eMedicine Specialties > Gastroenterology > Colon

Neutropenic Enterocolitis

Keith Sultan, MD, Faculty Practice, Division of Gastroenterology, Hepatology and Nutrition, North Shore University Hospital, Manhasset, New York
Rajeev Vasudeva, MD, FACG, Clinical Professor of Medicine, Consultants in Gastroenterology, University of South Carolina School of Medicine

Updated: Jul 9, 2009

Introduction

Background

Neutropenic enterocolitis, also known as typhlitis (from the greek "typhlon" for cecum) is an acute life-threatening condition classically characterized by transmural inflammation of the cecum, often with involvement of the ascending colon and ileum, in patients who are severely myelosuppressed.^{1,2,3,4,5,6,7,8}

The clinical presentation of neutropenic enterocolitis (typhlitis) can be dramatic, and the outcome may be devastating. Mortality rates are high, and treatment is controversial, with options varying from conservative medical management to surgical intervention.^{1,2,3,4,5,6,7,8} Early recognition of neutropenic enterocolitis (typhlitis) is paramount to a potentially good outcome.

Although initially described in children undergoing chemotherapy for leukemia⁹ over the past 3 decades, neutropenic enterocolitis (typhlitis) has increasingly been reported in adults with a variety of myeloproliferative disorders, solid malignant tumors, and in the setting of immunosuppression with solid organ and bone marrow transplantation. Some cases in adults are due to the increasing use of myelotoxic chemotherapeutic regimens.

For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education articles Colitis, Abdominal Pain in Adults, and Complete Blood Count.

Pathophysiology

Although the exact etiology and progression of neutropenic enterocolitis (typhlitis) are unknown, profound neutropenia appears to be the common denominator. Many factors have been described that may potentially play a role in the pathogenesis of neutropenic enterocolitis (typhlitis), and they include the following:

• Mucosal injury caused by cytotoxic drugs – However, mucosal injury can occur in the absence of cytotoxic drug therapy, and neutropenia itself can cause mucosal ulcerations.
• Cecal distention – Whether primary or secondary to vinca alkaloids, cecal distention may compromise the blood supply, leading to further mucosal damage.
• The use of antibiotics and steroids – These agents may contribute to an altered enteric bacterial flora and overgrowth of fungi.
• Bacterial, and sometimes fungal invasion of the impaired bowel wall – These may result in transmural inflammation, leading to perforation and peritonitis. Bacteremia is a frequent complication, with less frequent fungemia.¹⁰

The pathologic process of neutropenic enterocolitis (typhlitis) may involve the cecum alone, or it may extend to the ileum, ascending colon, or both. It is felt that cecal distensibility and limited blood supply may predispose the cecum to injury more often than other areas.

Frequency

United States

The exact incidence and prevalence rates of neutropenic enterocolitis (typhlitis) are unknown, because many patients survive and are never diagnosed with this condition. Also, because there is no gold standard of diagnosis for neutropenic enterocolitis (typhlitis), the inclusion criteria differ among studies.

An autopsy study in children reported a prevalence rate of 24%,¹¹ whereas a cohort study in children treated for acute myelogenous leukemia (AML) reported a frequency rate of 33%.¹² Data regarding neutropenic enterocolitis (typhlitis) in adults are sparse. In one systematic review, a 5.3% pooled incidence rate was been reported in adults.¹⁰  

International

An even greater paucity of information regarding the international incidence and prevalence rates of neutropenic enterocolitis (typhlitis) exists in the published literature. A study from India performed by Jain et al reported a frequency rate of 6.1% in 180 children undergoing chemotherapy for acute lymphocytic leukemia (ALL).¹³ A retrospective study from Turkey performed by Buyukasik et al reported an incidence rate of 6.5% for neutropenic enterocolitis (typhlitis) in acute myeloid leukemia and 4.6% for neutropenic enterocolitis (typhlitis) in acute lymphoblastic leukemia.¹⁴  Another Turkish study, a large prospective cohort study of adults, showed an incidence rate of 3.5%, which was significantly associated with acute leukemias and anthracycline administration in adults.¹⁵  

Mortality/Morbidity

• Mortality rates of 5-100% have been reported during conservative management of neutropenic enterocolitis (typhlitis), with an average mortality rate of about 40-50%.
• In a collective review of 178 published cases, the mortality rate of neutropenic enterocolitis (typhlitis) was reported at 48% for conservative management and 21% for surgical management; however, these numbers cannot be compared with each other because of selection bias. No prospective randomized trials comparing surgery to medical management have been performed.

