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\begin{document}

\title{Self-reported beta-lactam allergy: inpatients in government funded and
privately funded hospitals Cape Town, South Africa}



\author[1]{Cascia Day}%
\author[1]{M. Deetlefs}%
\author[2]{A. O’Brien}%
\author[2]{J. Smith}%
\author[3]{M. Boyd}%
\author[2]{N. Embling}%
\author[2]{S. Patel}%
\author[2]{K. Moody}%
\author[2]{T. Ramabele}%
\author[4]{A. Budge}%
\author[5]{Tapiwa Tavarwisa Tarwa}%
\author[2]{O. Jim}%
\author[2]{T. Maharaj}%
\author[2]{S. Pandy}%
\author[1]{JM. Abrahams}%
\author[2]{A. Panieri}%
\author[2]{S. Verhage}%
\author[2]{M. van der Merwe}%
\author[2]{A. Geragotellis}%
\author[2]{W. Amanjee}%
\author[2]{C. Joseph}%
\author[2]{Z. Zhao}%
\author[2]{S. Moosa}%
\author[2]{M. Bunting}%
\author[2]{Yanelisa Pulani}%
\author[2]{P. Mukhari}%
\author[2]{M. de Paiva}%
\author[2]{G. Deyi}%
\author[2]{R. Peigou Wonkam}%
\author[2]{N. Mancotywa}%
\author[2]{A. Dunge}%
\author[2]{T. Msimanga}%
\author[2]{A. Singh}%
\author[2]{O. Monnaruri}%
\author[2]{B. Molale}%
\author[4]{T. Butler}%
\author[1]{K. Browde}%
\author[6]{C. Muller}%
\author[1]{J. Van Der Walt}%
\author[2]{R. Whitelaw}%
\author[2]{D. Cronwright}%
\author[2]{N. Parker}%
\author[2]{S. Sinha}%
\author[2]{U. Binase}%
\author[2]{I. Francis}%
\author[2]{D. Boakye}%
\author[3]{S. Dlamini}%
\author[3]{M. Mendelson}%
\author[1]{Jonny PETER}%
\affil[1]{University of Cape Town Division of Immunology}%
\affil[2]{University of Cape Town Faculty of Health Sciences}%
\affil[3]{University of Cape Town Institute of Infectious Disease and Molecular Medicine}%
\affil[4]{University of Cape Town Department of Paediatrics and Child Health}%
\affil[5]{University of Cape Town Department of Pathology}%
\affil[6]{University of Cape Town Lung Institute}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background} Up to a quarter of inpatients in high-income
countries self-report beta-lactam allergy (BLA), which if incorrect, can
increase use of alternative antibiotics that impact on bacterial
resistance.. The epidemiology of BLA in low- and middle-income African
countries is unknown. \textbf{Methods} Point-prevalence surveys were
conducted at seven hospitals (adult, pediatric, government and
private-funded, district- and tertiary-level) in Cape Town, South Africa
between April 2019 and June 2021. Ward prescription records and
interviews were conducted to identify BLA patients. De-labeling was
attempted at the tertiary allergy clinic at Groote Schuur hospital.
\textbf{Findings} A total of 1486 hospital inpatients were surveyed
(1166 adults; 308 children). Only 48 (3.2\%) patients self-reported a
BLA with a higher rate amongst private- versus government-funded
hospitals {[}6.3\% vs 2.8\%, p=0.014{]}. Using the PEN-FAST tool, only
10.4\% (5/48) of self reported BLA patients were classified as high risk
for true penicillin hypersensitivity. Antibiotics were prescribed to
70.8\% (34/48) of self reported BLA patients, with 64.7\% (22/34)
receiving a beta-lactam. Despite three attempts to contact patients for
de-labelling at the allergy clinic, only 3/36 underwent in vivo testing,
with no positive results and one patient proceeded toa negative oral
challenge. \textbf{Interpretation} Unlike high-income countries,
self-reported BLA is low amongst inpatients in South Africa. The
majority of self-reported BLA were low risk for type 1 hypersensitivity,
but out-patient de-labeling efforts were largely unsuccessful.
\textbf{Funding} None%
\end{abstract}%



\sloppy


\textbf{Self-reported beta-lactam allergy: inpatients in government
funded and privately funded hospitals Cape Town, South Africa}

