What is the connection between methemoglobinemia and hemolytic anemia?

Methemoglobinemia coupled with hemolytic anemia (HA) has been reported under different clinical scenarios and may have therapeutic implications for treatment of methemoglobinemia in the setting of G6PD deficiency.

Increased methemoglobin levels have been observed during the hemolytic crisis of patients with favism due to G6PD deficiency. This finding has been attributed to excessive oxidative stress generated by divicine, an oxidizing constituent of fava beans, and the inability to reduce its stress because of an insufficient G6PD-dependent hexose monophosphate shunt. 1Hemolytic anemia may also follow drug-induced methemoglobinemia, especially with exposure to dapsone, sulfasalazine, or phenacetin, and may be a feature of hemoglobin MSaskatoon and MHyde Park , abnormal hemoglobin variants associated with genetic methemoglobinemia. 2The concurrence of hemolysis due to G6PD deficiency and methemoglobinemia is not just an academic curiosity and may in fact pose a therapeutic quandary. This is because methylene blue, the treatment of choice for methemoglobinemia, is also an oxidant and works only after it is reduced to leukomethylene blue by (you guessed it!) nicotinamide adenine nucleotide phosphate (NADPH), a G6PD-dependent process. 2,3 With plenty of methylene blue on hand and little leukomethylene around in G6PD-deficiency, treatment may be ineffective or even cause worsening of methemoglobinemia. It’s never simple!

Final fun fact: Did you know that methylene blue is the first synthetic drug (>100 years ago) and has been used in the prevention of UTIs in the elderly, and treatment of pediatric malaria and Alzheimer’s disease? 4References

  1. Schuurman M, van Waardenburg D, Da Costa J, et al. Severe hemolysis and methemoglobinemia following fava beans ingestion in glucose-6-phosphate dehydrogenase: Case report and literature review. Eur J Ped 2009;168:779-782. https://link.springer.com/article/10.1007/s00431-009-0952-x
  2. Rehman HU. Methemoglobinemia. West J Med 2001;175:193-96. https://www.researchgate.net/publication/11817876_Methemoglobinemia
  3. Hassan KS, Al-Riyami AZ, Al-Huneini M, et al. Methemoglobinemia in an elderly patient with glucose-6-phosphate dehydrogenase deficiency: A case report. Oman Med J 2014;29:135-37. https://squ.pure.elsevier.com/en/publications/methemoglobinemia-in-an-elderly-patient-with-glucose-6-phosphate-
  4. Schirmer RH, Adler H, Pickhardt M, et al. “Lest we forget you—Methylene blue…” Neurobiology of Aging 2011; 32:2325. https://www.ncbi.nlm.nih.gov/pubmed/21316815
What is the connection between methemoglobinemia and hemolytic anemia?

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!


  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  



  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?

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



  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?

Should I be concerned about piperacillin-tazobactam nephrotoxicity in the absence of vancomycin?

Nephrotoxicity associated with piperacillin-tazobactam (PT) combined with vancomycin (V) has been increasingly reported1,2,  with  some recommending that an alternative to V be used when PT is also on board 2. However, there are several reasons why the nephrotoxic potential of PT either alone or with antibiotics other than V also deserves further study before such recommendations can be widely embraced3.

First, most studies of VPT combination do not include comparative V or PT alone arms making it difficult to assess the relative contribution of these 2 antibiotics to kidney injury when used in combination. A small study that did include a PT-only  arm reported a similar rate of acute kidney injury (AKI) in PT and VPT arms ( 15.4% and 18.8% , respectively), both significantly higher that than of  V-only group (4%).4

 Other reasons not to readily dismiss PT as a cause of nephrototoxicity include the  lack of association between higher V trough levels and AKI in patients receiving VPT2, the association of PT with lower rates of renal function recovery in critically ill patients when compared to other selected β-lactams5,  and higher magnesium and potassium renal tubular loss with the use of PT compared to selected cephalosporins and ciprofloxacin6.  As with other penicillins, PT-associated acute interstitial nephritis may also occur7-8.

In short, even in the absence of V, nephrotoxic potential of PT should not be automatically dismissed.


Disclosure: Ref 3 was also authored by the creator of this pearl.


  1. Hammond DA, Smith MN, Chenghui Li, et al. Systematic review and meta-analysis of acute kidney injury associated with concomitant vancomycin and piperacillin/tazobactam. Clin Infect Dis 2017;64:666-74.
  2. Navalkele B, Pogue JM, Karino S, et al. Risk of acute kidney injury in patients on concomitant vancomycin and piperacillin-tazobactam compared to those on vancomycin and cefepime. Clin Infect Dis 2017;64:116-123.
  3. Manian FA. Should we revisit the nephrotoxic potential of piperacillin-tazobactam as well? Clin Infect Dis 2017; https://doi.org/10.1093/cid/cix321
  4. Kim T, Kandiah S, Patel M, et al. Risk factors for kidney injury during vancomycin and piperacillin/tazobactam administration, including increased odds of injury with combination therapy. BMC Res Notes 2015;8:579.
  5. Jensen J-U S, Hein L, Lundgren B, et al. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomized trial. BMJ Open 2012;2:e000635. http://bmjopen.bmj.com/content/2/2/e000635
  6. Polderman KH, Girbes ARJ. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med 2002;28:530-522.
  7. Muriithi AK, Leung N, Valeri AM, et al. Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney International 2015;87:458-464.
  8. Soto J, Bosch JM, Alsar Ortiz MJ, et al. Piperacillin-induced acute interstitial nephritis. Nephron 1993;65:154-155. 
Should I be concerned about piperacillin-tazobactam nephrotoxicity in the absence of vancomycin?

