My patient has developed isolated eosinophilia without symptoms while receiving an antibiotic. Should I consider discontinuing the antibiotic or can I just continue it as long as she has no symptoms?

Short answer: We don’t really know what’s the best way to manage patients with  isolated (asymptomatic) eosinophilia (IE) that develops during antibiotic therapy. We do know that the majority of patients with IE may never develop hypersensitivity reaction such as rash, renal or liver injuries, but predicting who will or will not get HSRs is a challenge.1-3 Couple of studies may help us in our decision making, however.

In a 2015 study1 involving patients receiving outpatient parenteral antibiotics, eosinophilia was present in 25% of patients during their course of treatment, of whom 30% subsequently developed HSR and 5% developed more than 1 sign of HSR. Patients with IE and subsequent HSR developed eosinophilia earlier in their course of treatment (median 11 vs 17 days) and had a higher peak absolute eosinophil count (~ 850 vs ~700/ ml).  The authors suggested that close monitoring for rash and renal injury in patient with IE during antibiotic therapy be considered, and that medication changes may be necessary when IE is associated with earlier onset of eosinophilia or higher absolute eosinophil count.

In a 2017 prospective study2 of patients with eosinophilic drug reactions (~20% related to antibiotics), the majority (56%) were asymptomatic. Earlier onset of eosinophilia and higher eosinophil count were associated with symptomatic eosinophilia, similar to the aforementioned study. The frequency of patients with IE who went on to have symptomatic eosinophilia when the suspect drug was continued vs those in whom it was not continued remains unclear from these studies.

Ultimately, the decision to continue or discontinue a suspect antibiotic when your patient has new-onset IE should be made on a case-by-case basis, taking into account the severity of the patient’s infection, availability of equally effective and tolerated alternative drugs and the ability to closely monitor for symptomatic disease. The timing of onset of eosinophilia and its peak absolute count may also play a role.

Bonus pearl: Did you know that only 18% of inpatients with cutaneous drug eruptions may have peripheral eosinophilia?4

The author acknowledges the invaluable input of Kimberly Blumenthal, MD in composing this pearl.

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References

  1. Blumenthal KG, Youngster I, Rabideau DJ, et al. Peripheral blood eosinophilia and hypersensitivity reactions among patients receiving outpatient parenteral antibiotics. J Allergy Clin Immunol 2015;136:1288.1294. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640981/
  2. Ramirez E, Mdrano-Casique N, Tong HY, et al. Eosinophilic drug reactions detected by a prospective pharmacovigilance programme in a tertiary hospital. Br J Pharmacol 2017;83:400-15. https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bcp.13096
  3. Rauscher C, Freeman A. Drug-induced eosinophilia. Allergy Asthma Proc 2018;39:252-56. https://www.ncbi.nlm.nih.gov/pubmed/29669671
  4. Romagosa R, Kapoor S, Sanders J, et al. inpatient adverse cutaneous drug erutpions and eosinophilia. Arch Dermatol 2001; 137:511-12. https://www.ncbi.nlm.nih.gov/pubmed/11295947   

 

 

My patient has developed isolated eosinophilia without symptoms while receiving an antibiotic. Should I consider discontinuing the antibiotic or can I just continue it as long as she has no symptoms?

Should I routinely treat my patients with acute COPD exacerbation with antibiotics?

The answer is “NO”! With an estimated 20% to 50% of acute chronic obstructive pulmonary disease (COPD) exacerbations attributed to noninfectious factors (1,2), routine inclusion of antibiotics in the treatment of this condition is not only unnecessary but potentially harmful.

 
Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommends the use of antibiotics in patients who have dyspnea, increased sputum volume, and increased sputum purulence—or at least 2 of these 3 criteria when sputum purulence is one of them (3)—, these recommendations are not based on robust evidence and have not been widely corroborated (2,4-6).