Race

No predilection for neutropenic enterocolitis (typhlitis) in any specific race is reported in the literature.

Sex

No sex predilection for neutropenic enterocolitis (typhlitis) is reported in the literature.

Age

• No known frequency differences in age groups exist for neutropenic enterocolitis (typhlitis) based on the published literature.
• Although neutropenic enterocolitis (typhlitis) was initially described in children, it is increasingly reported in adults.

Clinical

History

Most patients who are affected with neutropenic enterocolitis (typhlitis) are receiving antineoplastic drugs and are profoundly neutropenic (ie, <1000 cells/mm³).

• Symptoms of neutropenic enterocolitis (typhlitis) usually occur within 10-14 days after initiation of cytotoxic chemotherapy.
• The typical presentation mimics acute appendicitis.
• Symptoms include the following:
  • Right lower quadrant abdominal pain, which may be cramping and intermittent or a continuous dull ache
  • Fever
  • Watery or bloody diarrhea,¹⁵ which occurs in about 25-45% of patients
  • Nausea
  • Vomiting
  • Abdominal distention
• Oral and pharyngeal mucositis, which may manifest before the onset of colonic symptoms
  

  

  Ulcerative oral mucositis lesion on the lateral and ventral surfaces of the tongue.

  
  
• The time course and severity of the clinical presentation of neutropenic enterocolitis (typhlitis) is variable.

Physical

Physical findings in patients with neutropenic enterocolitis (typhlitis) vary depending on the severity of the disease and the presence or absence of complications.

• Abdominal distention, hypoactive bowel sounds, and a tympanitic abdomen may suggest an ileus.
• The abdomen may be markedly tender, especially in the right lower quadrant.
• The cecum may be palpated as a boggy mass.
• Rebound tenderness and rigidity may suggest colonic perforation.
• Shock may be present due to sepsis.

Causes

Although cytotoxic chemotherapeutic agents account for most cases of neutropenic enterocolitis (typhlitis), other conditions that may predispose some patients to develop this condition exist.

• The cytotoxic chemotherapeutic agents include cytosine arabinoside, vinca alkaloids, and doxorubicin.
• Other drugs that have been implicated anecdotally include paclitaxel, docetaxel, procainamide, sulfasalazine, 5-fluorouracil, vinorelbine, carboplatin, cisplatin, gemcitabine, and leucovorin. 
• There have been newly described cases of neutropenic enterocolitis (typhlitis) associated with the monoclonal antibody alemtuzumab¹⁶ as well as with pegylated interferon (PEG-INF) with ribavirin.¹⁷
• Other predisposing conditions for neutropenic enterocolitis (typhlitis) include the following:
  • Myelodysplastic syndromes, multiple myeloma, and aplastic anemia
  • Solid organ and bone marrow transplantation
  • Acquired immunodeficiency syndrome (AIDS)
  • Cyclic neutropenia
  • Solid malignant tumors
  • Lymphomas

Differential Diagnoses

Other Problems to Be Considered

Intussusception
Ischemic colitis
Leukemic or lymphomatous infiltration of the bowel wall
Small bowel obstruction

Workup

Laboratory Studies

• A complete blood cell (CBC) count is used to confirm neutropenia.
• A serum bicarbonate level and pH value should be obtained to rule out acidosis.
• Stool studies are obtained for the following:
  • Clostridium difficile toxin to rule out pseudomembranous colitis
  • Culture for enteric pathogens to rule out infectious causes of enterocolitis
• Blood cultures are obtained for aerobic/anaerobic bacteria and fungus to rule out bacterial and fungal sepsis.

