Gram-negatives;

Why do we often prescribe ceftriaxone in preference to fluoroquinolones for prophylaxis of infections in patients with cirrhosis and upper GI bleed?

FA Manian MD, MPH, , , , , , , , , , , Leave a comment

Preference of ceftriaxone over fluoroquinolones (FQs) for prophylaxis of infection in patients with cirrhosis and upper GI bleed (UGIB) can often be traced back to a small 2006 Spanish randomized controlled trial (RCT)1 which found a significantly lower rate of proved or possible bacterial infection and lower rate of fermentative Gram-negative bacilli infection in the ceftriaxone group (vs norfloxacin) over a 10-day period (11% vs 33% and 0% vs 11%, respectively). There was no significant difference in the incidence of proved bacterial infection (spontaneous bacterial peritonitis or bacteremia, P=0.07) or 10-day mortality between the 2 groups.   

It’s worth emphasizing that the primary impetus for this study was evaluation of the efficacy of ceftriaxone in patients with cirrhosis and UGIB in a setting where FQ Gram-negative bacilli was thought to be highly prevalent. Parenthetically, a similar RCT performed where the prevalence of FQ resistance was considered low failed to find a significant difference in breakthrough bacterial infection, rebleeding or mortality when ceftriaxone was compared to IV ciprofloxacin.2

Another caveat of the 2006 study was that an IV antibiotic (ceftriaxone) was compared to a oral antibiotic (norfloxacin) which, in the setting of active UGIB, may be problematic.

Despite these limitations, its favorable safety profile compared to FQs coupled with its ease of administration has often made ceftriaxone the drug of choice for prophylaxis of infections in patients with cirrhosis and UGIB. The 2016 Practice Guidance by the American Association for the Study of Liver Diseases considers ceftriaxone as the first choice in patients with advanced cirrhosis, on FQ prophylaxis, and in hospital settings with high prevalence of FQ resistant bacterial infection.3

Bonus Pearl: Did you know that the prevalence of FQ resistant in Enterobacteriaceae may be as high as 30% in certain regions of U.S. and >50% in certain regions of the world? 4

Also see related 2 P4P pearls (1, 2) on the association of UGIB bleed with infections in patients with cirrhosis.

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References

  1. Fernandez J, Del Arbol LR, Gomez C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterol 2006;131:1049-1056. https://pubmed.ncbi.nlm.nih.gov/17030175/
  2. Pittayanon R, Reknimir R, Kullavanijaya P, et al. Intravenous ciprofloxacin vs ceftriaxone for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding:A randomized controlled trial. Thai J Gastroenterol 2016;17:24-30. http://www.thaigastro.com/books.php?act=content&content_id=476&book_id=61
  3. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal hypertensive bleeding in cirrhosis:risk stratification, diagnosis and management: 2016 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology 2017;65:310-335. https://pubmed.ncbi.nlm.nih.gov/27786365/
  4. Spellberg B, Doi Y. The rise of fluoroquinolone-resistant Escherichia coli in the community:scarier than we thought. J Infect Dis 2015;212:1853-1855. https://pubmed.ncbi.nlm.nih.gov/25969562/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why do we often prescribe ceftriaxone in preference to fluoroquinolones for prophylaxis of infections in patients with cirrhosis and upper GI bleed?

Why are antibiotics routinely administered in patients with cirrhosis and upper gastrointestinal (GI) bleed?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , 1 Comment

Antibiotic prophylaxis in patients with cirrhosis and upper gastrointestinal bleed (UGIB) reduce bacterial infections, all-cause mortality, bacterial infection, mortality, rebleeding events and hospitalization.1

A 2011 Cochrane meta-analysis involving 12 trials comparing antibiotic prophylaxis to no prophylaxis or placebo found reduction in bacterial infection (RR 0.35, 95% C.I., 0.26-0.47) and overall mortality (RR 0.79, 95% C.I. 0.63-0.98). It also found a significant reduction in rebleeding and days of hospitalization, based on more limited data. Trials in this meta-analysis involved a variety of antibiotics, including norfloxacin, ciprofloxacin, cefazolin, cefotaxime, ceftriaxone and ampicillin-sulbactam. 1

So why is ceftriaxone the often-favored bacterial prophylaxis in UGIB? First, infections in cirrhotic patients often originate from bacterial translocation through the GI tract with aerobic gram-negative GI flora expected to be susceptible to ceftriaxone.2 Second, the emerging quinolone resistance among aerobic Gram-negative bacteria 2 and frequent use of ciprofloxacin for prophylaxis against spontaneous bacterial peritonitis have made use of ceftriaxone in this setting more desirable than quinolones.

Of note, a 2006 study involving patients with advanced cirrhosis (Child Pugh B or C) and GI hemorrhage receiving either norfloxacin or ceftriaxone for 7 days found a significantly lower risk of suspected or proven infections (11% vs 33%) and bacteremia or spontaneous bacterial peritonitis (2% vs 12%) in the ceftriaxone group; there was no difference in hospital mortality. 3 Although the overall prevalence of quinolone-resistant gram-negatives was unknown, 6 of 7 gram-negative bacilli isolated in the norfloxacin group were quinolone resistant.

