PRINCIPLE trial demonstrates scope for in-pandemic improvement in primary care antibiotic stewardship: a retrospective sentinel network cohort study

Simon de Lusignan; Mark Joy; Julian Sherlock; Manasa Tripathy; Oliver van Hecke; Kome Gbinigie; John Williams; Christopher Butler; FD Richard Hobbs

doi:10.3399/BJGPO.2021.0087

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Figure 1. Prescribing of azithromycin (Figure 1A) and doxycycline (Figure 1B) by month within the Research and Surveillance Centre. The 2020 prescription of both antibiotics (azithromycin = blue line, square markers; doxycycline = yellow line, square markers) was very similar in January and February to 2019 rates (azithromycin = green line, diamond markers; doxycycline = orange line; diamond markers). In March 2020, there was a peak of prescribing for both antibiotcs, coincident with the first wave of the COVID-19 pandemic. Thereafter azithromycin was prescribed in 2020 at or above the level in 2019, whereas doxycycline was prescribed less.
Azith = azithromycin. Doxy = doxycycline. Px = prescribing.
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Figure 2. Comparison of monthly incidence of consultations for lower respiratory tract infections (Figure 2A), upper respiratory tract infections (Figure 2B), and influenza-like illness (Figure 2C), comparing 2020 with 2019 in the Research and Surveillance Centre dataset. There was a lower incidence of LRTI and URI in 2020 compared with 2019, with a small peak when pupils returned to school in September 2020. ILI peaked with the first wave of the COVID-19 pandemic, and also with the return to school.
ILI = influenza-like illness. RTI = lower respiratory tract infections. URTI = upper respiratory tract infections.
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Figure 3. Monthly pattern of azithromycin (Figure 3A) and doxycycline (Figure 3B) prescription counts, for 2019 and 2020. OpenPrescribing data are only available up to October 2020.
Azith = azithromycin. Doxy = doxycycline. RCGP RSC = Royal College of General Practitioners Research and Surveillance Centre.

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Table 1. Comparison of rates of prescription of doxycycline and azithromycin in 2020 with 2019. In people aged ≥65 years there was a decrease in doxycycline use but an increase in azithromycin prescription. Lower respiratory tract infection and upper respiratory tract infection incidence fell across all age bands and both sexes. Influenza-like illness was much more similar between years.

	Age, years	2019	2020
Female	Male	Female	Male
Antibiotic rates per 100000 patients (95% CI)	Doxy.	<16	21.74(20.4 to 23.2)	17.75(16.5 to 19.0)	19.12(17.8 to 20.5)	15.96(14.8 to 17.2)
		16–64	385.28(382.1 to 388.5)	231.99(229.6 to 234.4)	380.15(377.8 to 383.3)	222.57(220.2 to 224.9)
		≥65	1136.15(1126.4 to 1145.9)	1038.78(1028.6 to 1048.9)	968.28(959.3 to 977.3)	913.57(904.1 to 923.1)
	Azith.	<16	56.89(54.6 to 59.2)	67.50(65.1 to 69.9)	53.29(51.1 to 55.5)	75.91(73.4 to 78.5)
		16–64	70.02(68.7 to 71.4)	39.39(38.4 to 40.4)	70.69(69.4 to 72.1)	40.77(39.8 to 41.8)
		≥65	305.17(300.1 to 310.3)	288.43(283.1 to 293.9)	339.13(333.8 to 344.5)	307.59(302.1 to 313.2)
Respiratory disease rates per 100000 patients (95% CI)	LRTI	<16	229.25(224.67 to 233.82)	292.18(287.1 to 297.2)	68.43(65.9 to 70.9)	90.9(88.1 to 93.8)
		16–64	191.30(189.1 to 193.54)	126.84(125.0 to 128.6)	81.45(79.9 to 82.9)	53.2(52.0 to 54.4)
		≥65	609.27(602.05 to 616.5)	568.32(560.8 to 575.8)	267.9(263.2 to 272.8)	268.0(262.9 to 273.2)
	URTI	<16	1320.33(1309.5 to 1331.3)	1349.86(1339.1 to 1360.7)	485.15(455.0 to 467.7)	493.1(486.6 to 499.7)
		16–64	485.65(482.1 to 489.2)	229.3(226.9 to 231.8)	265.73(254.9 to 260.1)	117.38(115.7 to 119.1)
		≥65	285.17(280.3 to 290.1)	208.6(204.1 to 213.2)	148.01(144.5 to 151.6)	104.61(101.4 to 107.9)
	ILI	<16	19.30(17.1 to 19.7)	20.78(19.5 to 22.2)	16.38(15.2 to 17.7)	16.23(15.1 to 17.5)
		16–64	32.57(30.8 to 32.6)	22.15(21.4 to 22.9)	37.68(36.7 to 38.7)	21.86(21.1 to 22.6)
		≥65	25.40(28.2 to 31.7)	22.18(20.7 to 23.7)	29.41(27.9 to 31.0)	24.38(22.9 to 25.9)