C. Day\textsuperscript{1}, M. Deetlefs\textsuperscript{1}, A.
O'Brien\textsuperscript{2}, J. Smith \textsuperscript{2}, M.
Boyd\textsuperscript{8}, N. Embling \textsuperscript{2}, S.
Patel\textsuperscript{2}, K. Moody \textsuperscript{2}, T.
Ramabele\textsuperscript{2}, A. Budge \textsuperscript{3} ,T.
Tarwa\textsuperscript{4}, O. Jim \textsuperscript{2}, T.
Maharaj\textsuperscript{2}, S. Pandy \textsuperscript{2}, JM.
Abrahams\textsuperscript{1}, A. Panieri \textsuperscript{2}, S.
Verhage\textsuperscript{2}, M. van der Merwe \textsuperscript{2}, A.
Geragotellis \textsuperscript{2}, W. Amanjee \textsuperscript{2}, C.
Joseph \textsuperscript{2} , Z. Zhao \textsuperscript{2}, S.
Moosa\textsuperscript{2}, M. Bunting \textsuperscript{2}, Y.
Pulani\textsuperscript{2}, P. Mukhari \textsuperscript{2}, M. de
Paiva\textsuperscript{2}, G. Deyi \textsuperscript{2}, R. Peigou
Wonkam\textsuperscript{2}, N. Mancotywa \textsuperscript{2}, A.
Dunge\textsuperscript{2}, T. Msimanga \textsuperscript{2}, A.
Singh\textsuperscript{2}, O. Monnaruri \textsuperscript{2}, B.
Molale\textsuperscript{2}, T. Butler \textsuperscript{3}, K.
Browde\textsuperscript{5}, C. Muller \textsuperscript{6}, J. Van Der
Walt\textsuperscript{1}, , R. Whitelaw \textsuperscript{8}, D.
Cronwright\textsuperscript{8}, N. Parker \textsuperscript{2}, S.
Sinha\textsuperscript{2}, U. Binase \textsuperscript{2}, I.
Francis\textsuperscript{8}, D. Boakye \textsuperscript{8}, , S.
Dlamini\textsuperscript{7}, M. Mendelson \textsuperscript{7}, J.
Peter\textsuperscript{1,6}

\textbf{Affiliations}

\begin{enumerate}
\tightlist
\item
  Division of Allergology and Clinical Immunology, Department of
  Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town
  South Africa.
\item
  Bachelor of Medicine and Surgery (MBChB), University of Cape Town,
  Faculty of Health Sciences, Cape Town South Africa.
\item
  Department of Pediatrics, Faculty of Health Sciences, University of
  Cape Town, Cape Town South Africa
\item
  Molecular Mycobacteriology Research Unit, Division of Medical
  Microbiology, Department of Pathology, University of Cape Town, Cape
  Town South Africa
\item
  Division of Allergology and Clinical Immunology, Department of
  Pediatrics, Red Cross Children's Hospital, University of Cape Town,
  Cape Town South Africa
\item
  Allergy and Immunology Unit, University of Cape Town Lung Institute,
  Cape Town South Africa
\item
  Division of Infectious Diseases and HIV Medicine, Department of
  Medicine, University of Cape Town, Cape Town South Africa
\item
  Department of Medicine, Faculty of Health Sciences, University of Cape
  Town, Cape Town South Africa
\end{enumerate}



\textbf{Background}

Up to a quarter of inpatients in high-income countries self-report
beta-lactam allergy (BLA), which if incorrect, can increase use of
alternative antibiotics that impact on bacterial resistance.. The
epidemiology of BLA in low- and middle-income African countries is
unknown.

\textbf{Methods}

Point-prevalence surveys were conducted at seven hospitals (adult,
pediatric, government and private-funded, district- and tertiary-level)
in Cape Town, South Africa between April 2019 and June 2021. Ward
prescription records and interviews were conducted to identify BLA
patients. De-labeling was attempted at the tertiary allergy clinic at
Groote Schuur hospital.

\textbf{Findings}

A total of 1486 hospital inpatients were surveyed (1166 adults; 308
children). Only 48 (3.2\%) patients self-reported a BLA with a higher
rate amongst private- versus government-funded hospitals {[}6.3\% vs
2.8\%, p=0.014{]}. Using the PEN-FAST tool, only 10.4\% (5/48) of self
reported BLA patients were classified as high risk for true penicillin
hypersensitivity. Antibiotics were prescribed to 70.8\% (34/48) of self
reported BLA patients, with 64.7\% (22/34) receiving a beta-lactam.
Despite three attempts to contact patients for de-labelling at the
allergy clinic, only 3/36 underwent in vivo testing, with no positive
results and one patient proceeded toa negative oral challenge.

