My diabetic patient complains of new onset tingling, burning, and numbness in her feet and ankles while taking levofloxacin for sinusitis. Could it be the antibiotic?

Although there are numerous culprits in peripheral neuropathy (PN), fluoroquinolones (FQs) are increasing reported as a potential cause, affecting about 1% of patients. 1

Besides many case reports, couple of large epidemiologic studies support the association between PN and FQs. A case-control pharmacoepidemiologic study of a cohort of men aged 45-80 years without diabetes found that current users of FQs were nearly twice as likely to develop PN (RR 1.83, 95% C.I. 1.49-2.27), with the highest risk found among current new users of FQ.2 The risk appeared similar among the 3 most commonly used FQs (levofloxacin, ciprofloxacin, moxifloxacin).

Another epidemiologic study with “pharmacovigilance analysis” based on the FDA Adverse Event Reporting System found significant disproportionality of PN for FQs compared to many other antibiotics. 3 The median onset of PN after exposure to FQ was 4 days (range 0-91). Contrary to initial reports of the mild and reversible course of FQ-associated PN, 1 study reported that 58% of patients had symptoms lasting greater than 1 year.4`

These findings prompted the FDA to update its boxed warnings for FQs in 2016 to stress the potential rapidity of onset and permanence of FQ-associated PN while strongly discouraging their use in conditions for which alternative therapy exists, such as in acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis and uncomplicated UTI.5

So while our patient may have other causes for her neurologic complaints, FQ exposure should also be in the differential!

References

  1. Dudewich M, Danesh A, Onyima C, et al. Intractable acute pain related to fluoroquinolone-induced peripheral neuropathy. J Pain Pall Care Pharmacotherapy 2017;31:144-7. https://www.ncbi.nlm.nih.gov/pubmed/28358229
  2. Etminan M, Brophy JM, Samii A. Oral fluoroquinolone use and risk of peripheral neuropathy: A pharmacoepidemiologic study.Neurology 2014;83:1261-63. https://www.ncbi.nlm.nih.gov/pubmed/25150290
  3. Ali AK. Peripheral neuropathy and Guillain-Barre syndrome risks associated with exposure to systemic fluorquinolones: a pharmacovigilance analysis. Ann Epidemiol 2014; 24:279-85. https://www.ncbi.nlm.nih.gov/pubmed/24472364
  4. Francis JK, Higgins E. Permanent peripheral neuropathy: A case report on a rare but serious debilitating side-effect of fluroquinolone administration. Journal Investigative Medicine High Impact Case Reports 2014; 1-4. DOI:10.1177/2324709614545225. https://www.ncbi.nlm.nih.gov/pubmed/26425618
  5. FDA.https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm.  Accessed December 8, 2017.
My diabetic patient complains of new onset tingling, burning, and numbness in her feet and ankles while taking levofloxacin for sinusitis. Could it be the antibiotic?

My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

Assuming no recent changes in the dose of warfarin, one potential culprit may be her recent antibiotic exposure. Of the long list of antibiotics associated with elevated INR, quinolones (e.g. ciprofloxacin, levofloxacin), trimethoprim-sulfamethoxazole, macrolides (e.g. azithromycin), and azole antifungals (e.g. fluconazole) are generally thought to carry the highest risk of warfarin toxicity, while amoxacillin and cephalexin may be associated with a more modest risk. 1-3

Other drugs such as amiodarone (Did she have atrial fibrillation during her recent hospitalization?), acetaminophen (Has she been receiving at least 2 g/day for several consecutive days?), and increasing dose of levothyroxine (Was she thought to be hypothyroid recently?) should also be considered.3,4

Also remember to ask about herbal supplements (eg, boldo-fenugreek, dong quai, danshen) that may potentiate the effect of warfarin. 3 Of course, poor nutrition in the setting of recent illness might have also played a role.5

As far as the mechanisms for drug interaction with warfarin, some drugs act as cytochrome p450 inhibitors (thus reducing the metabolism of warfarin), while others influence the pharmacodynamics of warfarin by inhibiting the synthesis or increasing the clearance of vitamin K-2 dependent coagulation factors.3

Antibiotics may increase the risk of major bleeding through disruption of intestinal flora that synthesize vitamin K-2 with or without interference with the metabolism of warfarin through cytochrome p450 isozymes inhibition.

