Is there a preference between ceftazidime and cefepine in patients undergoing hemodialysis?

Why is ceftazidime used in patients undergoing hemodialysis? Why choose ceftazidime over cefepime?

Comment by InpharmD Researcher

While there is no literature on the optimal cephalosporin for patients undergoing hemodialysis, ceftazidime and cefazolin are unique in allowing thrice weekly dosing after dialysis sessions. Both cefepime and ceftazidime are associated with neurotoxicity risk in patients with renal impairment, with no literature showing one agent to be safer than the other.

Background

Cefepime and ceftazidime are fourth- and third-generation cephalosporins, respectively, that have similar antimicrobial coverage due to a pyrrolidine group at the C3 position for stability and a carboxy-propanoxyamino group at C7 to aid in outer membrane transport. Both agents can penetrate the blood-brain barrier and cover bacteria in the cerebral spinal fluid. However, this can also result in neurotoxicity at higher doses or in patients with renal impairment due to accumulation. Concentration needs to be above the minimum inhibitory concentration (MIC) for as long as possible for time-dependent antibiotics, such as cephalosporins. Both cefepime and ceftazidime are associated with neurotoxicity in patients with renal impairment. However, renally excreted cephalosporins, such as ceftazidime and cefazolin, allow for streamlined dosing in hemodialysis. Due to the advantageous pharmacokinetics, ceftazidime can be given 3 times weekly after dialysis, which can optimize convenience and adherence. [1], [2]

Ceftazidime is described as a cost-effective, third-generation cephalosporin with a broad spectrum of activity against Gram-negative bacteria. It is largely eliminated through the urine, and its elimination is significantly impacted in patients with end-stage renal disease (ESRD), necessitating dose adjustments. Various studies have examined the efficacy of ceftazidime in dialysis patients, with a focus on achieving optimal drug levels to combat infections, especially those caused by P. aeruginosa. Dose adjustment based on the type of dialysis (low-flux vs. high-flux filters) and the renal function of the patient is important for safety and efficacy. Studies suggest that a dosing strategy that achieves concentrations above the minimum inhibitory concentration (MIC) for a significant portion of the dosing interval leads to better clinical outcomes. For ceftazidime, dosing recommendations for patients with ESRD and on intermittent hemodialysis (IHD) have evolved, with more recent models supporting adjusted doses to maintain effective drug levels and minimize toxicity. Cefepime offers a wide range of activity against both Gram-positive and Gram-negative bacteria but lacks efficacy against anaerobes and MRSA. Like ceftazidime, it is predominantly eliminated by the kidneys, with its pharmacokinetics significantly altered in patients undergoing IHD. Some studies suggest higher dosing to maintain effective drug concentrations in some patients. However, this increases the risk of cefepime-induced neurotoxicity, especially at elevated trough levels, underscoring the importance of dose adjustments in patients with renal impairments. Both antibiotics require careful dose adjustments in patients with renal impairment or those on hemodialysis to achieve therapeutic efficacy while minimizing the risk of toxicity. [3]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Why is ceftazidime used in patients undergoing hemodialysis? Why choose ceftazidime over cefepime?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

An optimal extended-infusion dosing of cefepime and ceftazidime in critically ill patients with continuous renal replacement therapy
Design	Pharmacokinetic modeling study
Objective	To determine optimal extended-infusion dosing regimens for cefepime and ceftazidime in critically ill patients receiving continuous renal replacement therapy (CRRT) using Monte Carlo Simulations
Methods	A one-compartment mathematical pharmacokinetic (PK) model with first-order elimination was developed using demographic and PK data derived from previously published studies on critically ill patients undergoing CRRT. The CRRT setup was modeled as continuous venovenous hemofiltration (CVVH) with post-hemofilter dilution techniques. The PK model aimed to achieve aggressive pharmacodynamic targets, particularly maintaining free drug concentrations above four times the minimum inhibitory concentration (MIC) of P. aeruginosa for at least 60% of the dosing interval. The study also assessed the risk of neurotoxicity by keeping trough plasma concentrations below certain levels (20 mg/L for cefepime and 80 mg/L for ceftazidime) to minimize adverse effects. Four conventional cefepime and ceftazidime dosing regimens were simulated: 2-g loading dose infused over 0.5 h, followed by 1 or 2-g every 8 or 12 h with a 4-h extended-infusion. Three different CRRT effluent flow rates were simulated: 20, 30, and 45 mL/kg/h. Monte Carlo simulations were then used to predict drug exposure in 5000 modeled critically ill patients.
Outcome Measures	Probability of target attainment (PTA), calculated by 60% of time in the first 48 h of antibiotic therapy, that the free fraction of a drug serum concentration was 4 times greater than the target MIC Neurotoxicity risk, the percentage of 5000 simulated patients that were at or above the suggested neurotoxicity thresholds (i.e. total trough plasma concentration (20 mg/L and 80 mg/L for cefepime and ceftazidime respectively) at the end of 48 h of antibiotic therapy
Baseline Characteristics	Simulated demographic data		Cefepime		Ceftazidime
	Weight, kg		86.6 ± 29.2
	Volume of Distribution, L/kg (range)		0.48 ± 0.24 (0.16 to 1.11)		0.34 ± 0.20 (0.13 to 1.1)
	Non-renal Clearance, mL/min (range)		24.33 ± 11.25 (13 to 24)		15.9 ± 9.9 (8 to 37.7)
	Sieving Coefficient		0.86		0.90
	Free fraction		0.79 ± 0.09		0.86 ± 0.05
Results	CVVH Effluent Flow Rate	Dose	Cefepime		Ceftazidime
	CVVH Effluent Flow Rate	Dose	PTA	Neurotoxicity risk	PTA	Neurotoxicity risk
	20 mL/kg/h	2 g + 1 g q12h	5.6%	42.7%	25.9%	0%
		2 g + 1 g q8h	42.6%	98.4%	75.7%	0.1%
		2 g + 2 g q12h	53.3%	95.3%	83.2%	0.6%
		2 g + 2 g q8h	91.1%	100%	99.1%	43.5%
	30 mL/kg/h	2 g + 1 g q12h	0.4%	7.6%	4.4%	0%
		2 g + 1 g q8h	19.6%	87.1%	44.6%	0%
		2 g + 2 g q12h	26.4%	82.2%	54.5%	0%
		2 g + 2 g q8h	81.6%	99.9%	95.8%	8.7%
	45 mL/kg/h	2 g + 1 g q12h	0%	0.06%	0%	0%
		2 g + 1 g q8h	3.4%	40.1%	10.9%	0%
		2 g + 2 g q12h	4.8%	35.7%	14.1%	0%
		2 g + 2 g q8h	59.8%	98.7%	79.7%	0.2%
	The bolded results represent optimal doses with ≥90% of PTA.
Study Author Conclusions	Cefepime and ceftazidime 2 g LD, followed by extended-infusion 2 g every 8 hours, may be optimal in CVVH with standard effluent rates.
InpharmD Researcher Critique	This study is limited by the pharmacokinetic modeling and dose simulations based on previously published literature, assuming patients were anuric adults. The modeling was based on patients receiving CVVH with no downtime. Additionally, models were only carried out over the first 48 hours of treatment, so the results may not apply to the remaining treatment course. Patients with recovering or residual renal function may need a higher cefepime or ceftazidime dose, while prolonged CVVH interruption may necessitate adjustment to a lower dose. The results also only apply to Pseudomonas aeruginosa with an assumed MIC of 32 mg/L, suggesting lower doses may be optimal for organisms with lower MICs (i.e., < 8 mg/L).