 
That’s why the findings of a 2019 New England Journal of Medicine study (PACE) supporting the use of serum C-reactive protein (CRP) as an adjunctive test in COPD exacerbation is particularly welcome (1). In this multicenter randomized controlled trial performed in the U.K., the following CRP guidelines (arrived from prior studies) were provided to primary care clinicians to be used as part of their decision making in determining which patients with COPD exacerbation may not need antibiotic therapy:

 
• CRP less than 20 mg/L: Antibiotics unlikely to be beneficial
• CRP 20-40 mg/L: Antibiotics may be beneficial, mainly if purulent sputum is present
• CRP greater than 40 mg/L: Antibiotics likely to be beneficial

 
Adoption of these guidelines resulted in significantlly fewer patients being placed on antibiotics without evidence of harm over a 4-week follow-up period (1).  Despite its inherent limitations (eg, single country, outpatient setting), CRP testing may be a step in the right direction in curbing unnecessary use of antibiotics in COPD exacerbation.  

 

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References

 
1. Butler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. N Engl J Med 2019;381:111-20. https://www.ncbi.nlm.nih.gov/pubmed/31291514
2. Llor C, Moragas A, Hernandez S, et al. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:716-23. https://www.ncbi.nlm.nih.gov/pubmed/22923662
3. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. GOLD, 2019 (http://www.goldcopd.org).
4. Brett AS, Al-Hasan MN. COPD exacerbations—A target for antibiotic stewardship. N Engl J Med 2018;381:174-75. https://www.ncbi.nlm.nih.gov/pubmed/31291521
5. Miravitlles M, Moragas A, Hernandez S, et al. Is it possible to identify exacerbations of mild to moderate COPD that do not require antibiotic treatment? Chest 2013;144:1571-7. https://www.ncbi.nlm.nih.gov/pubmed/23807094
6. Van Vezen P, Ter Riet G, Bresser P, et al. Doxycycline for outpatient-treated acute exacerbations of COPD: a randomized double-blind placebo-controlled trial. Lancet Respir Med 2017;5:492-9. https://www.ncbi.nlm.nih.gov/pubmed/28483402

Should I routinely treat my patients with acute COPD exacerbation with antibiotics?

Is meropenem a good choice of antibiotic for treatment of my patient’s intraabdominal infection involving enterococci?

Although meropenem is a broad spectrum antibiotic that covers many gram-negative and gram-positive organisms as well as anaerobes, its activity against enterococci is generally poor and leaves much to be desired.

In a study of ampicillin-sensitive E. faecalis isolates from hospitalized patients, only 36% of isolates were considered susceptible (MIC≤4 mg/L); activity against E. faecium isolates was similarly poor.1 Several other studies have reported the suboptimal activity of meropenem against both E. faecalis and E. faecium, 2-4 with susceptibility rates as low as 8.6% depending on the MIC break point used.3

A popular textbook and a handbook on infectious diseases also do not recommend the use of meropenem for treatment of enterococcal infections. 5,6

Of interest, the package insert states that meropenem is indicated for complicated skin and soft tissue infections due to a variety of organisms, including E. faecalis (vancomycin-susceptible isolates only), but not for complicated intra-abdominal infections or meningitis due this organism.7

In our patient with intraabdominal infection,  we may consider piperacillin-tazobactam instead.  Piperacillin-tazobactam is a broad spectrum antibiotic with excellent coverage against anaerobes and ampicillin-susceptible E. faecalis.1,8  

 