\textbf{Interpretation}

Unlike high-income countries, self-reported BLA is low amongst
inpatients in South Africa. The majority of self-reported BLA were low
risk for type 1 hypersensitivity, but out-patient de-labeling efforts
were largely unsuccessful.

\textbf{Funding}

None



\textbf{Introduction}

Beta-lactams are the commonest antibiotic class reported to cause
allergy, yet globally, there is a large burden of patients mis-labeled
as having a Beta-lactam allergy (BLA) (1). In high income countries
(HICs) 6-25\% of the population are labeled as having a BLA, but only
1-10\% of the population have a true BLA. In keeping with this low
prevalence rate, the prevalence of life-threating anaphylaxis to
beta-lactams is estimated to be 0.02-0.04\%, a rate unchanged in the
last sixty years (1-3). While the epidemiology of BLA in HICs is well
described, there is no published epidemiological data available on BLA
in Africa or other low- and middle -income countries (LMIC)(4).

Being labeled with a BLA is harmful to patients, including the risk of
antibiotic failure (1), increased duration of hospital stay (5), higher
rates of post operative sepsis (6, 7), and adverse reactions to
prescribed alternative antibiotics(1). In addition to increased patient
risk there is an additional financial cost to the health care system
with the increased cost of broad-spectrum antibiotics, longer duration
of hospital admission, and higher rates of readmission (8, 9). Globally
BLA drives antibiotic resistance (ABR) due to the increased use of
broader-spectrum antibiotics than the penicillins. This results in
increased risks of infection with vancomycin resistant enterococci (VRE)
(5), methicillin resistant \emph{Staphylococcus aureus} (MRSA) (10),
and\emph{Clostridiodes difficile} (1, 11). In 2019, 4.95 million people
worldwide died with an antibiotic resistant bacterial infection, and 1.3
million of those were as a direct result of bacteria being resistant to
antibiotics(12). The burden of ABR is highest in low-income countries
(LIC) (4, 13, 14). Western-sub-Saharan Africa has the highest all-age
death rate attributable to ABR (27.3 deaths per 100~000 {[}CI
20.9-35.3{]})(14). The high mortality due to ABR in sub-Saharan Africa
makes de-labeling BLA a public health and antibiotic stewardship
priority.

The success of programmatic antibiotic allergy testing incorporated into
antibiotic stewardship programs has been increasingly reported with the
use of clinical decision tools that can be used by allergists and
non-allergists (15). Direct de-labeling of inpatients is safe and
effective, with rates of negative testing being comparable to the
outpatient setting(16). The need to establish the true prevalence and
incidence of BLA in LMICs is paramount to improve our management of
beta-lactam allergy in settings with the highest burden of infectious
diseases (4).

\textbf{Methods}

We conducted a multicenter point prevalence survey of hospitalised
patients. Between 4\textsuperscript{th} of April 2019 and
14\textsuperscript{th} of June 2021, a total of 1486 hospital inpatients
were surveyed at five government-funded hospitals and two
privately-funded hospitals in Cape Town South Africa. The
government-funded hospitals included Groote Schuur Hospital (GSH,
tertiary level), Red Cross Memorial Children's Hospital (RXH, paediatric
tertiary level), and three secondary level Hospitals - Victoria Wynberg
Hospital (VWH), New Somerset Hospital (NSH), and Mitchells Plain
Hospital. The two privately-funded hospitals were Christiaan Barnard
Memorial Hospital (CBH) and University of Cape Town Academic Hospital
(UCTPAH) \textbf{(Figure 1, Table 1, see Appendix for descriptions of
hospitals)} .

This study was approved by the Human Ethics Research Counsel of the
University of Cape Town (UCT) (HREC: 417/2019) and the Netcare Research
Operations Committee. The delay in conducting the final surveys was due
to the COVID-19 pandemic, as six of the surveys were performed in
between the second and third COVID-19 waves in South Africa.