Imaging Studies

• Plain abdominal radiographs rarely help in the diagnosis of neutropenic enterocolitis (typhlitis). Radiographic findings usually are nonspecific and may even be normal. Nonspecific findings may include the following:
  • Right-sided colonic and small bowel dilatation
  • Thumbprinting (see Image 5 or below) of the right colon
    

    

    Plain abdominal radiograph in a 44-year-old man known to have long history of ulcerative colitis. The patient presented with an acute exacerbation of symptoms. Image shows thumbprinting in the region of the splenic flexure of the colon.

    
    
  • Paucity of air in the right colon due to a fluid-filled colon
  • Intramural air or pneumatosis
  • Soft-tissue mass displacing the small bowel
• Barium enema is usually contraindicated, especially if a potential for perforation exists. Water-soluble contrast may demonstrate rigidity and thickening of the cecum.
• Abdominal ultrasonography
  • Abdominal ultrasonography is one of the most important diagnostic studies for neutropenic enterocolitis (typhlitis), and it is preferable to contrast enemas. This may be useful as a follow-up tool to assess the gradual decrease in bowel wall thickening.
  • Findings include thickening of the bowel wall that produces a target or halo sign. However, this is a nonspecific finding and may be observed in other conditions listed under the differential diagnosis (see Differentials).
  • Bowel wall thickness has also been suggested as a significant prognostic factor regarding patient outcome in individuals with neutropenic enterocolitis (typhlitis). A retrospective study using ultrasonography showed that a bowel wall thickness of greater than 5 mm was associated with a higher mortality (29%) than in those without bowel wall thickening (0%).¹⁸ If one takes a bowel wall thickness cutoff of greater than 10 mm, the mortality was 60% compared with 4.2% in those without bowel wall thickening.
  • Bowel wall thickening has also been associated with the duration of illness and neutropenia in neutropenic enterocolitis (typhlitis).¹⁹
  • Ultrasonography also allows for follow-up imaging without repeated exposure to ionizing radiation, an especially important consideration in children and younger adults.
• Computed tomography (CT) scanning of the abdomen is the diagnostic procedure of choice in neutropenic enterocolitis (typhlitis), because this imaging modality has a lower false-negative rate (15%) compared with ultrasonography (23%) or plain abdominal radiographs (48%) (see Images 6-7 or below). CT scanning is the test of choice to diagnose alternative causes of abdominal pain such as megacolon, appendicitis, and small bowel obstruction.^16,20,21  
  

  

  Typhlitis. Marked asymmetric cecal wall thickening (arrow) in a 64-year-old patient whose status is postchemotherapeutic for lymphoma.

  
  
  

  

  Typhlitis. Marked circumferential cecal and ascending colon wall thickening (large arrows) with mild pericolonic inflammatory stranding (small arrows).

  
  Findings include the following:
  • Symmetrical thickening of the cecum
  • Fluid-filled cecum
  • Pericecal inflammation
  • Free air if an underlying perforation exists
  • Portal venous gas

Procedures

• Endoscopic procedures include colonoscopy or flexible sigmoidoscopy.
  • These procedures are relatively contraindicated in patients with neutropenic enterocolitis (typhlitis) due to an increased risk of complications, especially in the setting of underlying neutropenia and thrombocytopenia.
  • Usually, these procedures are unnecessary, except in rare circumstances in which a gentle sigmoidoscopy may aid in the diagnosis of pseudomembranous colitis (see Image 2 or below).
    

    

    Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M. Osgard, MD.

    
    

Histologic Findings

Gross and microscopic findings of neutropenic enterocolitis (typhlitis) include diffuse bowel wall thickening with mucosal and intramural edema and necrosis, mucosal ulcerations, and intramural or intraluminal hemorrhage. The bowel wall specimens obtained during colectomy or at autopsy demonstrate an abundance of bacteria, a striking lack of lymphoid inflammatory cells, and a virtual absence of neutrophils.

