxacin in a large teaching hospital's intensive care and intermediate care units. Infect Control Hosp Epidemiol. 2012 Apr;33(4):368-73. https://www.ncbi.nlm.nih.gov/pubmed/22418632

Presentado et al reported that "antibiotic restriction of ciprofloxacin reduces Acinetobacter spp. Colonization and improved the susceptibility profile of P. aeruginosa by means of a simple protocol that uses low cost antibiotics such as ampicillin sulbactam that are widely available in intensive care units.” Presentado JCM, et al. Ceftriaxone and ciprofloxacin restriction in an intensive care unit: fewer incidences of Acinetobacter spp. and improved susceptibility of Pseudomonas aeruginosa. Rev Panam Salud Publica. 2011 Dec;30(6):603-9. http://www.scielosp.org/pdf/rpsp/v30n6/a18v30n6.pdf

HOW TO SUCCEED

An example of a successful Quinolone restriction policy at my hospital:

The Antimicrobial Stewardship Team under ID service direction initially targeted the formulary quinolones as an opportunity after noting the overuse system-wide.
With Antibiogram susceptibilities dwindling for multiple organisms, education was done by continuing education programs, departmental meetings, and eventually individually one-to-one detailing.
SPECIFIC ACTION BY PHARMACISTS:
Every order set containing a Quinolone antibiotic was reviewed.
The quinolone option was removed where possible, and downgraded in all other order sets to facilitate utilization only in situations when no alternatives were available.
The program initially found that within the Emergency Department (during Quarter 2 of 2015), the highest utilization showed that 1 out of every 12 patients received at least one dose of intravenous levofloxacin.
Publication of the Antibiogram in FY2014: our overall use of Levofloxacin was at 2108 doses per month. This information was widely distributed.
Since then, with the above practices in place, and the addition of daily monitoring and feedback, doses were reduced to 556 doses per month by August 2016.
USAGE AUDITSwere possible with reduced number of doses-EPIC reports pulled all instances of daily use of quinolones, the results were shocking--even with all of above teaching, misuse was the rule:
Drug bug mismatches-quinolones were continued despite culture showing resistance which was widspread
Redundant use for example with azithromycin for atypical coverage
Misguided and ill educated attempts with double coverage of gram negatives and random gram positives
Empiric treatment in case of documented intolerances to Penicillin like stomach upset.
Long term treatment for prophylaxis in the immune competent
Long term use in MRSA osteomyelitis
Treatment of asymptomatic bacteriuria and imagined lung infiltrates
Treatment of rashes
Surgical prophylaxis for sterile procedures like punch biopsies and endoscopies without biopsies.
'Homeopathic doses' 100mg -250mg in the young and healthy

Over the past few years, with the amount of such Quinolone overuse –A steady trend towards more resistant isolates observed

ACTION BY ID/ME

I started discouraging the use initially as an ID consultant and Clinical Educator 2013-2014 later as Antibiotic Stewardship Administrator with 2 pharmacists

My Antimicrobial Stewardship Team finally recommended that Quinolones be moved to restricted status such that these antibiotics can be monitored closely and utilized when appropriate.

The initiative went into effect system wide in November 2016

Per networking in ID week 2016; tthe practice of quinolone restriction is rapidly becoming a standard in other large hospitals and teaching centers.

UPDATE 2017

Clinical Success?

Levofloxacin (Levaquin™)Utilization:

Initially a very limited form of Quinolone restriction has been implemented at my hospital through my education efforts of the Stewardship program.

FQ overuse was a specific target for urgent intervention by our Stewardship Program since its inception anf Full Function Feb 2016 onwards-The usage was evaluated at the point of the release of the last antibiogram, whereas as many as 1 in 5 inpatients were receiving Levofloxacin.

As a result Over FY 2015 there was dramatic reduction in quinolone usage with active ongoing educational efforts regarding the correct use of drugs. Although providers have been educated prior, the updated antibiogram further strengthened the ASP position on reducing unnecessary empiric use of Levofloxacin.

Over the next two years a steady trend towards less resistant isolates is noted as quinolone use has declined.

Reduction in Levofloxacin usage since the Antibiogram (greater than 52%) has paralleled the decline in clostridium difficile rates for the same period.

A key component of Antibiotic Stewardship is a daily audit of quinolone use-the numbers have been low in recent months to evaluate drug use specific to individual patient and even one dose of drug. Interestingly this review leads to frequent discontinuation of this drug class because of misuse and unrecognized side effects.

Adverse effects identified on a daily basis include:

Coagulation abnormalities
Dysrhythmias
Exacerbation of delirium often leading to re-admission
Clostridium difficile infection*

We emphasized that-Even one dose of Levofloxacin in a patient with a propensity to have clostridium difficile, may trigger an active infection.

it helped that FDA has issued a new black box warning on quinolones based on a safety review which found that both oral and injectable Fluoroquinolones are associated with disabling side effects involving tendons, muscles, joints, nerves and the central nervous system. These side effects can occur hours to weeks after exposure to Fluoroquinolones and may potentially be permanent.

In Late 2016 Medical Letter/JAMA published articles with alternatives to quinolones in most clinical syndromes where they have been used per outdated guidelines.

Alternatives to FluoroquinolonesJAMA. 2016;316(13):1404-1405. doi:10.1001/jama.2016.8383

The effort needs to continue....

Based on above evidence and local daily review of bug–drug mismatches and observed adverse events an Antibiotic Stewardship Program continues to push for discontinuation of the empiric use of quinolones and advises the restriction of these drugs to Infectious Disease and Pulmonary/Critical Care subspecialists and other providers in consultation with Antibiotic Stewardship pharmacists.