References:

Sember AM, LoFaso ME, Lewis SJ. An optimal extended-infusion dosing of cefepime and ceftazidime in critically ill patients with continuous renal replacement therapy. J Crit Care. 2022;69:154011. doi:10.1016/j.jcrc.2022.154011

Retrospective review of neurotoxicity induced by cefepime and ceftazidime
Design	Retrospective review N= 54
Objective	To compare cefepime- and ceftazidime-induced neurotoxicity
Study Groups	Cefepime-treated (n= 42) Ceftazidime-treated (n= 12)
Inclusion Criteria	Patients treated with cefepime and ceftazidime; presented with neurotoxicity
Exclusion Criteria	Neurological disturbance attributed to other causes
Methods	Patients were identified via retrospective chart review of a single center in Hong Kong as well as aggregated from previously published literature of those treated with cefepime and ceftazidime with documented neurotoxicity. Included reactions were confused state, dysarthria, somnolence, psychosis, myoclonus, seizures, and coma. Resolution of these effects after withdrawal of the implicated agent was considered supportive evidence. Other causes of neurologic disturbance were excluded. Improvement of electroencephalographic (EEG) abnormalities after intensified dialysis or resolution of uremia were not attributed to antibiotic neurotoxicity.
Duration	Patients were treated between 1999 to 2002
Outcome Measures	Neurologic effects in dialysis patients
Baseline Characteristics		Cefepime-treated patients (n= 42)	Ceftazidime-treated patients (n= 12)	p-Value
	Age, years	61 ± 19	65 ± 13	NS
	Female	22 (53%)	5 (42%)	NS
	Serum creatinine, mg/dL	8.3 ± 5.1	6.5 ± 3.7	NS
	Concurrent condition Regular dialysis therapy Acute renal failure Transplant recipient (kidney, lung)	9 (21%) 5 (12%) 4 (10%)	5 (42%) 4 (33%) 0	NS
	Clinical features Seizures Confusion Myoclonus	6 (14%) 39 (93%) 12 (29%)	1 (8%) 11 (91%) 6 (50%)	NS
	Length of drug therapy before symptom onset, days	5 (4-10)	6.5 (4-11)	NS
	Time lag between symptom onset and diagnosis, days	5 (4-6)	3 (2-4)	0.005
	Duration of symptoms, days	8 (5-10)	4 (4-6)	0.014
	Daily dose, g	2	4	-
	NS, not significant
Results	Endpoint	Cefepime-treated patients (n= 42)	Ceftazidime-treated patients (n= 12)
	Neurological effects while in patients undergoing dialysis	3	3
	Neurological status returned to normal in all patients after withdrawal of cefepime and ceftazidime.
Adverse Events	N/A
Study Author Conclusions	The authors found that cefepime can cause neurologic adverse effects similar to those induced by ceftazidime. However, delays have occurred in recognizing this problem. Clinicians awareness of the potential neurotoxicities with these agents must be increased so that the time between symptom onset and diagnosis can be reduced.
InpharmD Researcher Critique	This study provides little insight into reasoning regarding choice of either agent in patients undergoing hemodialysis. However, although both can cause similar neurologic effects, diagnosis of neurotoxicity was delayed in patients treated with cefepime.

References:

Chow KM, Szeto CC, Hui AC, Wong TY, Li PK. Retrospective review of neurotoxicity induced by cefepime and ceftazidime. Pharmacotherapy. 2003;23(3):369-373. doi:10.1592/phco.23.3.369.32100