^a95% confidence intervals. Azith = azithromycin. Doxy = doxycycline. ILI = influenza-like illness. LRTI = lower respiratory tract infections. URTI = upper respiratory tract infections.

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Table 2. Model reporting the incident rate ratio (IRR) comparing prescribing of azithromycin in 2020 with 2019. Taking the variables in the model into account there was a 22% increase, with people aged ≥65 years, female sex, the most deprived, northern regions and people with lower respiratory tract infections and upper respiratory tract infections all being associated with a higher rate of prescribing.

Azithromycin prescribing ratescomparing 2020 with 2019	IRR	Lower	Upper	P
	95% CI	95% CI
Year 2020 (reference level: 2019)	1.22	1.19	1.26	<0.0001
Age band (reference level: 0–15)
16–64	0.71	0.68	0.73	<0.0001
≥ 65	4.77	4.58	4.98	<0.0001
Sex (reference level: F)	0.91	0.88	0.93	<0.0001
IMD quintile (reference level: Q1, most deprived)
Q2	0.90	0.86	0.94	<0.0001
Q3	0.87	0.83	0.90	<0.0001
Q4	0.75	0.72	0.78	<0.0001
Q5 (least deprived)	0.67	0.64	0.70	<0.0001
NHS region (reference: London)
The Midlands and East	1.08	1.03	1.12	<0.0001
North East and Yorkshire	1.47	1.40	1.54	<0.0001
North West	1.13	1.08	1.18	<0.0001
South East	0.94	0.89	0.98	<0.0001
South West	0.72	0.69	0.76	<0.0001
Respiratory disease
LRTI count	1.0051	1.0043	1.0058	<0.0001
URTI count	1.0030	1.0026	1.0035	<0.0001
ILI count	1.0017	0.9982	1.0053	0.3400

ILI = influenza-like illness. IMD = Index of Multiple Deprivation. LRTI = lower respiratory tract infections. URTI = upper respiratory tract infections.

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Table 3. Azithromycin prescribing in cases of COVID-19. For each unit rise in COVID-19 cases there has been a 3% rise in azithromycin prescriptions. Aged ≥65 years, female sex, being more deprived, northern regions, lower respiratory tract infections or influenza-like-illness infections are all associated with a higher rate of prescribing.

Azithromycin prescribing rate	IRR	Lower	Upper	P
95% CI	95% CI
COVID-19 confirmed count	1.03	1.02	1.03	<0.0001
Age band (reference level: 0–15)
16–64	0.25	0.20	0.31	<0.0001
≥65	10.95	8.67	13.83	<0.0001
Sex (reference level: F)	0.54	0.45	0.65	<0.0001
IMD quintile (reference level: Q1 most deprived)
Q2	0.54	0.41	0.72	<0.0001
Q3	0.41	0.31	0.55	<0.0001
Q4	0.54	0.41	0.72	<0.0001
Q5 (least deprived)	0.66	0.50	0.88	0.0048
NHS region (reference: London)
The Midlands and East	5.73	4.28	7.69	<0.0001
North East and Yorkshire	12.88	9.18	18.07	<0.0001
North West	10.31	7.34	14.49	<0.0001
South East	2.82	2.01	3.96	<0.0001
South West	1.41	1.01	1.98	0.0453
Respiratory disease
LRTI count	1.94	1.92	1.97	<0.0001
URTI count	0.89	0.88	0.90	<0.0001
ILI count	1.60	1.54	1.68	<0.0001

ILI = influenza-like-illness. IMD = Index of Multiple Deprivation. LRTI = lower respiratory tract infections. URTI = upper respiratory tract infections.

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