Clinical considerations for oral beta-lactams as step-down therapy for Enterobacteriaceae bloodstream infections

Figures & data

Table 1. Summary of studies evaluating oral antibiotic regimens for Enterobacteriaceae bloodstream infections.

Study	Study design and population	Primary outcome	PO antibiotic studied	Most commonly reported dosing strategy of PO BL	Duration of therapy	Results
Kutob et al., 2016 [2]	Single-center, retrospective cohort study (n = 362)	Treatment failure rates of PO antibiotics for definitive therapy of GN BSI (all-cause mortality or recurrent infection within 90 days of initial episode)	High F (≥95%: levofloxacin [n = 106]) Moderate F (75–94%: ciprofloxacin [n = 151], TMP/SMX [n = 28]) Low F (penicillins [n = 42], cephalosporins [35])	A/C: 875/125 q12h (n = 21), 500/125 mg q8h (n = 9) Amoxicillin: 500 mg q8h (n = 10) Cephalexin: 500 mg q6h (n = 9) Cefuroxime: 500 mg q12h (n = 8) Cefdinir: 300 mg q12h (n = 7) Cefaclor: 250 mg q8h (n = 3) Cefpodoxime: 200 mg q12h (n = 1)	Mean 4.7 days of IV therapy followed by 9.1 days of PO therapy	Treatment failure risk greater with low F compared to high F: High F (2%); Moderate F (12%); Low F (14%); P = 0.02
Rieger et al., 2017 [4]	Single-center, retrospective cohort study (n = 241)	Treatment failure (escalation from PO to IV, antibiotic change, or 30-day readmission) of IV only versus partial or complete treatment with PO antibiotics for EB BSI from UTI source	Ciprofloxacin (63.5%) BL (19%) TMP/SMX (9.1%)	Not reported	Median IV therapy was 4 days (IQR 2–5) prior to PO switch	No statistically significant difference in treatment failure between IV only (3.8% [95% CI: 1.0–9.4%]) compared to IV/PO (8.2% [95% CI: 4.1 to 14.1%]; P = 0.19)
Mercuro et al., 2018 [3]	Single-center, retrospective cohort study (n = 224)	Compare efficacy (within 30 days after PO antibiotic completion) and safety between PO BL and FQ step-down therapy for EB BSI	BL (n = 84): A/C (n = 44), amoxicillin (n = 12), cephalexin (n = 19), cefdinir (n = 9); FQ (n = 140): ciprofloxacin (n = 84), levofloxacin (n = 55)	A/C: 875/125 mg q12h (n = 31), 500/125 mg q12h (n = 9), 500/125 mg q8h (n = 3), 500/125 mg q24h (n = 1); amoxicillin: 1000 mg q8h (n = 4), 1000 mg q12h (n = 2), 500 mg q8h (n = 3) 500 mg q12h (n = 3); cephalexin: 500 mg q6h (n = 11), 500 mg q8h (n = 6), 500 mg q12h (n = 2); cefdinir: NR	Median IV therapy was 3 days (IQR 3–4) Median total duration of therapy: 14 days (IQR 11–15)	PO BL was non-inferior to PO FQ (86.9% vs. 87.1%; mean difference 0.2%, 97.5% CI −10.3 to 10.7). Microbiological success (94.0% vs. 97.9%; P > 0.05) and 30-day re-admission (14.3% vs. 14.3%; P > 0.05) were similar

Abbreviations: A/C: amoxicillin-clavulanate; BL: beta-lactams; BSI: bloodstream infections; EB: Enterobacteriaceae; F: bioavailability; FQ: fluoroquinolone; GN: Gram-negative; IV: intravenous; NR: not reported; PO: oral; qxh: every x hours; TMP/SMX: trimethoprim-sulfamethoxazole; UTI: urinary tract infections.

Table 2. Pharmacokinetic parameters of commonly used oral penicillins and cephalosporins [8,9].

Antibiotic Class	Antibiotic	Bioavailability (%)	Protein binding (%)	Food Effect on Absorption	Peak Serum Concentration (mg/L)	Half-life (hours)
Oral Penicillins	Amoxicillin	74–92	20	Not Significant	3.5–5.0	1.0
	Amoxicillin- clavulanate	60	20	Not Significant	3.7–4.8	1.0
Oral Cephalosporins	Cephalexin	90–100	6–15	Not Significant	15–18	0.6–1.3
	Cefaclor	52–95	25	Not Significant	13–15	0.6–1.0
	Cefprozil	71–95	36	Not Significant	8.2–10.4	0.9–1.4
	Cefuroxime	30–52	33–50	Increase	7.0	1.0–2.0
	Cefdinir	21–25	60–70	Not Significant	1.6–2.3	1.7
	Cefpodoxime	29–53	22–33	Increase	3.9–4.5	2.2–2.8

Table 3. Percentage of free time above the minimum inhibitory concentration for various oral beta-lactam antibiotics.

Antibiotic	Dose (mg)/dosing interval (h)	%fT>MIC							Maximum MIC allowing for target attainment	Highest frequency wild-type MIC for E. coli*
		16 mg/L	8 mg/L	4 mg/L	2 mg/L	1 mg/L	0.5 mg/L	0.25 mg/L
Amoxicillin	500/8	–	13.0	23.0	33.0	43.0	53.0	63.0	0.5 mg/L	4 mg/L
Amoxicillin	1000/8	–	23.0	33.0	43.0	53.0	63.0	73.0	1 mg/L	4 mg/L
Amoxicillin-clavulanate	875/12	–	11.0	17.6	24.3	31.0	37.6	44.3	–	4 mg/L
Amoxicillin-clavulanate	875/8	–	16.4	26.4	36.4	46.4	56.4	66.4	0.5 mg/L	4 mg/L
Cephalexin	500/6	3.30	22.7	42.1	61.5	80.9	100	100	2 mg/L	4 mg/L
Cephalexin	1000/6	22.7	42.1	61.5	80.9	100	100	100	4 mg/L	4 mg/L
Cefaclor	500/6	–	11.0	23.5	36.0	48.5	61.0	73.5	0.5 mg/L	1 mg/L
Cefprozil	500/12	–	12.6	20.1	27.5	35.0	42.5	50.0	–	N/A
Cefuroxime	500/12	–	–	0.43	10.2	20.5	29.7	39.5	–	4 mg/L
Cefdinir	300/12	–	–	–	–	7.41	12.4	17.3	–	N/A
Cefpodoxime	400/12	–	–	–	22.8	39.7	56.6	73.5	0.25 mg/L	0.5 mg/L

Calculations are made according to a one-compartment first-order elimination model adapted from Turnidge JD [13] and are based on the mean bioavailability, mean protein binding percentage, and longest half-lives reported for each agent from Table 2. Calculated %fT>MIC is based on a 70-kg person and does not account for absorption time. Target attainment is based on a %fT>MIC of at least 50% and at least 60% for penicillins and cephalosporins, respectively. See Supplemental Material for calculations. *Based on the Antimicrobial Wild Type Distributions of Microorganisms from the European Committee on Antimicrobial Susceptibility Testing [16]. N/A; not available.

Abbreviations: %fT>MIC: percentage of time free drug concentrations remain above the minimum inhibitory concentration; MIC: minimum inhibitory concentration

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