Check out a related pearl on P4P: https://pearls4peers.com/2015/06/25/is-there-anyway-to-predict-a-significant-rise-in-inr-from-antibiotic-use-in-patients-who-are-also-on-warfarin  

 

References

  1. Baillargeon J, Holmes HM, Lin Y, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012 February ; 125(2): 183–189. https://www.ncbi.nlm.nih.gov/pubmed/22269622
  2. Juurlink DN. Drug interactions with warfarin: what every physician should know. CMAJ, 2007;177: 369-371. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1942100/pdf/20070814s00018p369.pdf
  3. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-e88S. doi:10.1378/chest.11-2292.  https://www.ncbi.nlm.nih.gov/pubmed/22315269
  4. Hughes GJ, Patel PN, Saxena N. Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy. Pharmacotherapy 2011;31:591-7. https://www.ncbi.nlm.nih.gov/pubmed/21923443
  5. Kumar S, Gupta D, Rau SS. Supratherapeutic international normalized ratio: an indicator of chronic malnutrition due to severely debilitating gastrointestinal disease. Clin Pract. 2011;1:e21. doi:10.4081/cp.2011.e21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981245

 

Contributed by Rachel Weitzman, Medical Student, Harvard Medical School, Boston, MA.

My elderly patient on chronic warfarin with recent hospitalization for soft tissue infection is now readmitted with gastrointestinal bleed and a newly-discovered supra-therapeutic INR? Why did her INR jump?

In my patient with a serious infection, when should I worry about a primary immunodeficiency disorder?

You may consider a primary immunodeficiency disorder (PID) when 2 or more of the following “warning signs” are present: 1

  • ≥ 4 ear infections in 1 year
  • ≥ 2 serious sinus infections in 1 year
  • ≥ 2 pneumonias in 1 year
  • Recurrent, deep skin or organ abscesses
  • Persistent thrush in mouth or persistent fungal infection on the skin
  • ≥ 2 deep-seated infections, including septicemia
  • ≥ 2 months on antibiotics with little effect
  • Need for IV antibiotics to clear infections
  • Failure of an infant to gain weight or grow normally
  • Family history of primary immunodeficiency

Other infectious conditions that may be a clue to PID include those in unusual locations (eg, pneumococcal arthritis) or caused by unusual pathogens (eg, Pneumocystis jirovecii).

Among non-infectious conditions, history of granulomas in multiple organs, early-onset eczema refractory to therapy, and autoimmunity (eg, autoimmune cytopenias, autoimmune thyroiditis, celiac disease, vitiligo, type I diabetes mellitus) may also be potential clues.2

But before you embark on searching for PID,  rule out local barrier disorders of the skin or mucosa (eg, foreign body, bronchiectasis, cystic fibrosis) and secondary causes of immunodeficiency (eg, HIV), syndromes of protein loss/deficiency (eg, cirrhosis, nephrotic syndrome, malnutrition), splenectomy, malignancy, and medications (eg, steroids, chemotherapy, tumor necrosis factor inhibitors).2

Final Fun Fact: Did you know that PID affects 1 in 1,200 people in the US? 3

References:

  1. Arkwright PD, Gennery AR. Ten warning signs of primary immunodeficiency: a new paradigm is needed for the 21st century. Ann N Y Acad Sci 2011; 1238:7-14 http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2011.06206.x/abstract
  2. Hausmann O, Warnatz K. Immunodeficiency in adults a practical guide for the allergist. Allergo J Int. 2014; 23: 261–268 https://link-springer-com.ezp-prod1.hul.harvard.edu/article/10.1007/s40629-014-0030-4
  3. Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol 2007; 27:497  https://link.springer.com/article/10.1007/s10875-007-9103-1

 

Contributed by Yousef Badran, MD, Mass General Hospital, Boston, MA.

In my patient with a serious infection, when should I worry about a primary immunodeficiency disorder?

The urine antigen for Legionella in my patient with severe community-associated pneumonia is negative. How well does it rule out Legionella pneumonia?

Not as well as you might think!

Legionella urine antigens are 60%-80% sensitive (>99% specific) for detecting L. pneumophila serogroup 1 which accounts for about 70%-80% of Legionnaire’s disease (LD) in the US1; there are at least 15 serogroups.2 So as many as 40% or more LD may be missed by urine antigen testing alone. 2 Urine antigen can be excreted as early 3 days after the onset of symptoms and can persist for >300 days which may present a problem in diagnosing a current illness in patients with recurrent pneumonia. 2 One study reported lowest sensitivity (80%) for antigen testing during days 4 to 7 days of symptoms.3Other means of looking for Legionella include culture of respiratory samples for L. pneumophila which can detect all types of Legionella species (sensitivity 20%-80%) but has a lengthy turnaround time. Paired antibody testing may also be performed (sensitivity 70%-80%) in undiagnosed cases of severe pneumonia. 1Take home point: Don’t depend totally on urine antigen testing to rule out LD.