Treatment

Medical Care

No published randomized control trials comparing conservative medical therapy with surgical intervention in neutropenic enterocolitis (typhlitis) exist; however, advocates for both types of therapy exist. The outcome appears to reflect the state of the underlying disease and other comorbidities at the time of clinical presentation rather than the treatment modality. Therefore, a uniform management strategy for neutropenic enterocolitis (typhlitis) cannot be recommended. Individualize the approach to each patient. Early recognition of neutropenic enterocolitis (typhlitis) in a patient who is neutropenic is paramount to a good outcome.

• Conservative management includes the following:
  • Bowel rest and nasogastric suction
  • Close monitoring of patients using serial abdominal examinations in an intensive care setting
  • Intravenous fluids, blood, and platelet transfusions as necessary
  • Parenteral broad-spectrum antibiotics: Antibiotics should include agents covering enteric gram-negative and anaerobic organisms, including Clostridium species. Metronidazole may also be considered if pseudomembranous colitis cannot immediately be excluded.
  • Cultures: Obtain blood cultures for fungus, and consider early use of antifungal agents if the disease does not respond to antibiotics.²²   
  • Avoidance of certain medications: Anticholinergic agents, antidiarrheal drugs, and narcotics may worsen the condition or further confuse the clinical picture of neutropenic enterocolitis (typhlitis).

Surgical Care

• Immediate surgery has been proposed by Shamberger et al in patients with neutropenic enterocolitis (typhlitis) and the following indications¹² :
  • Free intra-abdominal perforation
  • Clinical deterioration during conservative medical therapy
  • Differentiation from other acute abdominal conditions for which surgery is indicated
  • Unrelenting intra-abdominal sepsis or abscess formation
  • Continued hemorrhage with a platelet count and coagulation parameters within the reference range
• Tailor the surgical procedure to the operative findings.
• Choice of surgical procedures includes the following:
  • Cecostomy and drainage
  • A 2-stage right hemicolectomy or total abdominal colectomy, with or without a primary anastomosis
  • Defunctioning of the colon with a loop ileostomy
• Normal-appearing serosal surfaces may conceal mucosal breakdown and necrosis. Therefore, resection should be extensive to assure removal of the diseased bowel.
• Consider elective right hemicolectomy in patients who have required repeated courses of chemotherapy and who have responded to initial conservative medical therapy. Recurrent episodes of neutropenic enterocolitis (typhlitis) have been reported in such patients.

Consultations

Joint management between medical and surgical teams is extremely important for a good outcome in patients with neutropenic enterocolitis (typhlitis).

Diet

Because the patient is fasting and on bowel rest, consider parenteral nutrition.

Activity

Patients with neutropenic enterocolitis (typhlitis) are usually extremely ill and in the intensive care setting on complete bed rest.

Medication

Because patients with neutropenic enterocolitis (typhlitis) have received numerous courses of antibiotics previously for other indications, a specific agent or regimen cannot be recommended, and the decision must be made on an individual basis. However, a few possible choices of antibiotics and antifungals are listed below. The author favors a combination of amikacin plus imipenem or cefepime/ceftazidime plus metronidazole in addition to vancomycin.

Consider adding antifungal agents if clinical improvement does not occur with antibiotics.

Antibiotics

Empiric broad-spectrum antibiotics are recommended to cover potential primary or secondary infectious causes of neutropenic enterocolitis (typhlitis) and to control sepsis. The antibiotics should cover aerobic and anaerobic enteric organisms, including Clostridium species, because anecdotal reports reveal an association between Clostridium septicum and neutropenic enterocolitis (typhlitis).

Metronidazole (Flagyl)

Synthetic antibacterial with good activity against gram-negative anaerobes, including Bacteroides species, and gram-positive anaerobes, including Clostridium species.