Point prevalence surveys were conducted after-hours to ensure that all
inpatient prescription chart were available for review. All hospital
inpatients on the day of the survey had basic demographic information
(date of birth and gender) captured via electronic case record form
(eCRF) but detailed medical information was only captured for patients
who reported a BLA or non-beta-lactam (BL) antibiotic allergy. Medical
information included documentation of antibiotic allergies in the
patients notes and prescription charts, description of the allergic
event, and review of information on the antibiotic prescription chart.
Classification of patients with a self-reported BLA was completed by an
allergist after completion of all surveys using the PEN-FAST tool. The
PEN-FAST BLA phenotype clinical decision tool (developed by Trubiano et
al(15)) has a high negative predictive value of 96.3\% (95\% CI
94.1-97.8\%) (15, 17). The major criteria for the PEN-FAST tool are: the
allergy event occurring within the preceding five years (2 points);
anaphylaxis, angioedema or severe cutaneous delayed reactions (2
points). A single minor criterion of whether the allergic reaction
required treatment scores 1 point. The PEN-FAST tool has a validated
area under the curve of 0.805 (for a cut-off of 3 points chosen to
classify as low risk of penicillin allergy) (15). The novel PEN-FAST BLA
clinical decision mobile app was used by investigators to classify
patients as low risk (1-5\%), moderate risk (20\%), or high risk (50\%)
of a positive penicillin allergy test.

Descriptive statistics were performed using counts and proportions for
categorical data, and medians and interquartile ranges for continuous
variables. All statistical analyses were conducted using STATA version
14 (STATA Corp., College Station, TX, USA).

\textbf{Results}

A total of 1486 hospital inpatients (1166 adults [?]18 years and 320
children \textless{} 18 years) were surveyed in seven hospitals in Cape
Town, South Africa during the study period \textbf{(Figure 1, Table 1,
Table 2)} . Of these, 52.8\% were female with a median age of 40 years
(IQR 25;60). Overall, 48 (3.2\%) patients self-reported a BLA with a
significantly higher rate of self-reported BLA in the privately-funded
hospitals as compared to the government-funded hospitals (2.8\% vs 6.3\%
respectively, p=0.014). None of the facilities had 100\% bed capacity at
the time of the surveys (GSH=721/893 80.7\%; RXH= 189/300 63\%; VWH
107/206 51.9\%; NSH 200/330 60.6\%, MPDH 95/200 47.5\%, CBH 129/248
52\%, UCTPAH 45/124 36.3\%), six of the seven surveys occurred between
March 2021 and July 2021. The decreased bed occupancy in these
facilities was likely due to the COVID-19 pandemic and decreased
utilization of nonurgent clinical services.

\emph{Figure 1: Consort diagram}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Abbreviations: BLA Beta-lactam allergy, IDT Intradermal testing, SPT
skin prick testing

\emph{Table 1: Summary of all patients surveyed stratified by hospital
funding-base}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& All, n=1486 & Government funded hospitals, n=1312 & Privately funded
hospitals, n=174\tabularnewline
\midrule
\endhead
Bed capacity & 2301 & 1929 & 372\tabularnewline
Bed occupancy (\%) & 64 & 68 & 47\textsuperscript{*}\tabularnewline
Female & 785 (52.8) & 703 (53.6) & 81 (47)\tabularnewline
Age, IQR in yrs & 40 (25; 60) & 39 (24; 57) & 16 (1; 58)\tabularnewline
Unable to speak to patient/parent, (\%) & 303 (20.4) & 264 (20.1) & 40
(23)\tabularnewline
BLA reported, (\%) & 48 (3.2) & 37 (2.8) & 11 (6.3)\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{*}The low bed occupancy in these hospitals was the
result of COVID19 restrictions at the time of the survey