Bonus Pearl: Did you know that 30-40% of cirrhotic patients presenting with UGIB will develop a bacterial infection within a week of their admission? 1

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References

  1. Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila F, et al. Meta-analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding-an updated Cochrane review. Aliment Pharmacol Ther 2011;34:509-518. https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2036.2011.04746.x
  2. Mallet M, Rudler M, Thabut D. Variceal bleeding in cirrhotic patients. Gastroenterology Reports 2017;5:185-192. https://academic.oup.com/gastro/article/5/3/185/4002779
  3. Fernandez J, del Arbo LR, Gomez C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 2006;131:1049-1056. https://www.sciencedirect.com/science/article/abs/pii/S0016508506015356

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why are antibiotics routinely administered in patients with cirrhosis and upper gastrointestinal (GI) bleed?

Is cefepime an acceptable alternative to carbapenems in the treatment of cefepime susceptible extended spectrum beta-lactamase (ESBL) Gram-negatives?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , Leave a comment

Irrespective of in-vitro susceptibility results, cefepime should be avoided in the treatment of serious ESBL infections associated with bacteremia, pneumonia, intraabdominal infection, endocarditis, bone/joint infection or whenever a high bacterial inoculum is suspected. Cefepime should be considered only in non-severe infections (eg, uncomplicated urinary tract infection) when the minimum inhibitory concentration (MIC) is 2 mg/L or less (1).

 

To date, clinical studies comparing cefepime vs carbapenem have been small and/or retrospective, often with conflicting results (1). A 2016 propensity score-matched study of patients with ESBL bacteremia receiving cefepime therapy followed by carbapenem therapy vs carbapenem for the entire treatment duration found higher 14 day mortality in the cefepime group (41% vs 20% in the carbapenem group) (2).  Of note, 2 of the patients receiving cefepime who died were infected with an ESBL organism with MIC of 1 mcg/mL. 

 

Another study found cefepime to be inferior to carbapenem therapy in ESBL bacteremic patients with better outcome when cefepime MIC was 1 ug/m or less (3).

 

Two studies involving patients with ESBL UTIs found no significant difference between cefepime and carbapenem in clinical and microbiological response or in-hospital mortality, while another UTI study with a high rate of septic shock (33%) found that cefepime was inferior to carbapenem in clinical and microbiological response (2).

 

The diminished efficacy of cefepime for the treatment of ESBL infections may be related to its “inoculum effect” ie, marked increase in MIC with increased inoculum size compared to that used in standard laboratory susceptibility testing (1,4).   

 

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References

  1. Karaiskos I, Giamarellou H. Carbapenem-sparing strategies for ESBL producers: when and how. Antibiotics 2020;9,61. https://pubmed.ncbi.nlm.nih.gov/32033322/
  2. Wang R, Cosgrove S, Tschudin-Sutter S, et al. Cefepime therapy for cefepime-susceptible extended-spectrum beta-lactamase-producing Enerobacteriaceae bacteremia. Open Forum Infect Dis 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942761/
  3. Lee NY, Lee CC, Huang WH, et al. Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamase-producing Enterobacteriaceae: MIC matters. Clin Infect Dis 203;56:488-95. https://academic.oup.com/cid/article/56/4/488/351224
  4. Smith KP, Kirby JE. The inoculum effect in the era of multidrug resistance:minor differences in inoculum have dramatic effect on MIC determination. Antimicrob Agents Chemother 2018;62:e00433-18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105823/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Is cefepime an acceptable alternative to carbapenems in the treatment of cefepime susceptible extended spectrum beta-lactamase (ESBL) Gram-negatives?

My patient with pyelonephritis has positive blood cultures for E. coli? Should I order repeat blood cultures to make sure the bacteremia is clearing?

FA Manian MD, MPH, , , , , , , , , Leave a comment

Although a common practice, follow-up blood cultures (FUBCs) may not be necessary in otherwise clinically stable or improving patients with aerobic gram-negative bacteremia. This is probably due to the often-transient nature of gram-negative bloodstream infections  and less propensity of these organisms to cause intravascular infections (eg, endocarditis) compared to gram-positives. 1

A 2017 study addressing the value of FUBCs in gram-negative bacteremia found that repeat positive blood cultures were uncommon with positive results not associated with mortality or higher ICU admissions. 1 Specifically, 17 FUBCs had to be drawn to yield 1 positive result.  Although the numbers of positive FUBCs were too low for in-depth analysis, it was concluded that FUBCs added little value in the management of gram-negative bacteremias.

