Is neurotoxicity caused by cefepime common?

The incidence of cefepime-induced neurotoxicity (CIN) has varied from 1% to 15%.1 Potential clinical manifestations of CIN include delirium, impaired level of consciousness, disorientation/agitation, myoclonus, non-convulsive status epilepticus, seizures, and aphasia.1  Many of these signs and symptoms (eg, delirium) are common among hospitalized patients.

Although renal dysfunction and inadequately adjusted dosages are often cited as risk factors, one-half of patients develop suspected CIN despite apparently proper adjustment for renal function.In addition,  several case reports of CIN have involved patients with normal renal function. 2  A study of 1120 patients receiving cefepime found epileptiform discharges in 14 cases, most having normal renal function.3 Of interest, in the same study, the prevalence of epileptiform discharges was 6-fold higher than that of meropenem!

Proposed mechanisms for CIN include its avidity for central nervous system GABA-A receptors (higher than that of many beta-lactam antibiotics) combined with its high concentration in brain tissue.1 Renal impairment, decreased protein binding, increased organic acid accumulation can increase transfer of cefepime across the blood brain barrier from an expected 10% to up to 45% of its serum concentration, further contributing to its neurotoxicity.4



  1. Appa AA, Jain R, Rakita RM, et al. Characterizing cefepime neurotoxicity: a systematic review. Open Forum Infectious Diseases 2017 Oct 10;4(4):ofx170. doi: 10.1093/ofid/ofx170. eCollection 2017 Fall.
  2. Meillier A, Rahimian D. Cefepime-induced encephalopathy with normal renal function. Oxford Medical Case Reports, 2016;6, 118-120.
  3. Naeije G, Lorent S, Vincent JL, et al. Continuous epileptiform discharges in patients treated with cefpime or meropenem Arch Neurol 2011;68:1303-7.
  4. Payne LE, Gaganon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Critical Care 017;21:276.


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Is neurotoxicity caused by cefepime common?

My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

The most helpful lab data favoring corticosteroid-induced granulocytosis (CIG) is the absence of a shift to the left in the peripheral WBC (ie, no more than 6% band forms) and toxic granulation.1 Although the total WBC itself is less helpful, experimental studies have reported a mean maximum neutrophil counts 2.4 times the base line after IV injection of hydrocortisone (200 mg) 2, and a mean increase of 4,000 neutrophils/mm3 after prednisone (20-80 mg). 3

Several possible mechanisms for CIG revolving around altered neutrophil characteristics and dynamics have been proposed4, including

  • Reduced egress from blood into tissues
  • Demargination from vascular endothelial surfaces
  • Delayed apoptosis
  • Enhanced release from the bone marrow.

An experimental animal study reported that only 10% of CIG is related to bone marrow release of neutrophils with the rest related to demargination (61%) and reduced egress from blood or delayed apoptosis (29%).4 This study may explain why high percentage of band forms would not be expected CIG.


  1. Shoenfeld Y, Gurewich Y, Gallant LA, et al. Prednisone-induced leukocytosis: influence of dosage, method, and duration of administration on the degree of leukocytosis. Am J Med 1981;71:773-78. Link
  2. Bishop CR, Athens JW, Boggs DR, et al. Leukokinetic studies: A non-steady-state kinetic evaluation of the mechanism of cortisone-induced granulocytosis. J Clin Invest 1986;47:249-60.
  3. Dale DC, Fauci AS, Guerry DuPont, et al. Comparison of agents producing a neutrophilic leukocytosis in man. J Clin Invest 1975;56:808-13. PDF
  4. Nakagawa M, Terashma T, D’yachkova YD, et al. Glucocorticoid-induced granulocytosis: Contribution of marrow release and demargination of intravascular granulocytes. Circulation 1998;98:2307-13. PDF

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My patient with COPD exacerbation on corticosteroids has an elevated white blood cell and neutrophil count. How can I tell if his elevated neutrophil count is caused by the corticosteroids or an acute infection?