References

  1. Endtz HP, van Dijk WC, Verbrugh HA, et al. Comparative in-vitro activity of meropenem against selected pathogens from hospitalized patients in the Netherlands. J Antimicrob Chemother 1997;39:149-56. https://www.ncbi.nlm.nih.gov/pubmed/9069534
  2. Pfaller MA, Jones RN. A review of the in vitro activity of meropenem and comparative antimicrobial agents tested against 30,254 aerobic and anaerobic pathogens isolated world wide. Diag Microbiol Infect Dis 1997;28:157-63. https://www.ncbi.nlm.nih.gov/pubmed/9327242
  3. Hallgren A, Abednazari H, Ekdahl C, et al. Antimicrobial susceptibility patterns of enterococci in intensive care units in Sweden evaluated by different MIC breakpoint systems. J Antimicrob Chemother 2001;48:53-62. https://www.ncbi.nlm.nih.gov/pubmed/11418512
  4. Hoban DJ, Jones RN, Yamane N, et al. In vitro activity of three carbapenem antibiotics comparative studies with biapenem (L-627), imipenem, and meropenem against aerobic pathogens isolated worldwide. Diag Microbiol Infect Dis 993;17:299-305.https://www.ncbi.nlm.nih.gov/pubmed/8112045
  5. Chambers HF. Carbapenem and monobactams. In Mandell GL et al. eds. Principles and practice of infectious diseases. 2010, pp 341-45.
  6. Cunha CB, Cunha BA. Antibiotic essentials. 2017, pp 689-91.
  7. Meropenem.http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7253?searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dmeropenem%26t%3Dname
  8. Perry CM, Markham A. Piperacillin/tazobactam. Drugs 1999;57:805-43. https://link.springer.com/article/10.2165%2F00003495-199957050-00017

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Is meropenem a good choice of antibiotic for treatment of my patient’s intraabdominal infection involving enterococci?

Should I choose a bactericidal over bacteriostatic antibiotic in the treatment of my patient with pneumonia complicated by bacteremia?

You don’t have too!  Although “bacteriostatic” antibiotics have traditionally been regarded as inferior to “bactericidal” antibiotics in the treatment of serious infections, a 2018 “myth busting” systemic literature review1 concluded that bacteriostatic antibiotics are just as effective against a variety of infections, including pneumonia, non-endocarditis bacteremia, skin and soft tissue infections and genital infections; no conclusion can be made in regards to endocarditis or bacterial meningitis, however, due insufficient clinical evidence.1-3

Interestingly, most of the studies included in the same systemic review showed that bacteriostatic antibiotics were more effective compared to bactericidal antibiotics.1 So, for most infections in hospitalized patients, including those with non-endocarditis bacteremia, the choice of antibiotic among those that demonstrate in vitro susceptibility should not be based on their “cidal” vs “static” label.

Such conclusion should not be too surprising since the definition of bacteriostatic vs bactericidal is based on arbitrary in vitro constructs and not validated by any available in vivo data. In addition, static antibiotics may kill bacteria as rapidly as cidal antibiotics in vitro at higher antibiotic concentrations.3

Another supportive evidence is a 2019 study finding similar efficacy of sequential intravenous-to-oral outpatient antibiotic therapy for MRSA bacteremia compared to continued IV antibiotic therapy despite frequent use of bacteriostatic oral antibiotics (eg, linezolid, clindamycin and doxycycline). 4

 

References

  1. Wald-Dickler N, Holtom P, Spellberg B. Busting the myth of “static vs cidal”: as systemic literature review. Clin Infect Dis 2018;66:1470-4. https://academic.oup.com/cid/article/66/9/1470/4774989
  2. Steigbigel RT, Steigbigel NH. Static vs cidal antibiotics. Clin Infect Dis 2019;68:351-2. https://academic.oup.com/cid/article-abstract/68/2/351/5067395
  3. Wald-Dickler N, Holtom P, Spellberg B. Static vs cidal antibiotics; reply to Steigbigel and Steigbigel. Clin Infect Dis 2019;68:352-3. https://academic.oup.com/cid/article-abstract/68/2/352/5067396?redirectedFrom=fulltext
  4. Jorgensen SCJ, Lagnf AH, Bhatia S, et al. Sequential intravenous-to-oral outpatient antbiotic therapy for MRSA bacteraemia: one step closer.  J Antimicrob Chemother 2019;74:489-98.  https://www.ncbi.nlm.nih.gov/pubmed/30418557

 

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Should I choose a bactericidal over bacteriostatic antibiotic in the treatment of my patient with pneumonia complicated by bacteremia?