Abbreviations: BLA: Beta lactam allergy, IQR: interquartile range

\emph{Table 2: Summary of all patients surveyed stratified by hospital
funding-base and age group}\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllll@{}}
\toprule
Age & All, n=1486 & Reported BLA & Government funded hospitals, n=1312 &
GSH, n=721 & VWH, n=107 & RXH, n=189 & MPDH, n=99 & NSH, n=200 &
Privately funded hospitals, n=174 & CBH, n=129 & UCTPAH,
n=45\tabularnewline
\midrule
\endhead
\textless{} 1 year & 147 (9.9) & 0 & 124 (9.5) & 0 & 8 (7.5) & 81 (42.9)
& 10 (10.1) & 25 (12.5) & 23 (13.2) & 23 (17.8) & 0\tabularnewline
1- 5 years & 89 (6) & 0 & 84 (6.4) & 7 (1) & 7 (6.5) & 63 (33.3) & 7 (7)
& 0 & 5 (2.9) & 3 (1.7) & 2 (4.4)\tabularnewline
6-11 years & 43 (2.9) & 0 & 39 (3) & 5 (0.7) & 0 & 34 (18) & 0 & 0 & 4
(2.3) & 0 & 4 (8.8)\tabularnewline
12-18 years & 29 (2) & 0 & 26 (2) & 12 (1.7) & 0 & 11 (5.8) & 0 & 3
(1.5) & 3 (1.7) & 2 (1.1) & 1 (2.2)\tabularnewline
\textgreater{} 18 years & 1166 (78.5) & 48 (3.2) & 1027 (78.3) & 685
(95) & 92 (86) & 0 & 78 (78.8) & 172 (86) & 139 (79.9) & 101 (78.3) & 38
(84.4)\tabularnewline
Unknown & 12 (0.8) & 0 & 12 (0.9) & 12 (1.7) & 0 & 0 & 0 & 0 & 0 & 0 &
0\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: BLA: Beta-lactam allergy; CBH: Christiaan Barnard
Memorial Hospital; GSH: Groote Schuur Hospital; IQR: Interquartile
range; MPDH: Mitchell's Plain District Hospital; NSH: New Somerset
Hospital; UCTPAH: University of Cape Town Academic Hospital; VWH:
Victoria Wynberg Hospital

Of the 48 self-reported BLA patients, 60.4\% were female, and the median
age was 59 years (IQR 37;68). There were no reported BLA under the age
of 18 years (\textbf{Table 3} , \textbf{Supplement Table 2} ). There
were 12 patients (0.8\%) that reported non-BL antibiotic allergies. The
majority (n=35 {[}71\%{]}) of participants reported that the allergic
event had taken place more than ten years previously. Most (64.6\%
{[}n=31{]}) could recall the details of the allergic event, but 12.5\%
(n=6) of patients reported a BLA based on family history alone. In total
64.6\% (n=31) patients were classified as low risk, 22.9\% (n=11) as
moderate risk, while only 10.4\% (n=5) patients were classified as high
risk for positive penicillin testing. Eight patients reported
anaphylaxis and ten reported angioedema (six of whom had laryngeal
angioedema). The most common reported symptoms were a mild/self-limiting
skin rash in 25\% (n=12) of patients. In total, 30 patients (62.5\%)
required treatment for the BLA but only 10 (20.8\%) required adrenaline.

\emph{Table 3: Summary of self-reported beta-lactam antibiotic allergy
stratified by hospital funding-base and age group}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
All, n=48\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Government funded hospitals, n=37\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Privately funded hospitals, n=11\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Female, (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
29 (60.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22 (59.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8 (72.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age, years (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
59 (38; 68)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
59 (38; 68)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
58 (52; 63)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PENFAST, \%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Low risk\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
31 (64.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
24 (64.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (63.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Moderate risk\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
11 (22.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8 (21.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (27.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
High risk\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5 (10.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (10.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (2.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Questions from PENFAST\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Penicillin allergy reported\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
48 (100)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
37 (100)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
11 (100)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Five years or less since reaction\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
9 (18.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5 (13.5)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (36.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Anaphylaxis or angioedema\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
10 (20.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (18.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (27.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Severe cutaneous adverse reaction\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (14.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (16.2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Required treatment\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
30 (62.5)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
24 (64.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (54.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Reaction \textgreater{}10 years\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
35 (72.9)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
28 (75.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (63.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Patient can recall event\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
31 (64.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22 (59.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (81.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Family history only\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (12.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (10.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (18.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Required adrenaline\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10 (20.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8 (21.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (18.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Hospital admission and re-admission details\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Duration of admission, days (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (4; 15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6 (4;15)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Duration of admission not known\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12 (24.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (2.6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11 (100)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Number of re-admissions in following 6 months\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0 (0;2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0 (0;2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: IQR: interquartile range

A BLA was documented on 52.1\% (n=25) of the inpatient prescription
charts, with significantly higher rates of documentation in the
privately-funded facilities (n=9, 81.8\%) as compared to the
government-funded facilities (n=16, 43.2\%) (p=0.02) (\textbf{Table 4}
,\textbf{Supplement Table 3} ). A total of 34 (71\%) of the reported BLA
patients were prescribed antibiotics, of which 22 (64.7\%) still
received a beta-lactam containing antibiotic: Beta-lactam /
beta-lactamase inhibitor combination (amoxicillin-clavulanate or
Piperacillin-tazobactam) n= 6; Aminopenicillin n=5; Cephalosporins n=9;
Carbapenem n=2.