My hypertensive patient needs hemodialysis. How dialyzable are common antihypertensives?

Among antihypertensives, most commonly used angiotensin converting enzyme inhibitors (ACE-Is) such as captopril, enalapril, lisinopril, and benazepril are at least partially removed by hemodialysis; ramipril and fosinopril are not appreciably removed.1,2

In contrast, none of the commonly used angiotensin receptor blockers such as losartan, valsartan, and irbesartan are removed by hemodialysis.

Among β-blockers and combined α- and β-blockers, atenolol and metoprolol are removed by hemodialysis while carvedilol, bisoprolol, propranolol and labetalol are not.

Many other antihypertensives such as calcium channel blockers, α-blockers, clonidine, and hydralazine are not appreciably removed by hemodialysis, while isosorbide dinitrate appears to be.

Of interest, a 2015 retrospective cohort study found that initiation of high- dialyzability β-blockers (atenolol, acebutolol, or metoprolol) was associated with a higher risk of death in the following 180 days compared to that of low-dialyzability  β-blockers (bisoprolol or propranolol), suggesting that perhaps we should be more selective in our choice of β-blockers in this patient population.2 In contrast, no significant difference in all-cause mortality was noted among older patients receiving ACE-Is with high vs low dialyzability potential.3



  1. Inrig JK, Antihypertensive agents in hemodialysis patients: A current perspective. Semin dial 2010;23:290-7.
  2. β-Blocker dialyzability and mortality in older patients receiving hemodialysis. J Am Soc Nephrol 2015;26:987-96.
  3. Weir MA, Fleet JL, Dixon SN, et al. Angiotensin converting enzyme inhibitor dialyzability and outcomes in older patients receiving hemodialysis. Blood Purif 2015;40:232-42.   

Contributed in part by Andrew Lundquist, MD, PhD, Mass General Hospital, Boston, MA.

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My hypertensive patient needs hemodialysis. How dialyzable are common antihypertensives?

Can non-steroidal anti-inflammatory drugs (NSAIDs) suppress cancer metastasis?

A 2017 meta-analysis reported that NSAIDs are associated with lower risk of distant metastasis in patients with breast, prostate, lung, and colorectal cancer.1

The mechanism accounting for this observation is not fully understood. However, since inflammation has been implicated as a driving force for tumor metastasis 2, blunting the inflammatory microenvironment that surrounds tumors may explain NSAIDs’ reported beneficial effect.

NSAIDs may also have a direct effect on cancer cells. In-vitro studies demonstrate that NSAIDs induce the expression of a protein (p75 neurotrophic receptor, p75NTR) associated with suppression of tumor growth and metastasis in prostate cancer; this protein also suppresses growth of bladder cancer cells.3,4

Ibuprofen and indomethacin are among the commonly available NSAIDS shown to exhibit such anti-tumor effect. Interestingly, non-COX-inhibiting NSAIDS (eg, [R] flurbiprofen, an enantiomer of ibuprofen) may also be effective suggesting that inhibition of cell survival may not be COX-mediated.

Although these findings and observations are promising, randomized-controlled trials are clearly needed to better define the role of NSAIDs in the clinical management of cancer.



  1. Zhao X, Xu Z, Li H. NSAIDs use and reduced metastasis in cancer patients: Results from a meta-analysis. Sci Rep 2017; 7:1875.
  2. Qian BZ. Inflammation fires up cancer metastasis. Semin Cancer Biol 2017; 47:170-176.
  3. Khwaja F, Allen J, Lynch J, Andrews P, Djakiew D. Ibuprofen inhibits survival of bladder cancer cells by induced expression of the p75NTR tumor suppressor protein. Cancer Res 2004; 64:6207-6213.
  4. Krygier S, Djakiew D. Neurotrophin receptor p75NTR suppresses growth and nerve growth factor-mediated metastasis of human prostate cancer cells. Int J Cancer 2002; 98:1-7.