When should I consider prophylaxis for Pneumocystis pneumonia (PCP) in my patient on prednisone?

It is generally recommended that patients on ≥20 mg of daily prednisone (or its equivalent) for ≥1 month be considered for PCP prophylaxis. 1

Couple of studies in 1990s helped define the dose and duration of corticosteroids (CS) that should prompt PCP prophylaxis. A Mayo Clinic study of patients without AIDS found that a median daily CS dose of 30 mg of prednisone or equivalent—with 25% of patients receiving as little as 16 mg of prednisone daily— was associated with PCP.The median duration of CS therapy before PCP was 12 weeks. A similar study found a mean CS dose of 33 mg of prednisone or equivalent with mean duration of 7 months (range 1-154 months) among patients with PCP without AIDS. 3

A 2018 retrospective study4  of patients with rheumatic diseases receiving prolonged high-dose CS therapy (≥30 mg prednisone for ≥4 weeks) found that PCP prophylaxis with trimethoprim/sulfamethoxazole (TMP/STX) resulted in 93% reduction in the incidence of PCP with an overall number needed to treat (NNT) of 52. It was suggested that PCP prophylaxis could be discontinued in patients receiving < 15 mg of prednisone daily.

Bonus Pearl: Did you know that TMP/STX may be given either as double-strength 3x/week or single-strength daily? 5,6

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References

1. Limper AH, Knox KS, Sarosi SA, et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-128. https://www.ncbi.nlm.nih.gov/pubmed/21193785

2. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc 1996;71:5-13. https://www.sciencedirect.com/science/article/abs/pii/S0025619611649148

3. Arend SM, Kroon FP, van’t Wout JW. Pneumocystis carinii pneumonia in patients without AIDS, 1980 through 1993: An analysis of 78 cases. Arch Intern Med 1995;155:2436-2441. https://www.ncbi.nlm.nih.gov/pubmed/7503602

4. Park JW, Curtis JR, Moon J, et al. Prophylactic effect of trimethoprim-sulfamethoxazole for Pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoieds. Ann Rheum Dis 2018;77:664-9. https://www.ncbi.nlm.nih.gov/pubmed/29092853

5. Anevlavis S, Kaltsas K, Bouros D. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV infected patients. PNEUMON 2012;25, October-December.http://www.pneumon.org/assets/files/789/file483_273.pdf

6. Stern A, Green H, Paul M, Leibovici L. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients (Review). Cochrane data of Systematic Reviews 2014, issue 10. DOI: 10.1002/14651858.CD005590.pub3. https://www.ncbi.nlm.nih.gov/pubmed/25269391

 

When should I consider prophylaxis for Pneumocystis pneumonia (PCP) in my patient on prednisone?

My patient with community-acquired pneumonia (CAP) will be going home on an oral antibiotic. Is there a significant difference in the risk of Clostridium difficile infection among the usual CAP antibiotics?

Not all antibiotics are equal in their risk of CDI. Among the common antibiotics used for respiratory tract infections, doxycycline appears to be the least likely to be associated with CDI. 

A population-based case-control study of community-acquired CDI found that while recent exposure increased the risk of CDI for fluoroquinolones, macrolides, cephalosporins, sulfonamides and trimethoprim and penicillins, the risk of CDI with tetracycline use was not increased (1).  Similar findings (with the exception of sulfonamides also appearing risk-neutral) have been reported by others (2). 

Among patients receiving ceftriaxone, receipt of doxycycline has been associated with protection against development of CDI (3).  A 2018 systematic review and meta-analysis also concluded that tetracyclines were associated with a decreased risk of CDI; OR 0.55 (95% CI 0,40-0.75) for doxycycline alone (4). 