The 11 patients (32.4\%) that were prescribed a beta-lactam /
aminopenicillin, either alone or in combination with clavulanate,
completed treatment with no subsequent allergic reaction. Seven of these
patients who received a beta-lactam / aminopenicillin had no
documentation of the reported BLA in the prescription charts or patient
notes. Ten of these 11 patients were classified as low risk by PEN-FAST
scoring; however one patient's risk was high with previous anaphylaxis
and laryngeal angioedema. The remaining 14 (41.2\%) patients were
prescribed: Lincosamides n=5; Aminoglycosides n=3; Fluoroquinolones/
quinolones n=2; Macrolides n=2; and Nitroimidazole n=1.

Over a quarter of the patients were prescribed more than one antibiotic.
As per antibiotic stewardship requirements 15 (44.1\%) patients had the
indication for the antibiotic documented on the antibiotic chart. The
difference between the government funded and privately funded hospitals
was not significant (p=0.1): n=10 {[}37\%{]} in the government funded
hospitals and n=5 {[}71.4\%{]} in the privately funded hospitals. The
most common indication for antibiotic therapy was pneumonia (n=4),
followed by bloodstream infection (n=2), and finally
gynecological/obstetric, urinary tract infection, and abdominal
infection (n=1 respectively). In five patients the indication for an
antibiotic was documented as ``not defined''.

\emph{Table 4: summary of antibiotic use in self-reported beta-lactam
antibiotic allergy patients divided by government funded vs privately
funded hospitals}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
All, n=48\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Government funded hospitals, n=37\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Privately funded hospitals, n=11\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BLA documented on antibiotic script, \%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
25 (52.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16 (43.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (81.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
On antibiotic, \%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34 (71)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
27 (73)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (63.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Indication for antibiotics on script (\% of patients on
antibiotics)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15 (44.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10 (37)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (71.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Not defined\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5 (33.3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (20)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (60)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Pneumonia\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (26.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (30)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (20)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Blood stream\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (13.3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (20)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Gynecological / obstetric\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (6.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (10)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Abdominal infection\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (6.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (20)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Urinary tract infection\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (6.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (10)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Type of antibiotics, \%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Beta-lactam antibiotics\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22 (64.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Beta-lactam / beta-lactamase inhibitor (amoxicillin-clavulanate or
Piperacillin-tazobactam)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (17.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (14.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (18.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Aminopenicillin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5 (14.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (14.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (14.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Carbapenam\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (5.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (3.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (14.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Cephalosporin\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
9 (26.5)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8 (29.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (14.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Non beta-lactam antibiotics\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
14 (41.2\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Fluroquinalone / Quinalone\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (5.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (7.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Glycopeptide\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (2.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (14.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Lincosamide\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5 (14.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (7.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (42.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Macrolide\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (5.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (7.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Nitroimidazole\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (2.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (3.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Aminoglycoside\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (6.3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (7.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
(14.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Antibiotic Unknown, \%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (14.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (18.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
More than one antibiotic, \%\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (26.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (18.5)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (57.1)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: BLA: Beta lactam allergy

The median duration of admission for the government funded hospital
patients was six days (IQR 4;15) with longer admission durations at GSH
and MPDH as compared to NSH and VWH (\textbf{Table 3, Supplement Table
2} ). There were 37 re-admissions to government-funded hospitals in the
six months following hospitalization. Overall, 34 of these admissions
occurred in seven patients (four patients had four readmissions, and
three patients had three readmissions). The data for admission, length
of stay, and readmission rates were not available for the
privately-funded hospitals. A total of eight patients were contactable
after discharge with 21 patients lost to follow up (not including two
deaths and five patients that declined further investigation)
(\textbf{Table 5} ). However, only 3/8 patients returned to the GSH
Allergy Clinic for evaluation, 5 patients missed clinic follow up and
were subsequently not contactable. All three patients had negative
epidermal testing but, two of these patients declined an oral challenge.
Ultimately only one patient proceeded to direct oral challenge, which
was negative.