Dosing

Adult

Loading dose for 70-kg adult: 15 mg/kg or 1 g IV over 1 h
Maintenance dose for 70-kg adult: 6 h following loading dose, infuse 7.5 mg/kg or 500 mg over 1 h q6-8h; not to exceed 4 g/d

Pediatric

Not established

Interactions

Cimetidine may increase the toxicity of metronidazole; may increase the effects of anticoagulants; may increase the toxicity of lithium and phenytoin; disulfiramlike reaction may occur with orally ingested ethanol

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust the dose in hepatic disease; monitor for seizures and development of peripheral neuropathy; alcoholic beverages should be avoided, because a disulfiramlike reaction may occur and manifest as nausea, vomiting, abdominal cramps, headaches, and flushing; the IV form has to be diluted and neutralized before infusion because of low pH of reconstituted product

Cefepime (Maxipime)

Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage. Covers pseudomonads.

Dosing

Adult

2 g IV q8h

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

At a high dose, probenecid decreases cefepime clearance; when used concurrently, aminoglycosides increasenephrotoxic potential of cefepime

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust the dose in patients with severe renal insufficiency; prolonged use of cefepime may predispose patients to superinfection

Ceftazidime (Ceptaz, Fortaz)

Semisynthetic, broad-spectrum, third-generation cephalosporin covering predominantly gram-negative aerobes, including pseudomonads. Provides poor coverage against gram-positive organisms and anaerobes.

Dosing

Adult

2 g IV q8h

Pediatric

30-50 mg/kg/dose IV q8h; not to exceed 6 g/d

Interactions

Nephrotoxicity may increase with aminoglycosides, furosemide, and ethacrynic acid; probenecid may increase ceftazidime levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust the dose in patients with renal impairment

Ceftriaxone (Rocephin)

Semisynthetic, broad-spectrum, third-generation cephalosporin covering gram-negative aerobes and anaerobes, including Bacteroides and Clostridium species. Not reliable for coverage against pseudomonads.

Dosing

Adult

1-2 g IV qd or divided bid; not to exceed 4 g/d

Pediatric

50-75 mg/kg/d IV/IM divided q12h; not to exceed 2 g/d

Interactions

Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust the dose in those with renal impairment; caution in women who are breastfeeding and in patients with an allergy to penicillin; reports of sonographic abnormalities in gallbladders of patients on this antibiotic exist, but clinical significance uncertain

Ticarcillin and clavulanate (Timentin)

Antipseudomonal penicillin plus beta-lactamase inhibitor that provides coverage against most gram-positive organisms, most gram-negative organisms, and most anaerobes.

Dosing

Adult

3.1 g IV q4-6h

Pediatric

200-300 mg/kg/d IV divided q4-6h

Interactions

Tetracyclines may decrease the effects of ticarcillin; high concentrations of ticarcillin may physically inactivate aminoglycosides if administered in the same IV line; effects when administered concurrently with aminoglycosides are synergistic; probenecid may increase penicillin levels

Contraindications

Documented hypersensitivity; treatment of severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, or purulent or septic arthritis with oral penicillin during acute stage

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Perform CBCs before the initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; exercise caution in patients diagnosed with hepatic insufficiencies; perform urinalysis and BUN and creatinine determinations during therapy and adjust the dose if values become elevated; monitor blood levels to avoid possible neurotoxic reactions

Piperacillin and tazobactam (Zosyn)

Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during stage of active multiplication.

Dosing

Adult

3.375 g IV q6h

Pediatric

Not established

Interactions

Tetracyclines may decrease effects; high concentrations may physically inactivate aminoglycosides if administered in the same IV line; effects when administered concurrently with aminoglycosides are synergistic; probenecid may increase penicillin levels

Contraindications

Documented hypersensitivity; treatment of severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, or purulent or septic arthritis with an oral penicillin during the acute stage

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Perform CBCs before the initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; exercise caution in patients diagnosed with hepatic insufficiencies; perform urinalysis and BUN and creatinine determinations during therapy and adjust the dose if values become elevated; monitor blood levels to avoid possible neurotoxic reactions

Vancomycin (Vancocin, Lyphocin)

Tricyclic glycopeptide indicated for the treatment of suspected or confirmed serious infection with methicillin-resistant staphylococci, an entity not uncommonly observed in patients who are severely ill and in the intensive care setting.

To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h before next dosing. Use creatinine clearance to adjust dose in patients diagnosed with renal impairment.

