Antimicrobial desensitization

Background

• Goal of creating temporary tolerance to an antimicrobial to which the patient has a history of hypersensitivity reaction
• Best described for beta-lactam antibiotics with immediate IgE-mediated hypersensitivity reaction
• Must carefully evaluate risks and benefits

Procedure

• No well-defined universal procedure
• Most use a dilution of 0.1% or 1% of therapeutic dose as a continuous infusion (or oral, or subcut), with dose increased steadily over hours to days

Standardized IV Protocol

• As published in UpToDate
• Typically 12 steps with 3 concentrations
  • Can extend to 16 steps with 4 concentrations for particularly severe past reactions
  • Each step administered over 15 minutes with no waiting between doses
  • Total time is typically 5 to 6 hours
• Calculator exists at https://globalrph.com/medcalcs/desensitization-protocol-12-step/
• Preparation:
  • Hold beta blocks if possible
  • Transfer to ICU for 1:1 care
  • Have epinephrine, albuterol, diphenhydramine, and methylprednisolone available at bedside
• Managing reactions:
  • Mild reactions: stop the infusion and given IV diphenhydramine; once the symptoms resolve resume the protocol by repeating the step at which the reaction occurred
  • Severe reactions: stop the infusion and give epinephrine, diphenydramine, and methylprednisolone, as well as oxygen if needed, inhaled albuterol for bronchospasm, and IV normal saline; consider glucagon 1 to 2 mg IV bolus followed by 1 to 5 mg/hour infusion if patient was on beta-blockers
• For a 250 mL volume of 1 g of antimicrobial, the following is one example protocol:

Solution	Total Volume in mL	Dose (mg)	Concentration (for 1 g dose)
1	250 mL	1% of target dose (e.g. 10 mg)	0.04 mg/mL
2		10% of target dose (e.g. 100 mg)	0.4 mg /mL
3		100% of target dose (e.g. 1000 mg)	4 mg/mL

Step	Solution	Rate (mL/hour)	Time (min)	Volume (mL)	Dose Administered (for 1 g dose)	Cumulative Dose (for 1 g dose)
1	1	2	15	0.5	0.02 mg	0.02 mg
2		5		1.25	0.05 mg	0.07 mg
3		10		2.5	0.1 mg	0.17 mg
4		20		5	0.2 mg	0.37 mg
5	2	5		1.25	0.5 mg	0.87 mg
6		10		2.5	1 mg	1.87 mg
7		20		5	2 mg	3.87 mg
8		40		10	4 mg	7.87 mg
9	3	10		2.5	10 mg	18 mg
10		20		5	20 mg	38 mg
11		40		10	40 mg	78 mg
12		80	175	232	920 mg	1000 mg

Further Reading

• Antimicrobial Desensitization: A Review of Published Protocols. Pharmacy (Basel). 2019;7(3):112. doi: 10.3390/pharmacy7030112. PMID: 31405062; PMCID: PMC6789802.
• Evaluation of desensitization protocols to betalactam antibiotics. J Clin Pharm Ther. 2022;47(5):592-599. doi: 10.1111/jcpt.13578.
  • Tested and published protocols for several antimicrobials, including meropenem, ceftriaxone, ceftazidime, ampicillin, ceftolozane-tazobactam, cloxacillin, piperacillin-tazobactam, amoxicillin-clavulanate, and penicillin G sodium