Is treatment of pneumococcal pneumonia with bacteremia any different than pneumococcal pneumonia without bacteremia?

In the absence of disseminated infection such as meningitis or endocarditis, there is no convincing evidence that bacteremic pneumococcal pneumonia (BPP) requires either longer course of IV or oral antibiotics.

In fact, although previously thought to have a worse prognosis, recent data have failed to demonstrate any difference in time to clinical stability, duration of hospital stay or community-associated pneumonia (CAP)-related mortality with BPP when other factors such as patient comorbidities and severity of disease are also considered1,2

Although many patients with CAP receive 7-10 days of antibiotic therapy, shorter durations as little as 5 days may also be effective3,4.  Generally, once patients with BPP have stabilized on parenteral therapy, a switch to an appropriate oral antibiotic (eg, a β-lactam or a respiratory quinolone such as levofloxacin) can be made safely5

Although large randomized-controlled studies of treatment of BPP are not available, a cumulative clinical trial experience with levofloxacin for patients with BPP reported a successful clinical response in >90% of patients (median duration of therapy 14 d)6. Resistance to levofloxacin and failure of treatment in pneumococcal pneumonia (with or without bacteremia), however, has been rarely reported7.



  1. Bordon J, Peyrani P, Brock GN. The presence of pneumococcal bacteremia does not influence clinical outcomes in patients with community-acquired pneumonia. Chest 2008;133;618-624.
  2. Cilloniz C, Torres A. Understanding mortality in bacteremic pneumococcal pneumonia. J Bras Pneumol 2012;38:419-421.
  3. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27-72.
  4. Shorr F, Khashab MM, Xiang JX, et al. Levofloxacin 750-mg for 5 days for the treatment of hospitalized Fine Risk Class III/IV community-acquired pneumonia patients. Resp Med 2006;100:2129-36.
  5. Ramirez JA, Bordon J. Early switch from intravenous to oral antibiotics in hospitalized patients with bacteremic community-acquired Streptococcus pneumonia pneumonia. Arch Intern Med 2001;161:848-50.
  6. Kahn JB, Bahal N, Wiesinger BA, et al. Cumulative clinical trial experience with levofloxacin for patients with community-acquired pneumonia-associated pneumococcal bacteremia. Clin Infect Dis 2004;38(supp 1):S34-42.
  7. Davidson R, Cavalcanti R, Brunton JL, et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;346:747-50.
Is treatment of pneumococcal pneumonia with bacteremia any different than pneumococcal pneumonia without bacteremia?

How does azithromycin (AZ) benefit patients with severe COPD or cystic fibrosis (CF)?

AZ is a macrolide antibiotic which interferes with bacterial protein synthesis by binding to the 50S ribosomal subunit. It is often used to treat acute respiratory tract infections due to Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, as well as Mycoplasma, Chlamydia, and Legionella sp1. Although it has no in vitro activity against many aerobic gram-negative bacilli such as Pseudomonas aeruginosa, its chronic use has often been associated with a significant reduction in the frequency of disease exacerbations in patients with chronic bronchiectasis and colonization due to this organism, including patients with COPD or CF1-3.

Because P. aeruginosa is invariably macrolide-resistant, the beneficial effect of AZ in chronically infected or colonized patients must be due to factors other than its direct effect on bacterial replication.  Several mechanisms have been invoked including: 1. Inhibition of quorum-sensing dependent virulence factor and biofilm production 2.Blunting of host inflammatory response (eg, ↑IL-10, and ↓ IL-1ß, IL-6, IL-8, TNF-α, and ↓ chemotaxis); and 3. Enhanced antiviral response1.

The latter finding is quite unexpected but AZ appears to augment interferon response to rhinovirus in bronchial cells of COPD patients3.  With respiratory viruses (including rhinoviruses) causing 20-55% of all COPD exacerbations, perhaps this is another way AZ may help the host! Who would have thought!!


  1. Vos R, Vanaudenaerde BM, Verleden SE, et al. Anti-inflammatory and immunomodulatory properties of azithromycin involved in treatment and prevention of chronic lung allograft rejection. Transplantation 2012;94:101-109.
  2. Cochrane review. Treatment with macrolide antibiotics for people with cystic fibrosis and chronic chest infection. Nov 14, 2012. http://www.cochrane.org/CD002203/CF_treatment-with-macrolide-antibiotics-for-people-with-cystic-fibrosis-and-chronic-chest-infection
  3. Menzel M, Akbarshahi H, Bjermer L, et al. Azithromycin induces anti-viral effects in cultured bronchial epithelial cells from COPD. Scientific Reports 2016; 6:28698. DOI:10.1038/srep 28698.
How does azithromycin (AZ) benefit patients with severe COPD or cystic fibrosis (CF)?