Dosing

Adult

500 mg IV q6h or 1 g IV q12h

Pediatric

10 mg/kg IV q6h

Interactions

Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; when taken concurrently with aminoglycosides, the risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in the presence of renal failure and neutropenia; red man syndrome is caused by IV infusion administered too rapidly (dose administered over a few min) but rarely happens when the dose is administered as 2-h administration or as PO or IP administration; red man syndrome is not an allergic reaction

Imipenem and cilastatin (Primaxin)

Potent broad-spectrum combination antibiotic consisting of a thienamycin class of antibiotic and cilastatin, which is an inhibitor of renal dipeptidase. Coverage includes gram-negative aerobes and anaerobes.

Dosing

Adult

500 mg IV q6h

Pediatric

15-25 mg/kg/dose IV q6h

Interactions

Coadministration with cyclosporine may increase the CNS adverse effects of both agents; coadministration with ganciclovir may result in generalized seizures

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust the dose in patients with renal insufficiency; avoid use in children <12 y

Amikacin (Amikin)

For gram-negative bacterial coverage of infections resistant to gentamicin and tobramycin. Effective against Pseudomonas aeruginosa.
Irreversibly binds to 30S subunit of bacterial ribosomes. Blocks recognition step in protein synthesis and causes growth inhibition. Use the patient's IBW for dosage calculation.

Dosing

Adult

7.5 mg/kg IV/IM q12h

Pediatric

Administer as in adults

Interactions

Coadministration with other aminoglycosides, penicillins, cephalosporins, and amphotericin B increases nephrotoxicity; enhances the effects of neuromuscular blocking agents; causes respiratory depression; irreversible hearing loss may occur with the coadministration of loop diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not intended for long-term therapy; caution in patients with renal failure (not on dialysis), hypocalcemia, myasthenia gravis, and conditions that depress neuromuscular transmission; aminoglycosides have the potential to cause tubular necrosis and renal failure, deafness due to cochlear toxicity, vertigo due to damage to the vestibular organs, and, rarely, neuromuscular blockade; the risk of nephrotoxicity is decreased by concomitant administration of antipseudomonal penicillin and once-daily dosing method; adjust the dose in the presence of renal impairment

Gentamicin (Garamycin)

Water-soluble aminoglycoside antibiotic with good coverage against gram-negative aerobes. Used in conjunction with other antibiotics for broad-spectrum coverage in intra-abdominal infections. Coadministration with carbenicillin or piperacillin provides synergistic effects against most strains of Pseudomonas aeruginosa. Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing). May draw a peak level 0.5 h after 30-min infusion.

Dosing

Adult

2 mg/kg IV loading dose, followed by 1.7 mg/kg IV q8h

Pediatric

2-2.5 mg/kg IV q8h

Interactions

Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; aminoglycosides enhance the effects of neuromuscular blocking agents, prolonged respiratory depression may occur; coadministration with loop diuretics may increase the auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly)

Contraindications

Documented hypersensitivity; nondialysis-dependent renal insufficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Narrow therapeutic index (not intended for long-term therapy); caution in patients with renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust the dose in the presence of renal impairment; aminoglycosides have the potential to cause tubular necrosis and renal failure, deafness due to cochlear toxicity, vertigo due to damage to vestibular organs, and, rarely, neuromuscular blockade; the risk of nephrotoxicity is decreased by concomitant administration of antipseudomonal penicillin and once-daily dosing method

Tobramycin (Nebcin)

Used in skin, bone, and skin structure infections caused by Staphylococcus aureus, P aeruginosa, Proteus species, Escherichia coli, Klebsiella species, and Enterobacter species. Indicated in the treatment of staphylococcal infections when penicillin or potentially less toxic drugs are contraindicated and when bacterial susceptibility and clinical judgment justifies its use.