 

The most likely explanation for why doxycycline may be associated with lower risk of CDI is its in vitro activity against anaerobes, including C. difficile. Additionally, because of its ability to inhibit protein synthesis, doxycycline may attenuate C. difficile toxin production. Its high bioavailability and maximal absorption from the upper gastrointestinal tract may also mitigate its impact on gut flora, further reducing its risk of CDI (3). 

 

References
1. Delaney JAC, Dial S, Barkun A et al. Antimicrobial drugs and community-acquired Clostridium difficile-associated disease-UK. Emerg Infect Dis 2007:13;761-63. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738472
2. Kuntz JL, Chirchilles EA, et al. Incidence of and risk factors for community-associated Clostridium difficile infection : A nested case-control study. BMC Infect Dis 2011;11:194. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154181/ 
3. Doernberg SB, Winston LG, Deck DH, et al. Does doxycycline protect against development of Clostridium difficile infection. Clin Infec Dis 2012;44:615-20. https://www.academia.edu/7814406/Does_Doxycycline_Protect_Against_Development_of_Clostridium_difficile_Infection
4. Tariq R, Cho J, Kapoor S, et al. Low risk of primary Clostridium difficile infection with tetracyclines: a systematic review and metanalysis. Clin Infect Dis 2018; 766:514-27. https://academic.oup.com/cid/article/66/4/514/4161552 

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My patient with community-acquired pneumonia (CAP) will be going home on an oral antibiotic. Is there a significant difference in the risk of Clostridium difficile infection among the usual CAP antibiotics?

Is my hospitalized patient with possible pneumonia at risk of Clostridium difficile-associated disease after only 1-3 days of empiric antibiotic therapy?

Yes! Even relatively brief duration of antibiotic therapy may increase the risk of Clostridium difficile-associated disease (CDAD) in a susceptible host.
In a study of hospitalized patients with new-onset diarrhea, prior exposure to levofloxacin and cefazolin was significantly associated with CDAD with the median duration of therapy for levofloxacin of 3 days (range 1-18 days), and for cefazolin 2 days (range 1-3 days) (1). Similarly, a study in hospitalized patients during a CDAD epidemic found a significantly increased risk of CDAD among patients who received fluoroquinolones for only 1-3 days (hazard ratio 2.4) with a 95% confidence interval (1.6-3.6) that overlapped 4-6 days and ≥ 7 days treatment groups (2). Yet another study found no significant difference in the risk of CDAD between those on antibiotic for < 4 days vs 4-7 days of antibiotics (3). CDAD following a single dose of cefazolin has also been reported (4).
Of interest, laboratory studies in mice have shown a profound alteration of intestinal microbiota following a single dose of clindamycin, resulting in increased susceptibility to C. difficile colitis (5).
So although duration of antibiotic therapy is an important factor in CDAD (3, 6) and we should minimize the duration of antibiotic therapy whenever possible, not starting antibiotics in the absence of clear indication is even better!

References
1. Manian FA, Aradhyula S, Greisnauer S, et al. Is it Clostridium difficile infection or something else? A case-control study of 352 hospitalized patients with new-onset diarrhea. S Med J 2007;100:782-786. https://www.ncbi.nlm.nih.gov/pubmed/17713303
2. Pepin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41:1254-60. https://www.ncbi.nlm.nih.gov/pubmed/16206099
3. Stevens V, Dumyati G, Fine LS, et al. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis 2011;53:42-48. https://www.ncbi.nlm.nih.gov/pubmed/21653301
4. Mcneeley SG, Anderson GD, Sibai BM. Clostridium difficile colitis associated with single dose cefazolin prophylaxis. Ob Gynecol 1985;66:737-8. https://www.ncbi.nlm.nih.gov/pubmed/4058831
5. Buffie CG, Jarchum I, Equinda M, et al. Profound alterations of intestinal microbiota following a single dose of clindamycin results in sustained susceptibility to Clostridium difficile-induced colitis. Infect Immun 2011;80: 62-73. https://www.ncbi.nlm.nih.gov/pubmed/22006564
6. Chalmers JD, Akram AR, Sinanayagam A, et al. Risk factors for Clostridium difficile infection in hospitalized patients with community-acquired pneumonia. J Infect 2016;73:45-53. https://www.ncbi.nlm.nih.gov/pubmed/27105657

Disclosure: The contributor of this post was a coinvestigator of a cited study (ref. 1).