\emph{Table 5: BLA de-labeling efforts at the tertiary Groote Schuur
hospital allergy clinic}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& All, n=48 & Government funded, n=37 & Privately funded,
n=11\tabularnewline
\midrule
\endhead
Uncontactable, \% & 21 (43.8) & 16 (43.2) & 5 (45.4)\tabularnewline
Contacted but now living in a different province, \% & 5 (10.4) & 5
(13.5) & 0\tabularnewline
Contacted and declined testing, \% & 5 (10.4) & 3 (8.1) & 2
(18.2)\tabularnewline
Deceased, \% & 2 (4.2) & 1 (2.7) & 1 (9)\tabularnewline
BL antibiotic given in ward, \% & 12 (25) & 9 (24.3) & 3
(27.2)\tabularnewline
Intradermal testing and SPT negative, declined oral challenge, \% & 2
(4.2) & 2 (2.7) & 0\tabularnewline
Intradermal testing and SPT negative, declined oral challenge, \% & 1
(2.1) & 1 (2.7) & 0\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: BL: Beta lactam, SPT: skin prick testing

\textbf{Discussion}

Spurious BLA labels are dangerous to patients and pose a public health
emergency in terms of health care costs and driving ABR. In what we
believe to be the first publication on the epidemiology of reported BLA
in Africa, we found that the prevalence of reported BLA in hospitalised
patients was only 3.3\%, a rate considerably lower than HIC rates. The
self reported BLA rates were lower in government-funded hospitals than
in the privately-funded hospitals. Sadly, very few participants in our
study with a BLA label returned for allergy de-labeling.

The lowest rate of self-reported BLA from a HIC inpatient settings is
9.9\% of 1738 patients enrolled over a one-year period in Montreal,
Canada (9). Our study reports a rate less than half of this low-end
rate. Furthermore, more than 80\% of our small number of self-reported
cases of BLA were considered low risk for true BLA, meaning that the
prevalence of confirmed beta-lactam hypersensitivity may in fact be even
lower in our South African population. There are several possible
contributing factors that may explain both a lower rate of BLA label as
well as a possible lower rate of true beta-lactam hypersensitivity in
our population. Antibiotic prescribing patterns differ across the world,
and involve a complex interplay of social, patient, provider, and
economic factors(18). The majority of BLA labels are the result of viral
or drug-related exanthems in childhood (2). But difficulties in
accessing healthcare in South Africa (particularly in rural areas)
resulting in less antibiotics being given(18), may limit the childhood
exposure to BLA allergens and so contribute to less identification of
true BLA in our setting.

Drug-related (and viral) exanthems, considered to be the predominant
driver of incorrect BLA labels, are predominantly T-cell mediated, the
majority of which are HLA-restricted. A recent genome-wide association
study (GWAS) linked HLAB55:01 with penicillin allergy label.
Interestingly, this allele has relatively low frequencies in Black
African populations. This contrasts with another recent GWAS amongst
confirmed cases of immediate hypersensitivity to beta-lactams, that
identify HLA-DRB1*10:01 as a risk allele. HLA-DRB1*10:01 is carried
twice as frequently in those of African ancestry (19). Other genetic
studies in European populations with confirmed beta-lactam
hypersensitivity have linked polymorphisms in cytokine genes (TNFA,
IL-13, IL-4, IL4R)(20), which are also likely to be population-specific.
Thus, it is possible that genetically African populations may have
similar or higher risk for true immediate beta-lactam hypersensitivity,
but less likelihood of mild delayed reactions, the major drivers of
incorrect BLA labeling in childhood. Finally, skin colour may impact the
detection of maculopapular exanthems in those with Fitzpatrick skin type
IV, V and VI (Lehloenya North American clinics accepted for
publication), as erythema and fine rashes are harder to detect in
pigmented skin. Taken together, there may be several genetic, and
biological factors that explain self reported BLA prevalence in in
African populations.

BLA labels were significantly more common in patients attending private
compared to (government funded) hospitals. South Africa is the most
inequitable country in Africa with a GINI coefficient of 0.63 in 2015,
an inequality reflected in its public versus private healthcare. Race
and socioeconomic status are a major factor(21-23). The population
utilizing privately funded health care sector in South Africa more
closely resembles that of a HIC in that the predominant racial group is
white (European ancestry)(22) with a higher income. The population that
accesses government-funded health care has a high percentage of black
African, Indian, or mixed race patients. Thus, the difference in BLA
rates between government and private hospital inpatients may reflect
both differences in access to healthcare in childhood with different
levels of antibiotic exposure, as well as genetic and skin pigment
biological factors related to populations of origin. Further qualitative
and basic science research is required to understand these differences.