Dosing

Adult

2 mg/kg IV loading dose, followed by 1.7 mg/kg IV q8h; to prevent increased toxicity caused by excessive blood levels, not to exceed 5 mg/kg/d unless serum levels are monitored

Pediatric

2-2.5 mg/kg IV q8h

Interactions

Increases the effects of neuromuscular blockers and potentiates the effect of extended-spectrum penicillins; concurrent administration with amphotericin B, cephalosporins, and loop diuretics increases the risk of nephrotoxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Avoid use in patients with renal impairment, preexisting auditory or vestibular impairment, or neuromuscular disorders; aminoglycosides are associated with nephrotoxicity and ototoxicity

Antifungal Agents

Consider adding antifungal agents if no clinical improvement occurs with broad-spectrum antibiotics. Amphotericin B is the preferred agent because non-albicans candidemia is more likely to be present and is usually fluconazole resistant. Consider liposomal amphotericin B if the infection is refractory to conventional amphotericin or in patients with renal failure.

Amphotericin B (Amphocil, Fungizone)

Produced by a strain of Streptomyces nodosus. Can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death.

Dosing

Adult

Nonlipid amphotericin B: 0.3-1 mg/kg/d IV as single infusion
Liposomal amphotericin B: 1-5 mg/kg/d IV as single infusion

Pediatric

Administer as in adults

Interactions

Antineoplastic agents may enhance potential for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine, azole antifungals, and skeletal muscle relaxants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC, and hemoglobin concentrations; resume therapy at the lowest level (eg, 0.25 mg/kg) when therapy is interrupted for >7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients who are neutropenic and receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); infusions can cause acute chills, fever, myalgia, anorexia, nausea, and, occasionally, hypotension, presumably due to the release of proinflammatory cytokines; febrile episodes cannot be prevented by premedicating with acetaminophen or diphenhydramine (responds to meperidine 25-50 mg IV)

Follow-up

Further Inpatient Care

• The patient with neutropenic enterocolitis (typhlitis) must be monitored in an intensive care setting with serial abdominal examinations.
• Use of recombinant granulocyte colony-stimulating factor (GCSF) may be considered in individual patients, depending on the clinical progression. Controlled trials using GCSF in this specific entity are lacking, although several case reports of a successful outcome have been reported in the literature. Moreover, a better understanding and definition of specific subsets of patients that may benefit from treatment or prevention of neutropenic enterocolitis (typhlitis) is needed.

Deterrence/Prevention

• Withhold further chemotherapy until complete recovery from neutropenic enterocolitis (typhlitis).
• Consider antibiotic prophylaxis in neutropenic patients. A meta-analysis by Gafter-Gvili  suggested an overall mortality benefit of antibiotic prophylaxis, although not specific to neutropenic enterocolitis (typhlitis).²³
• Another meta-analysis suggested a mortality benefit to primary prophylaxis with GCSFs in adult cancer patients, also not specific to neutropenic enterocolitis (typhlitis).²⁴
• Consider an elective right hemicolectomy in patients with neutropenic enterocolitis (typhlitis) who have successfully recovered and may require repeated courses of chemotherapy in the near future.¹

Complications

• Bowel perforation and peritonitis
• Gastrointestinal bleeding
• Gastrointestinal obstruction
• Intra-abdominal abscess
• Sepsis
• Death

Prognosis

• The prognosis of neutropenic enterocolitis (typhlitis) is generally poor, with mortality rates varying from 5% to 100% and averaging about 40-50%.
• The prognosis depends highly on the rapidity of restoration of the white blood cell (WBC) count.
• The potential for recovery from neutropenic enterocolitis (typhlitis) may be improved by early, accurate diagnosis along with aggressive and meticulous medical and supportive therapy.²⁵

Miscellaneous

Medicolegal Pitfalls

• Consider the possibility of neutropenic enterocolitis (typhlitis) in all patients who are immunosuppressed and have right lower quadrant pain.
• Early recognition of this condition is paramount to reducing mortality rates and achieving a potentially good outcome.
• Monitor the patient in an intensive care setting with frequent serial abdominal examinations.
• Joint management by the medical and surgical teams is essential for optimal management of neutropenic enterocolitis (typhlitis).

Multimedia

Media file 1: Ulcerative oral mucositis lesion on the lateral and ventral surfaces of the tongue.