In contrast, FUBCs are recommended in the following situations: 1-3

  • Staphylocccus aureus bacteremia given the propensity of this organism to cause intravascular (eg, endocarditis) and metastatic infections.
  • Presumed or documented endocarditis or intravascular device infections (eg, intravenous catheters and pacemakers) to document timely clearance of bacteremia
  • Infections involving organisms that may be difficult to clear such as fungemia or multi-drug resistant pathogens.

As with many things in medicine, clinical context is important before ordering tests and blood cultures are no different. The urge to order FUBCs should also be balanced with the possibility of having to deal with  contaminants. 

References

  1. Canzoneri CN, Akhavan BJ, Tosur Z et al. Follow-up blood cultures in gram-negative bacteremia: Are they needed? Clin Infect Dis 2017;65:1776-9. https://www.ncbi.nlm.nih.gov/pubmed/29020307
  2. Tabriz MS, Riederer K, Baran J, et al. Repeating blood cultures during hospital stay: Practice pattern at a teaching hospital and a proposal for guidelines. Clin Microbiol Infect 2004;10:624-27. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1469-0691.2004.00893.x
  3. Mylotte JM, Tayara A. Blood cultures: Clinical aspects and controversies. Eur J Clin Microbiol Infect Dis 200;19:157-63. https://www.ncbi.nlm.nih.gov/pubmed/10795587

 

 

My patient with pyelonephritis has positive blood cultures for E. coli? Should I order repeat blood cultures to make sure the bacteremia is clearing?

When should I pay attention to the minimum inhibitory concentration (MIC) of an antibiotic despite the lab reporting it to be in the “Susceptible” range?

FA Manian MD, MPH, , , , , , , , 1 Comment

In most situations, you will most likely choose an antibiotic based on the laboratory reporting of “Susceptible” (vs “Resistant”), not the actual MIC value of the drug and that’s fine.  

However, there may be a few instances when you may need to pay more attention to the actual MICs. Many experts recommend caution when “high” MICs within a susceptible range are observed in the following situations:   

  1. Vancomycin MIC >1 ug/ml in Staphylococcal aureus (methicillin-sensitive or –resistant) infections because of its possible association with clinical failure and, at times, increased mortality1,2.
  2. Ciprofloxacin or levofloxacin MIC>0.25 ug/ml in bacteremia caused by Gram-negative bacilli (including Enterobacteriacae as well as Pseudomonas aeruginosa) because of its association with an adverse outcome (eg, longer average hospital stay post-culture and duration of infection) but not necessarily mortality3-5.
  3. Levofloxacin MIC ≥ 1.0 ug/ml in Streptococcus pneumoniae infections, because of its association with an adverse clinical outcome based on drug pharmacodynamics and anecdotal reports of treatment failure6,7.

 

References

  1. Jacob JT, DiazGranados CA. High vancomycin minimum inhibitory concentration and clinical outomces in adults with methicillin-resistant Staphylococcus aureus infections: a meta-analysis. Int J Infect Dis 2013;17:e93-e100.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3780595/
  2. Kalil AC, Van Schooneveld TC, Fey PD, et al. Association between vancomycin minimum inhibitory concentration and mortality among patients with Staphylococcus aureus bloodstream infections: A systematic review and meta-analysis. JAMA 2014;312:1552-1564. https://www.ncbi.nlm.nih.gov/pubmed/25321910
  3. DeFife R, Scheetz MH, Feinglass J, et al. Effect of differences in MIC values on clinical outcomes in patients with bloodstream infections caused by Gram-negative organisms treated with levofloxacin. Antimicrob Agents Chemother 2009;53:1074-79. http://aac.asm.org/content/53/3/1074.full
  4. Falagas ME, Tansarli GS, Rafailidis PI, et al. Impact of antibiotic MIC on infection outcome in patients with susceptible Gram-negative bacteria a systematic review and meta-analysis. Antimicrob Agents Chemother 2012;56:4214-22. https://www.ncbi.nlm.nih.gov/pubmed/22615292
  5. Zelenitsky SA, Harding GKM, Sun S, et al. Treatment and outcome of Pseudomonas aeruginosa bacteremia: an antibiotic pharmacodynamics analysis. J Antimicrob Chemother 2003;52:668-674. https://www.ncbi.nlm.nih.gov/pubmed/12951354
  6. Davidson R, Cavalcanti R, Brunton JL, et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;346:. 2002;346:747-50. https://www.ncbi.nlm.nih.gov/pubmed/11882730
  7. De Cueto M, Rodriguez JM, Soriano MJ, et al. Fatal levofloxacin failure in treatment of a bacteremic patient infected with Streptococcus pneumoniae with a preexisting parC mutation. J Clin Microbiol 2008;46:1558-1560.  http://jcm.asm.org/content/46/4/1558.full

Contributed in part by Nick Van Hise, Pharm.D., BCPS, Infectious Diseases Clinical Pharmacist, Edward-Elmhurst Hospitals, Naperville, Illinois.

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When should I pay attention to the minimum inhibitory concentration (MIC) of an antibiotic despite the lab reporting it to be in the “Susceptible” range?