Using the PEN-FAST tool, most patients with BLA label in our study were
considered low risk for true type 1 hypersensitivity to beta-lactams.
However, despite several attempts to contact and assist patients to
attend our tertiary allergy clinic at GSH, only 1 patient could complete
direct oral challenge for de-labeling. Multiple factors play into this
failure, including: patient-perceived lack of importance of carrying a
BLA label, fear of the testing and procedures or the time involved,
changes in contact details and a mobile patient population, or even lack
of resources to return for clinic visits (18, 22, 24). This inability to
have patients return and attend allergy clinics or elective procedures
has been highlighted, even in HICs, and undoubtedly aggravated across
the world by the COVID-19 pandemic (25). In paediatric patients
recommendations now exclude the use of SPT as a possible barrier to care
and with concerns regarding increased false positive test rates(26).
This data supports that the only viable option for BLA de-labeling in
LMICs will be direct de-labelling or challenges in low-risk patients by
non-allergists at the bedside. The development, validation and
implementation of risk-stratification tools will be critical to this
effort. A comprehensive framework for incorporation of BLA de-labeling
in LMIC/LIC has been recently outlined (4).

The inclusion of several hospitals across different levels of the health
system, and inclusion of private and government-funded hospitals,
improved the generalizability of this data. However, the fact that the
study was only performed in one city of SA is a limitation. The COVID-19
pandemic meant that there was a several month gap between the initial
survey at GSH in April 2019 and the other surveys in the study, as well
as limiting bed occupancy at the time of surveys in several hospitals,
which may have impacted results. The lack of reported BLA in patients
under 18 years is likely due to the low bed occupancy rates the high
percentage of paediatric patients under the age of one year in the
cohort, likely limits the generalisability of paediatric data.

In conclusion, this study provides the first data on the epidemiology of
BLA in Africa and demonstrates that the overall prevalence of BLA is
much lower than that reported in HICs. Furthermore, there is disparity
of our results across health sectors, which highlights several of the
complex social and biological determinants of both true and incorrectly
labeled BLA. The inability to confirm BLA in the majority of cases
through skin testing and direct oral challenge in the allergy clinic
highlights the challenges of incorporating BLA de-labeling strategies in
antibiotic stewardship programs in LMICs, and demands a different
solution than HICs, by shifting the site of testing to the bedside.
Epidemiology data from other LMIC is required to confirm our findings
and help LMIC policy makers decide on the importance of targeting BLA
de-labeling in local antibiotic stewardship efforts. Affordable
strategies for direct de-labeling or inpatient challenge are supported
by this data.

\textbf{Conflict of Interest}

None

\textbf{Funding}

None

\textbf{Contributions}

J. Peter, M. Mendelson, and S. Dlamini devised proposal and protocol. C.
Day organized hospital surveys, and analysed data. C Day and J. Peter
wrote and edited the manuscript. M. Deetlefs conducted all allergy
testing. M. Boyd assisted with data cleaning and A.O'Brien assisted with
communication with the survey team. All authors conducted the point
prevalence surveys and reviewed the manuscript.

\emph{Conducted one survey} : J. Peter, M. Mendelson, S. Dlamini, A.
Geragotellis, Z. Parker , W. Amanjee, C. Joseph , Z. Zhao, S. Moosa, M.
Bunting, Y. Pulani, P. Mukhari, M. de Paiva, G. Deyi, R. Peigou Wonkam,
N. Mancotywa, A. Dunge, , T. Msimanga, A. Singh, O. Monnaruri, B.
Molale, T. Butler, K. Browde, C. Muller, M. Evreva, J. Van Der Walt, R.
Whitelaw, D. Cronwright, N. Parker, S. Sinha, U. Binase, I. Francis, D.
Boakye, S. Wasserman.

\emph{Conducted two surveys} : A. Budge, T. Tarwa, O. Jim, T. Maharaj,
S.Pandy, A. Panieri, S. Verhage, M. van der Merwe, M. Deetlefs.

\emph{Conducted three surveys:} N. Embling, S. Patel, K. Moody, T.
Ramabele.

\emph{Conducted four surveys:} A. O'Brien, J Smith.

\emph{Conducted six surveys:} C. Day

\textbf{Dedication:}

In memory of Tokoloho (Tuks) Ramabele.

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