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A retrospective analysis: Do bacterial culture and sensitivity data supportempiric use of piperacillin-tazobactam and antipseudomonal fluoroquinolones in hospitalized patients?

The mortality benefit of early recognition of infection with empiric initiation of antibiotics is well documented. (1) Pseudomonas aeruginosa has been a particularly problematic bacterial infection whose antibiotic resistance is increasing at an alarming rate. (2) Inappropriate empiric antibiotic coverage of Pseudomonal blood stream infections has shown mortality rates as high as 43.4%. (3) This high mortality rate, in addition to prior studies showing an increased mortality rate with empiric monotherapy, (4-6) has led to empiric combination antimicrobial coverage becoming the clinical standard for suspected infection with gram-negative bacteria. "Double coverage" for Pseudomonas infection usually includes the addition of an antipseudomonal fluoroquinolone or aminoglycoside to an antipseudomonal beta-lactam.

At our institution as well as other military and civilian medical centers, it is common to use the antipseudomonal beta lactam piperacillin-tazobactam in combination with a fluoroquinolone for empiric gram-negative coverage. Fluoroquinolones are commonly selected for double coverage due to the ease of dosing, decreased monitoring, and decreased toxicity (compared to aminoglycoside agents). Our institution provides an annual cumulative antimicrobial susceptibility report to estimate percentages of resistance of a particular organism to an antibiotic. Based on the William Beaumont Army Medical Center (WBAMC) 2015 antimicrobial susceptibility report, * 88% of Pseudomonas isolates were susceptible to piperacillin-tazobactam, 77% of isolates were susceptible to levofloxacin, and 79% of isolates were susceptible to ciprofloxacin. In order for our current strategy of double coverage to be effective, (ideally) the 12% of Pseudomonas isolates not susceptible to piperacillin-tazobactam would be susceptible to levofloxacin or ciprofloxacin.

We conducted a 6-month retrospective record review to determine whether there is bacterial culture data to support our initial empiric gram-negative double coverage with extended antipseudomonal beta-lactam (piperacillin-tazobactam) and fluoroquinolones (ciprofloxacin and levofloxacin) in our military hospital patient population.

Based on our institution's antiobiogram, a previous study showing no benefit in Pseudomonas coverage with use of an antipseudomonal fluoroquinolone and antipseudomonal beta-lactam, (7) along with our knowledge of mechanisms of resistance, led us to hypothesize that providing "double coverage" for empiric Pseudomonas coverage with floroquinolones in addition to piperacillin-tazobactam would provide no additional coverage.

METHODS

We examined 6-months of culture and sensitivities data of Pseudomonas bacteria from urine, blood, sputum, wound, joint, or body fluid in our hospitalized patient population.

Exclusion criteria for our study were cultures from patients under the age of 18; concomitant gram-positive organisms; and gram-negative organisms other than Pseudomonas, Proteus, Klebsiella, and E coli. Isolates from same anatomical site or person were included as separate data points, only if these isolates are phenotypically different.

The terms "susceptible" and "resistant" are determined by standard Clinical and Laboratory Standards Institute (http://clsi.org/) guidelines, and criteria used by the WBAMC lab. Culture and sensitivities are reported as "susceptible," "intermediate," or "resistant." Susceptible is defined as having been found as susceptible based on reported culture data. Given that intermediate sensitivities indicate the level of antibiotic needed to achieve the maximum inhibitory concentration approaches or exceeds the level of antibiotic that can ordinarily be achieved, (8) "resistant" included sensitivities reported as intermediate or resistant.

Over a 6-month period, 64 Pseudomonas isolates that were sensitive or resistant to levofloxacin, ciprofloxacin, and piperacillin-tazobactam were identified. The cultures that were identified as resistant to Piperacillin-tazobactam were then further evaluated for susceptibility to levofloxacin or ciprofloxacin.

RESULTS

A total of 64 isolates of Pseudomonas were identified during a 6-month period. Of these, 32 were from urine, 11 from sputum, 12 from wound cultures, 3 from blood, and 6 from body fluid cultures. Of the cultures, 57 isolates were of Pseudomonas auergi nosa and 7 isolates of Pseudomonas puti da.

Of the 64 isolates of Pseudomonas identified, 90.6% (58/64) of isolates were susceptible to piperacillin-tazobactam, 66.1% (42/64) to levofloxacin, and 67.2% (47/64) susceptible to ciprofloxacin. The results are graphically represented in the Figure. Four of the isolates were multidrug resistant organisms resistant to all fluoroquinolones and beta-lactams. Of the 6 isolates resistant to piperacillin-tazobactam, none of those isolates were susceptible to fluoroquinolones.

COMMENT

Our initial hypothesis questioning the efficacy of empiric double coverage of suspected pseudomonal infections was confirmed by our 6-month retrospective review. None of the 64 isolates cultured were resistant to piperacillin-tazobactam but sensitive to fluoroquinolones. This suggests there is no additional coverage or benefit conferred with empiric Pseudomonas double coverage with an antipseudomonal beta-lactam and an antipseudomonal fluoroquinolone in our hospital population. Fluoroquinolone use has associated with adverse effects including QT prolongation, photoxicity, tendon rupture, gastrointestinal discomfort, headache, confusion, and delirium. (9) These side effects, coupled with the fact that no antibacterial coverage improvement is achieved, would indicate that double coverage for suspected Pseudomonal infection within our hospital patient population would produce more harm than benefit.

