Antibiotic Treatment Failure Research Articles

Are Bacterial Persisters Dormant Cells Only?

Bacterial persisters are a sub-population of phenotypic variants that tolerate high concentrations of antibiotics within the genetically homogeneous cells. They resume division upon the removal of drugs. Bacterial persistence is one of major causes of antibiotic treatment failure and recurrent infection. Cell dormancy, triggered by toxin/antitoxin pair, (p)ppGpp, SOS response and ATP levels, is known to be the mechanistic basis for persistence. However, recent studies have demonstrated that bacteria with active metabolism can maintain persistence by lowering intracellular antibiotic concentration via an efflux pump. Additionally, others and our work have showed that cell wall deficient bacteria (CWDB), including both L-form and spheroplasts that produced by β-lactam antibiotics, are associated with antibiotic persistence. They are not dormant cells as their cell walls have been completely damaged. In this review, we discuss the various types of persisters and highlight the contribution of non-walled bacteria on bacterial persistence.

A Comparative Computational Analysis Approach to Predict Significant Protein-Protein Interactions of Human and Vancomycin Resistant Enterococcus faecalis (VRE) to Prioritize Potential Drug Targets

Background: Various challenges exist in the treatment of infectious diseases due to the significant rise in drug resistance, resulting in the failure of antibiotic treatment. As a consequence, a dire need has arisen for the rethinking of the drug discovery cycle because of the challenge of drug resistance. The underlying cause of the infectious diseases depends upon associations within the Host-pathogen Protein- Protein Interactions (HP-PPIs) network, which represents a key to unlock new pathogenesis mechanisms. Hence, the elucidation of significant PPIs is a promising approach for the identification of potential drug targets. Objective: Identification of the most significant HP-PPIs and their partners, and targeting them to prioritize potential new drug targets against Vancomycin-resistant Enterococcus faecalis (VRE). Methods: We applied a computational approach based on one of the emerging techniques i.e. Interolog methodology to predict the significant Host-Pathogen PPIs. Structure-Based Studies were applied to model shortlisted protein structures and validate them through PSIPRED, PROCHECK, VERIFY3D, and ERRAT tools. Furthermore, 18,000 drug-like compounds from the ZINC library were docked against these proteins to study protein-chemical interactions using the AutoDock based molecular docking method. Results: The study resulted in the identification of 118 PPIs for Enterococcus faecalis, and prioritized two novel drug targets i.e. Exodeoxyribonuclease (ExoA) and ATP-dependent Clp protease proteolytic subunit (ClpP). Consequently, the docking program ranked 2,670 and 3,154 compounds as potential binders against Exodeoxyribonuclease and ATP-dependent Clp protease proteolytic subunit, respectively. Conclusion: Thereby, the current study enabled us to identify and prioritize potential PPIs in VRE and their interacting proteins in human hosts along with the pool of novel drug candidates.

Appendicoliths, Antibiotic Treatment Failure, and Appendectomy—Is the Glass Half Full or Half Empty?

Appendicoliths, Antibiotic Treatment Failure, and Appendectomy—Is the Glass Half Full or Half Empty?

The Role of Integration Host Factor in Escherichia coli Persister Formation.

ABSTRACTPersisters represent a small subpopulation of cells that are tolerant of killing by antibiotics and are implicated in the recalcitrance of chronic infections to antibiotic therapy. One general theme has emerged regarding persisters formed by different bacterial species, namely, a state of relative dormancy characterized by diminished activity of antibiotic targets. Within this framework, a number of studies have linked persister formation to stochastic decreases in energy-generating components, leading to low ATP and target activity. In this study, we screen knockouts in the main global regulators of Escherichia coli for their effect on persisters. A knockout in integration host factor (IHF) had elevated ATP and a diminished level of persisters. This was accompanied by an overexpression of isocitrate dehydrogenase (Icd) and a downregulation of isocitrate lyase (AceA), two genes located at the bifurcation between the tricarboxylic acid (TCA) cycle and the glyoxylate bypass. Using a translational ihfA-mVenus fusion, we sort out rare bright cells, and this subpopulation is enriched in persisters. Our results suggest that noise in the expression of ihf produces rare cells with low Icd/high AceA, diverting substrates into the glyoxylate bypass, which decreases ATP, leading to antibiotic-tolerant persisters. We further examine noise in a simple model, the lac operon, and show that a knockout of the lacI repressor increases expression of the operon and decreases persister formation. Our results suggest that noise quenching by overexpression serves as a general approach to determine the nature of persister genes in a variety of bacterial species and conditions.