Final fun fact: Did you know that legionellae survive in the aquatic environment by parasitizing free-living protozoa?

References

  1. CDC. Legionellosis: United States, 2000-2009. MMWR 2011;60:1083-86. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6032a3.htm
  2. Fields BS, Benson RF, Besser RE. Legionella and Legionnaire’s disease: 25 years of investigation. Clin Micro Rev 2002;15:506-26. https://www.ncbi.nlm.nih.gov/pubmed/12097254  
  3. Kohler RB, Zimmerman SE, Wilson E, et al. Onset and duration of urinary antigen excretion in Legionnaire’s disease. J Clin Microbiol 20:605-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC271393
The urine antigen for Legionella in my patient with severe community-associated pneumonia is negative. How well does it rule out Legionella pneumonia?

Should I use qSOFA to screen for severe infections in my non-ICU patient?

Sepsis-3 qSOFA criteria—systolic BP ≤100 mg Hg, altered mental state, and RR≥22, with ≥2 considered positive— should NOT be used as either a screening or diagnostic tool for sepsis until properly designed prospective studies validate its utility.1

An important issue with qSOFA is its poor sensitivity for identifying patients with sepsis and its complications.  In a retrospective study of over 30,000 hospitalized patients suspected of infection in the emergency department or hospital wards, qSOFA ≥2 had a sensitivity of only 54% and specificity of 67% for in-hospital mortality or ICU transfer vs a much higher sensitivity of 91% but lower specificity of 13% for SIRS ≥2. Interestingly, most patients in this study met qSOFA criteria only 5 h before the studied outcome vs 17 h for SIRS ≥2 criteria.2

In another retrospective study of over 15,000 patients presenting to the Emergency Department with suspected infection, qSOFA ≥2 had a sensitivity of  49% and a specificity of 79% for hospital mortality vs  84% and 35% for SIRS≥2, and 65% and 74% for “severe sepsis” (Sepsis-2), respectively.3

So, using qSOFA alone to decide who needs prompt management of their infection (eg, blood cultures, serum lactate, antibiotics, fluids) may delay timely intervention in a substantial proportion of patients with infection that may become complicated by ICU transfer or death.  As is usually the case in medicine, it pays to look at the entire picture!

References

  1. Machado FR, Nsutebu E, AbDulaziz S, et al. Sepsis 3 from the perspective of clinicians and quality improvement initiatives. J Crit Care 2017:40: 315-17. https://www.ncbi.nlm.nih.gov/pubmed/28478045
  2. Churpek MM, Synder A, Han X, et al. Quick sepsis-related organ failure assessment, systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration n infected patients outside the intensive care unit. Am J Respir Crit Care Med 2017; 195: 906-11. https://www.ncbi.nlm.nih.gov/pubmed/27649072
  3. Lembke K, Parashar S, Simpson S. Sensitivity and specificity of SIRS, qSOFA, and severe sepsis for mortality of patients presenting to the emergency department with suspected infection. Chest Annual Meeting, Toronto, October 29, 2017. http://dx.doi.org/10.1016/j.chest.2017.08.427
Should I use qSOFA to screen for severe infections in my non-ICU patient?

Can Salmonella enterocolitis predispose to inflammatory bowel disease?

Yes, enteric pathogens such as Salmonella can predispose patients to inflammatory bowel disease (IBD) through several potential mechanisms: 1

  • Causing permanent changes in the intestinal microbiota
  • Altering the epithelial barrier in the gut
  • Altering the interaction between the body’s immune system and the intestines

More specifically, Salmonella utilizes oxidized endogenous sulfur compounds released during acute intestinal inflammation to outgrow the fermentative microbiota of the colon.2  In addition, the neutrophil response to Salmonella infection can alter the constituent microbiome.3 Salmonella also modifies the tight junctions in the intestinal epithelium as it invades, thus activating the immune system (particularly toll-like-receptors), and creating a pro-inflammatory state with structural loss of the intestinal mucosa. 4 Lastly, Salmonella promotes cytokine release and neutrophil migration through pathogen recognition receptors, leaving the intestine in a pro-inflammatory state even following resolution of the infection. 1