The resistance of Pseudomonas isolates to fluoroquinolones when concomitantly resistant to piperacillin-tazobactam is unsurprising when examining the mechanism by which resistance of the bacteria is developed. Fluoroquinolone resistance occurs with mutations to the AmpR gene that negatively regulate the Mex-EF-OprN efflux which can pump out fluoroquinolones, or changes in the quinolone target of type II topoisomerase or type IV topoisomerase. Beta-lactam resistance is also mediated in part by the AmpR gene by positively regulating AmpC production of beta-lactamase. AmpR is a major part of Pseudomonas genome, and is one of the few genes that may confer resistance to multiple antibiotic classes, including beta-lactams and fluoroquinolones. (10)

Although this study meets the 30-isolate standard set by the Clinical and Laboratory Standards Institute M39-A2 recommendations for cumulative antiobiogram preparation, (11) the study could be improved by an increased sample size, either through duration of retrospective review or enrollment of a larger population pool from which to extract Pseudomonas isolates. Also, future studies may seek to identify which antibiotics can confer the greatest additional antibacterial coverage in the setting of resistance to antibiotics used for empiric therapy, thereby creating a double coverage regimen that would provide benefit to the patient.

This study brings to the forefront inappropriate antibiotic use for a common hospital infection. Previously an afterthought, this empiric double coverage can lead to the emergence of new multidrug resistant antibiotics, (12) as well as exposing a patient to a medication with significant side effects with no concurrent medical advantage in therapy. Based on our institution's culture data, we advocate that each institution reevaluate the empiric double coverage of gram-negative bacteria with the addition of an antipseudomonal fluoroquinolone or amino-glycoside to an antipseudomonal beta-lactam based on their specific patient subset.

REFERENCES

(1.) Dellinger RR Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;410:580-637.

(2.) Zilberberg MD, Shorr AF. Prevalence of multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae among sped mens from hospitalized patients with pneumonia and bloodstream infections in the United States from 2000 to 2009. J Hosp Med 2013;8(10):559-563.

(3.) Kang C, Kim S, Park W, et al. Pseudomonas aeruginosa bacteremia: risk factors for mortality and influence of delayed receipt of effective antimicrobial therapy on clinical outcome. Clin Infect Dis 2003;37:745-751.

(4.) Garnacho-Montero J, Ortiz-Leyba C, Herrera-Melero I, et al. Mortality and morbidity attributable to inadequate empirical antimicrobial therapy in patients admitted to the ICU with sepsis: a matched cohort study. J Antirricrob Chemother 2008;61(2):436-441.

(5.) Kumar A, Ellis R Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009;136(5):1237-1248.

(6.) Lueangarun S, Leelarasamee A. I mpact of inappropriate empiric antimicrobial therapy on mortality of septic patients with bacteremia: a retrospective study. Interdiscip Perspect Infect Dis. 2012:756205. Available at: http://www.ncbi.nlm.nih.gov/pmc/ar ticles/PMC3419419/. Accessed September 15,2016.

(7.) Mizuta M, Linkin DR, Nachamkin I, et al. Identification of optimal combinations for empirical dual antimicrobial therapy of Pseudomonas ae-ruginosa infection: potential role of a combination antibiogram. Infect Control Hosp Epidemiol 2006;27:413-415.

(8.) Jorgensen JH, Ferraro MJ. Antimicrobial susceptibility testing: a review of general principles and contemporary practices. Clin Infect Dis 2009;49(11):1749-1755. Avalable at: http://cid.ox fordjournals.org/content/49/11/1749. Accessed September 15,2016.

(9.) Lipsky BA, Baker CA. Fluoroquinolone toxicity profiles: a review focusing on newer agents. Clin Infect Dis 1999;28(2):352-364. Available at: http:// cid.oxf ordj ou mal s.org/content/28/2/352. Accessed September 15,2016.

(10.) Balasubramanian D, Schneper L, Merighi M, et al. 2012. The Regulatory Repertoire of Pseudomonas aeruginosa AmpC Beta-Lactamase Regulator AmpR Includes Virulence Genes. PLoS One 7(3):e34067. Avalable at: http://journals.plos.org/ plosone/article?id=10.1371/journal.pone.0034067. Accessed September 15,2016.

(11.) Clinical and Laboratory Standards Institute (CLSI). M39-A2: Analysis and Presentation of Cumulative Antimicrobial Susceptibility Test Data. 2nd ed. Wayne, FA: CLSI;2006.

(12.) Hildreth CJ, Burke AE, Glass RM. Inappropriate Use of Antibiotics. JAMA. 2009;302(7):816. Avalable at: http://jama.jamanetwork.com/article. aspx?articleid=184426. Accessed September 15, 2016.

* WBAMC Cumulative Antimicrobial Susceptibility Report: Uan2015-31Dec2015. Internal medical facility document not readily accesible by the general public.

CPT Pul kit Saxena, MC, USA

CPT Ryan V. Burkhart, MC, USA

MAJ Craig R. Ainsworth, MC, USA

AUTHORS

CPT Saxena is an Internal Medicine Resident Post-Graduate Year 3 a William Beaumont Army Medica Center, El Paso, Texas.

CPT Burkhart is a First Year Cardiology Fellow a the San Antonio Military Medical Center, San Antonio, Texas.

MAJ Ainsworth is the Medical Director, Burn Intensive Care Unit, US Army Institute of Surgical Research, Joint Base San Antonio-Fort Sam Houston, Texas.
Pseudomonas sensitivity.

Cipro   Zosyn   Levaquin
67.2%   90.6%   66.1%

Note: Cipro is ciprofloxacin: Zosyn is piperacillin-tazobactam:
Levaquin is levofloxacin.
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Author:Saxena, Pulkit; Burkhart, Ryan V.; Ainsworth, Craig R.
Publication:U.S. Army Medical Department Journal
Article Type:Report
Date:Jul 1, 2017
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