Contributed by Camilo Campo, Medical Student, Harvard Medical School, Boston, MA.

Can non-steroidal anti-inflammatory drugs (NSAIDs) suppress cancer metastasis?

Can my patient with renal insufficiency safely undergo gadolinium-based contrast MRI?

It may be possible for patients with renal insufficiency, including those with end-stage kidney disease (ESKD), to undergo MRI using potentially safer preparations of gadolinium-based contrast agents (GBCAs) with “very low, if any” risk of the feared nephrogenic systemic sclerosis (NSF). 1

In contrast to the so called “linear” chelates of gadolinium (eg, gadodiamide, gadopentetate), “cyclic” GBCA’s (eg, gadoteridol) have not been clearly associated with NSF. 2 A Veterans Administration study involving gadoteridol identified no cases of NSF among the 141 patients on hemodialysis following 198 exposures. 2 In fact, the 2017 American College of Radiology (ACR) Manual on Contrast Media reports the risk of NSF with cyclic chelates as “very low, if any”. 1 Even when a cyclic GBCA is used in patients with ESKD, however, hemodialysis is recommended as soon as possible after MRI. 3

GBCAs are chelates with 2 major components: gadolinium and either a linear or cyclic ligand. Cyclic ligands bind to gadolinium more avidly, resulting in lower probability of circulating renally-cleared free gadolinium which when deposited in tissue is thought to potentially trigger NSF.2

Although NSF is characterized by progressive fibrosis of skin and soft tissue, it may involve multiple organs with an estimated 30% mortality rate. 4

 Bonus Pearl: Did you know NSF is really a new disease, with no evidence of its existence before 1997?


  1. “Nephrogenic Systemic Fibrosis”. In ACR Manual on Contrast Media; Version 10.3; May 31, 2017.
  2. Reilly RF. Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long-term hemodialysis. Clin J Am Soc Nephrol 2008;3:747-51.
  3. Wang Y, Alkasab TK, Nari O, et al. Incidence of nephrogenic systemic fibrosis after adoption of restrictive gadolinium-based contrast agent guidelines. Radiology 2011;260:105-111.
  4. Schlaudecker JD, Bernheisel CR. Gadolinium-associated nephrogenic systemic fibrosis. Am Fam Physician 2009;80:711-14.


Contributed by Richard Newcomb, MD, Mass General Hospital, Boston, MA.

Can my patient with renal insufficiency safely undergo gadolinium-based contrast MRI?

Why isn’t my patient with congestive heart failure or end-stage liver disease losing weight despite being on diuretic therapy? Is the diuretic dose too low, or is the salt intake too high?

When a patient with congestive heart failure (CHF) or end-stage liver disease (ESLD) doesn’t respond as expected to diuretic therapy, measurement of urinary sodium (Na) can be helpful.

In low effective arterial blood volume states (eg, CHF and ESLD) aldosterone secretion is high, resulting in high urine potassium (K) and low urine Na concentrations. However, in the presence of diuretics, urinary Na excretion should rise.

Patients undergoing active diuresis are often restricted to a 2 g (88 mEq) Na intake/day, with ~10 mEq excreted via non-urinary sources (primarily stool), and ~ 78 mEq excreted in the urine to “break even” — that is, to maintain the same weight.