Keep in mind that initial Salmonella infection may also mimic IBD, as it causes diffuse lesions in the colon similar to ulcerative colitis, and may cause ileitis in some patients. Stool cultures and biopsies of the colonic mucosa should help differentiate IBD from Salmonella infection. 5

 

References

  1. Schultz BM, Paduro CA, Salazar GA, et al. A potential role of Salmonella infection in the onset of inflammatory bowel diseases. Front Immunol 2017;8:191. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5329042/pdf/fimmu-08-00191.pdf
  2. Winter SE, Baumler AJ. A breathtaking feat: to compete with the gut microbiota, Salmonella drives its host to provide a respiratory electron acceptor. Gut Microbes 2011;2:58-60. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225798/pdf/gmic0201_0058.pdf
  3. Gill N, Ferreira RB, Antunes LC, et al. Neutrophil elastase alters the murine gut microbiota resulting in enhanced Salmonella colonization. PLoS ONE 2012;7:e49646. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049646
  4. Bueno SM, Riquelme S, Riedel CA, et al. Mechanisms used by virulent Salmonella to impair dendritic cell function and evade adaptive immunity. Immunology 2012;137:28-36. https://www.ncbi.nlm.nih.gov/pubmed/22703384
  5. De Hertogh G, Geboes K. Crohn’s disease and infections: a complex relationship. MedGenMed 2004;6:14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1435589

 

 

 

 

 

 

Contributed by Yasmin Islam MD, Mass General Hospital, Boston, MA.

Can Salmonella enterocolitis predispose to inflammatory bowel disease?

My patient with ulcerative colitis has had colectomy. Can she still get C. difficile infection?

Yes! Although a common cause of colitis, an increasing number of reports in the literature suggest C. difficile can cause enteritis as well.Antibiotic use is a major risk factor in most reports, with nearly one-half of the cases reported in patients with inflammatory bowel disease, many post-colectomy. 1-3

Mortality of C. difficile enteritis based on the first 83 cases in the literature appears to be 23%,1 but as high as 60%-83% depending on the report!2 Its diagnosis post-colectomy requires a high index of suspicion, as patients may not complain of “diarrhea” with chronically loose stools in the ileostomy bag.  Be particularly on the lookout for C. difficile enteritis in these patients when there is increased stool output, fever, hypotension, and/or leukocytosis2, and when in doubt, send a stool specimen from the ileostomy bag for C. difficile testing.

Although the pathophysiology of C. difficile enteritis is not fully understood, few observations are particularly intriguing: 

  • Small bowel mucosa may be colonized by C. difficile in about 3% of the population, potentially serving as a reservoir.2
  • Patients with ileostomy may develop a metaplasia of the terminal end mimicking colonic environment.4  
  • Exposure of rabbit ileum to C. difficile toxin A also causes significant epithelial necrosis with destruction of villi and neutrophil infiltration.5

 

References

  1. Dineen SP, Bailey SH, Pham TH, et al. Clostridium difficile enteritis: a report of two cases and systematic literature review. World J Gastrointest Surg 2013;5:37-42. https://www.wjgnet.com/1948-9366/full/v5/i3/37.htm
  2. Boland E, Thompson JS. Fulminant Clostridium difficile enteritis after proctocolectomy and ileal pouch-anal anastomosis. Gastroenterology Research and Practice 2008; 2008: Article ID 985658. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633454/pdf/GRP2008-985658.pdf
  3. Freiler JF, Durning SJ, Ender PT. Clostridium difficile small bowel enteritis occurring after total colectomy. Clin Infect Dis 2001;33:1429-31. https://pdfs.semanticscholar.org/333b/d84978cfc4ac8fd21a15bc8fd26ff3160387.pdf
  4. Apel R, Cohen Z, Andrews CW, et al. Prospective evaluation of early morphological changes in pelvic ileal pouches. Gastroenterology 1994;107:435-43. http://www.gastrojournal.org/article/0016-5085(94)90169-4/pdf
  5. Triadafilopoulos G, Pothoulakis C, Obrien MJ, et al. Differential effects of Clostridium difficile toxins A and B on rabbit ileum. Gastroenterology 1987;93:273-279. https://www.ncbi.nlm.nih.gov/pubmed/3596162
My patient with ulcerative colitis has had colectomy. Can she still get C. difficile infection?