key: cord-1020843-q1y20d66
authors: Heesom, Lesley; Rehnberg, Lucas; Nasim-Mohi, Myra; Jackson, Alexander I.R.; Celinski, Michael; Dushianthan, Ahilanadan; Cook, Paul; Rivinberg, William; Saeed, Kordo
title: Procalcitonin as an antibiotic stewardship tool in COVID-19 patients in the intensive care
date: 2020-07-25
journal: J Glob Antimicrob Resist
DOI: 10.1016/j.jgar.2020.07.017
sha: d02cb123ffe6ed0caf576acf91fb48eb6197ad66
doc_id: 1020843
cord_uid: q1y20d66

nan

The coronavirus-2019 (COVID-19) pandemic caused by the virus SARS-CoV-2 infection has imposed significant demand on all health care systems. Based on national and international guidance which were mostly anecdotal [1] , COVID-19 patients admitted to our General Intensive Care Unit (GICU) were routinely commenced on antibiotics to cover possible secondary bacterial lower respiratory tract infection (LRTI). The antibiotics should have been reviewed after 48 hours, however, it was challenging to stop early due to the many factors such as persistent hyperinflammatory status, ongoing/worsening lung infiltrates with the need for continued mechanical ventilation, and also partly due to the lack of reliable indicators of bacterial infection.

As a quality improvement project (QIP), procalcitonin (PCT) was introduced in our GICU in April-2020, as an antibiotic stewardship (ABS) tool. Around a month from this the UK's National Institute for Health and Care Excellence (NICE), published COVID-19 rapid guideline and suggested that there is insufficient evidence to recommend routine PCT testing to guide decisions about antibiotics and encouraged centres already using PCT to participate in research and data collection [2] . Here, we report our findings of the use of PCT in COVID-19 critically ill patients in order to determine the following;

1. The antibiotic usage in COVID-19 patients post introduction of PCT within 7 days of ICU admission.

2. If mortality and length of stay in intensive care will be affected based on PCT values and antibiotic decision making

Prospective, single-centre, cohort study involving pragmatic assessment of PCT in COVID-19 patients admitted to GICU at University Hospital Southampton NHS Foundation Trust, from April 6 th to May22nd, 2020 (our peak).

All patients were tested positive for SARS-CoV-2 by real time polymerase chain reaction (RT-PCR) from a combined nose and throat swabs in a VIROCULT virus transport medium. Samples were extracted and purified using magnetic particle extraction on the Thermo Scientific KingFisher Flex. PCR amplification was performed on the Applied Biosystems (ABI) 7500 by using the Viasure SAR-CoV-2 RT-PCR kit, targeting ORF1ab and N gene. Additionally, primers and probes for the World Health J o u r n a l P r e -p r o o f Organisation E gene assay (including an internal positive amplification control from extraction), was also used to enhance the sensitivity. All patients were followed up to 30 days, or till they died, to ascertain outcome data.

PCT was measured from serum samples using sequential two-step immunoenzymatic ("sandwich") assay, Beckman Coulter as part of its access range for the DxI immunoassay instruments (800 version).

Proposed antibiotic decisions based on PCT cut off levels have previously been published in an international consensus guide incorporating PCT values with clinical judgement and experience [3] . A level of 0.5µg/L was used as the upper limit to help determine the probability of bacterial infection, along with clinical judgement, of a bacterial infection.

This was done as a QIP hence ethical approval wasn't sought.

Fifty two patients received PCT testing, on their admission to GICU, were categorised into PCT valve <0.5µg/L (low PCT group n= 25) and PCT value >0.5µg/L (high PCT group n=27). Comparison of these 2 groups is summarised in Table 1 .

The use of antibiotics within first 7 days of admission was lower in the low PCT group (5 days) compared to 7 days with high PCT (P <0.001). There was also significant difference in the duration ICU stay between both groups [5 days vs 15 days (P 0.03)]. Furthermore larger number of patients requiring invasive ventilation in high PCT group compared to the low PCT group, and a better survival trend in low PCT group were noted. These were not statistically significant.

Although there has been a rapid increase in COVID-19 related publications recently, none are specific to the use of PCT to guide antimicrobial de-escalation in critically unwell COVID-19 pneumonia. A meta-analysis concluded that PCT > 0.5 ng/mL is associated with increased risk of progression to critical illness even particularly when the WBC is initially normal or reduced [4] .

Limitations of our study include, being a single centre, relatively small number of patients and lack of randomisation. Additionally, the clinician's might have been more inclined to stop antibiotics sooner J o u r n a l P r e -p r o o f in the low PCT group as they appeared less unwell, however in reality these would have continued for 7 days as per GICU protocol.

Despite these, our data suggests that the use of PCT as a guide for de-escalation of antibiotics significantly reduced antibiotic usage by 2 days in COVID-19 patients and can be used as an ABS tool.

Larger randomised controlled trials are needed to evaluate this further and to confirm these findings and cost effectiveness.

Thanks to all staff at Southampton University, particularly at the General Intensive Care unit, microbiology, virology and biochemistry departments.

None Table 1 White Cell Count (10*9/L) (Day 1) 2 9.6 (6.32-11.5) 10.6 (7.08 -12) Length of hospital stay (days) 2*** 15.5 (11-24-2) 20(10-23) Table 1 . Description data, severity score and outcome of procalcitonin (PCT) < 0.5µg/L versus PCT > 0.5µg/L *Culture from normally sterile site e.g. blood culture; or pure growth of a significant isolate from bronchoalveolar lavage, or positive legionella or pneumococcal antigen tests or an organism deemed significant by an infection specialist.

**Compliance to de-escalate or stop antibiotics in the low PCT group was only 56%, i.e. 44% of the time clinicians ignored the low PCT results and carried on antibiotics *** Amongst patients discharged from hospital [n= 24 (PCT <0.5) and n=16 (PCT >0.5)]

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Tests to guide decisions about using antibiotics | COVID-19 rapid guideline: antibiotics for pneumonia in adults in hospital | Guidance | NICE n

Procalcitonin (PCT)-guided antibiotic stewardship: an international experts consensus on optimized clinical use

Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis

Data were collected from our intensive care clinical information system (CIS) (Metavision, iMDsoft, Israel) and hospital laboratory information system (eQuest, University Hospital Southampton, UK).All statistical analysis and data processing were performed using R (R Core Team, Vienna, Austria). Normally distributed data are presented as mean and standard deviation, while data suspected to be non-normally distributed, were confirmed by a Shapiro-Wilk test. These data are presented as median, and IQR. Significance testing of continuous, non-parametric, variables was performed using a Mann-Whitney-U test. Categorical variables were examined using Fisher's Exact test. A cut-off of P <0.05 was used throughout.

None to declare

Not applicable