Although historically measured 1, a 24-hour urine Na and K collection is tedious, making spot urine Na/K ratio more attractive as a potential proxy.  Approximately 90% of patients who achieve a urinary Na/K ratio ≥1 will have a urinary Na excretion ≥78 mEq/day — that is to say, they are sensitive to the diuretic and will have a stable or decreasing weight at the current dose. 2,3

Urine Na/K may be interpreted as follows:

  • ≥1 and losing weight suggests effective diuretic dose, adherent to low Na diet
  • ≥1 and rising weight suggests effective diuretic dose, non-adherent to low Na diet
  • <1 and rising weight suggests ineffective diuretic dose

The “ideal” Na/K ratio as relates to responsiveness to diuretics has ranged from 1.0 to 2.5.4 In acutely decompensated heart failure patients on spironolactone, a K-sparing diuretic, Na/K ratio >2 at day 3 of hospitalization may be associated with improved outcome at 180 days. 5

Remember also that if the patient’s clinical syndrome is not correlating well with the ratio, it’s always a good idea to proceed to a 24-hour urine collection.



  1. Runyon B. Refractory Ascites. Semin Liver Dis. Semin Liver Dis. 1993 Nov;13(4):343-51.
  2. Stiehm AJ, Mendler MH, Runyon BA. Detection of diuretic-resistance or diuretic-sensitivity by spot urine Na/K ratios in 729 specimens from cirrhotics with ascites: approximately 90 percent accuracy as compared to 24-hr urine Na excretion (abstract). Hepatology 2002; 36: 222A.
  3. da Silva OM, Thiele GB, Fayad L. et al. Comparative study of spot urine Na/K ratio and 24-hour urine sodium in natriuresis evaluation of cirrhotic patients with ascites. GE J Port Gastroenterol 2014;21:15-20
  4. El-Bokl M, Senousy, B, El-Karmouty K, Mohammed I, Mohammed S, Shabana S, Shelby H. Spot urinary sodium for assessing dietary sodium restriction in cirrhotic ascites. World J Gastroenterol 2009; 15:3631.
  5. Ferreira JP, Girerd N, Medeiros PB, et al. Spot urine sodium excretion as prognostic marker in acutely decompensated heart failure: the spironolactone effect. Clin Res Cardiol 2016;105:489-507.


Contributed by Alyssa Castillo, MD, with valuable input from Sawalla Guseh, MD, both from Mass General Hospital, Boston, MA.

Why isn’t my patient with congestive heart failure or end-stage liver disease losing weight despite being on diuretic therapy? Is the diuretic dose too low, or is the salt intake too high?

My patient just developed a fixed drug reaction from ibuprofen. What is the mechanism of this type of skin reaction?

Although its mechanism is not full elucidated, fixed drug eruption (FDE) is thought to result from the drug-induced cytotoxic activation of CD8+ memory T cells.1 ,2

In this context, the culprit medication behaves as a hapten that adheres to basal keratinocytes which in turn results in the recruitment of T cells and inflammation.  However, as the inflammation resolves, CD8+  effector-memory T cells remain in the area in question,  setting the stage for more rapid immunologic reaction when the drug is reintroduced.

Why a systemic drug triggers a reaction only at specific sites in the body is a fascinating question. Prior herpes simplex virus (HSV) infection (eg, on the lips or genitalia) may explain some cases.1 Interestingly, despite the absence of prior herpetic lesions, most patients with FDE are seropositive for HSV. Previously traumatized body sites (e.g. from burns or insect bites) may also create an immune microenvironment conducive to FDE.

The classic presentation of FDE is reappearance of a rash in the genitals, perianal areas, hands, and feet within 30 min to 8 hours of taking the culprit medication.3 Look specifically for NSAIDs, tetracyclines, sulfonamides, and aspirin on the patient’s drug list. 4


  1. Shiohara, T. Fixed drug eruption: Pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol 2009; 9:316-21.
  2. Butler, DF. Fixed Drug Eruptions. Medscape. Accessed March 26, 2018.
  3. Korkij W, Soltani K. Fixed drug eruptions: A brief review. Arch Dermatol 1984;120:520.
  4. Oakley, A. Fixed Drug Eruption. Accessed March 26, 2018.


Contributed by Amir Hossein Ameri, Medical Student, Harvard Medical School

My patient just developed a fixed drug reaction from ibuprofen. What is the mechanism of this type of skin reaction?