Media file 2: Colonic pseudomembranes of pseudomembranous colitis. Photographs courtesy of Eric M. Osgard, MD.

Media file 3: Frontal abdominal radiograph in a patient with proved pseudomembranous colitis. Note the nodular haustral thickening, most pronounced in the transverse colon.

Media file 4: Perforated appendicitis with abscess; computed tomography scan. Note the appendicolith (arrow) and air within the abscess. The terminal ileum lies anterior to the appendiceal abscess, and inflammatory change is noted in its wall, which appears thickened (open arrow).

Media file 5: Plain abdominal radiograph in a 44-year-old man known to have long history of ulcerative colitis. The patient presented with an acute exacerbation of symptoms. Image shows thumbprinting in the region of the splenic flexure of the colon.

Media file 6: Typhlitis. Marked asymmetric cecal wall thickening (arrow) in a 64-year-old patient whose status is postchemotherapeutic for lymphoma.

Media file 7: Typhlitis. Marked circumferential cecal and ascending colon wall thickening (large arrows) with mild pericolonic inflammatory stranding (small arrows).

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Keywords

neutropenic enterocolitis, typhlitis, necrotizing enterocolitis, ileocecal syndrome, pseudomembranous colitis, typhlitis, acute ileocecal enterocolitis, transmural inflammation of the small bowel and large bowel in myelosuppression and immunosuppression, profound neutropenia, cecum, ileum, ascending colon, cecitis, right lower quadrant pain

Contributor Information and Disclosures

Author

Keith Sultan, MD, Faculty Practice, Division of Gastroenterology, Hepatology and Nutrition, North Shore University Hospital, Manhasset, New York
Keith Sultan, MD is a member of the following medical societies: American College of Gastroenterology and American Gastroenterological Association
Disclosure: Nothing to disclose.

Coauthor(s)

Rajeev Vasudeva, MD, FACG, Clinical Professor of Medicine, Consultants in Gastroenterology, University of South Carolina School of Medicine
Rajeev Vasudeva, MD, FACG is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, Columbia Medical Society, South Carolina Gastroenterology Association, and South Carolina Medical Association
Disclosure: Pricara Honoraria Speaking and teaching; UCB Consulting fee Consulting

Medical Editor

Robert J Fingerote, MD, MSc, BSc, FRCPC, Consultant, Clinical Evaluation Division, Biologic and Gene Therapies, Directorate Health Canada; Consulting Staff, Department of Medicine, Division of Gastroenterology, York Central Hospital, Richmond Hill, Ontario
Robert J Fingerote, MD, MSc, BSc, FRCPC is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, Canadian Medical Association, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Douglas M Heuman, MD, FACP, FACG, AGAF, Chief of Hepatology, Hunter Holmes McGuire Department of Veterans Affairs Medical Center; Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Douglas M Heuman, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, and American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

Related eMedicine Topics

• Colitis, Pseudomembranous [in the Radiology section]
• Necrotizing Enterocolitis [in the Radiology section]
• Necrotizing Enterocolitis, Surgical Treatment [in the Pediatrics: Surgery section]
• Neutropenia [in the Hematology section]
• Pseudomembranous Colitis [in the Infectious Disease section]
• Pseudomembranous Colitis, Surgical Treatment [in the General Surgery section]
• Typhlitis [in the Radiology section]

National Guideline Clearinghouse

• ACR Appropriateness Criteria® acute abdominal pain and fever or suspected abdominal abscess. American College of Radiology - Medical Specialty Society. 1996 (revised 2006). 7 pages. NGC:005138
• ASGE guideline: endoscopy in the diagnosis and treatment of inflammatory bowel disease. American Society for Gastrointestinal Endoscopy - Medical Specialty Society. 2006 Apr. 8 pages. NGC:004977
• Evidence-based care guideline for necrotizing enterocolitis (NEC) among very low birth weight infants. Cincinnati Children's Hospital Medical Center - Hospital/Medical Center. 2005 Jul 14 (revised 2007 Feb). 12 pages. NGC:005522

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