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Is my hospitalized patient with possible pneumonia at risk of Clostridium difficile-associated disease after only 1-3 days of empiric antibiotic therapy?

My previously healthy patient is admitted with a multi-drug resistant E. coli urinary tract infection. Could her urinary tract infection (UTI) be foodborne?

Yes! Although foodborne infections are often thought to cause infections limited to the GI tract, an increasing number of studies have linked foodborne E.coli to extraintestinal infections in humans, including UTIs.1

Supportive data include frequent genetic similarly between antimicrobial-resistant E. coli from humans and poultry-associated E. coli. 2 In fact, antimicrobial-resistant E. coli isolates from humans may be  genetically more similar to poultry isolates than susceptible commensal E. coli strains in the human GI tract.3

A U.S. study found that 14% of chicken meat products were contaminated with E. coli strains capable of causing extraintestinal disease, 1/3 of which were mutli-drug resistant.4  Another study found that 94% of retail chicken meat samples contained E. coli with ESBL-genes,  of which nearly 40% contained isolates present in humans.5

Among women, UTI caused by antimicrobial-resistant extraintestinal pathogenic E. coli has been linked to high levels of self-reported chicken consumption.6

The plausibility of foodborne transmission of antimicrobial-resistant E. coli to humans is further supported by the finding that drug resistant E coli from chicken carcasses widely contaminate the kitchen during meal preparation and can appear in the intestinal tract of those who prepare such food.2

Bonus Pearl: Did you know that women with multi-drug resistant E. coli UTI are 3.7 times more likely to report frequent consumption of chicken? 6

References

  1. Manges AR. Escherichia coli and urinary tract infections: the role of poultry-meat. Clin Microbiol Infect 2016;22:122-29. https://www.ncbi.nlm.nih.gov/pubmed/26679924
  2. Manges AR, Johnson JR. Reservoirs of extraintestinal pathogenic Escherichia coli. Microbiol Spectrum 2012;3(5):UTI-0006-2012. https://www.ncbi.nlm.nih.gov/pubmed/26542041
  3. Johnson JR, Menard M, Johsnton B, et al. Epidemic clonal groups of Escherichia coli as a cause of antimicrobial-resistant urinary tract infections in Canada, 2002 to 2004. Antimicrob Agents Chemother 53;2733-2739. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704706/
  4. Johnson JR, Porter SB, Johnston B, et al. Extraintestinal pathogenic and antimicrobial-resistant Escherichia coli, including sequence type 131 (ST131) from retail chicken breasts in the United States in 2013. Apppl Environ Microbiol 83:e02956-16. https://www.ncbi.nlm.nih.gov/pubmed/28062464
  5. Leverstein-van Hall MA, Dierikx CM, Stuart JC, et al. Dutch patients, retail chicken meat and poultry share the same ESBL genes, plasmids and strains. Clin Microbiol Infect 2011;17:873-880. https://www.ncbi.nlm.nih.gov/pubmed/21463397
  6. Manges AR, Smith SP, Lau BJ, et al. Retail meat consumption and the acquisition of antimicrobial resistant Escherichia coli causing urinary tract infections: a case-control study. Foodborne Path Dis 4:419-431. https://www.ncbi.nlm.nih.gov/pubmed/18041952

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My previously healthy patient is admitted with a multi-drug resistant E. coli urinary tract infection. Could her urinary tract infection (UTI) be foodborne?

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!

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?