Antibiotic treatment failure in children aged 1 to 59 months with World Health Organization-defined severe pneumonia in Malawi: A CPAP IMPACT trial secondary analysis

Antibiotic treatment failure in children aged 1 to 59 months with World Health Organization-defined severe pneumonia in Malawi: A CPAP IMPACT trial secondary analysis

Ferroptotic stress promotes macrophages against intracellular bacteria.

Rational: Intracellular bacterial survival is a major factor causing chronic or recurrent infection, leading to the failure of both host defense and/or antibiotic treatment. However, the elimination of intracellular bacteria is challenging as they are protected from antibiotics and host immune attack. Recent studies have indicated that iron helps macrophages against intracellular bacteria, contradictory to traditional “nutritional immunity”, in which iron is considered a key nutrient for bacterial survival in host cells. However, how iron facilitates intracellular bacterial death has not been fully clarified. In this study, we found that ferroptotic stress can help macrophages suppress intracellular bacteria by reversing the importation of ferrous iron into bacterial vacuoles via ferroportin and thereby inducing in situ ferroptosis-like bacterial death.Methods: A macrophage model of bacterial invasion was established to monitor dynamic changes in ferroptotic hallmarks, including ferrous iron and lipid peroxidation. Ferroptosis inducers and inhibitors were added to the model to evaluate the relationship between ferroptotic stress and intracellular bacterial survival. We then determined the spatiotemporal distributions of ferroportin, ferrous iron, and lipid peroxidation in macrophages and intracellular bacteria. A bacterial infection mouse model was established to evaluate the therapeutic effects of drugs that regulate ferroptotic stress.Results: Ferrous iron and lipid peroxidation increased sharply in the early stage of bacterial infection in the macrophages, then decreased to normal levels in the late stage of infection. The addition of ferroptosis inducers (ras-selective lethal small molecule 3, sulfasalazine, and acetaminophen) in macrophages promoted intracellular bacterial suppression. Further studies revealed that ferrous iron could be delivered to the intracellular bacterial compartment via inward ferroportin transportation, where ferrous iron induced ferroptosis-like death of bacteria. In addition, ferroptotic stress declined to normal levels in the late stage of infection by regulating iron-related pathways in the macrophages. Importantly, we found that enhancing ferroptotic stress with a ferroptosis inducer (sulfasalazine) successfully suppressed bacteria in the mouse infection models.Conclusions: Our study suggests that the spatiotemporal response to ferroptosis stress is an efficient pathway for macrophage defense against bacterial invasion, and targeting ferroptosis may achieve therapeutic targets for infectious diseases challenged by intracellular pathogens.

Antibiotic Heteroresistance in Klebsiella pneumoniae.

Klebsiella pneumoniae is one of the most common pathogens responsible for infections, including pneumonia, urinary tract infections, and bacteremias. The increasing prevalence of multidrug-resistant K. pneumoniae was recognized in 2017 by the World Health Organization as a critical public health threat. Heteroresistance, defined as the presence of a subpopulation of cells with a higher MIC than the dominant population, is a frequent phenotype in many pathogens. Numerous reports on heteroresistant K. pneumoniae isolates have been published in the last few years. Heteroresistance is difficult to detect and study due to its phenotypic and genetic instability. Recent findings provide strong evidence that heteroresistance may be associated with an increased risk of recurrent infections and antibiotic treatment failure. This review focuses on antibiotic heteroresistance mechanisms in K. pneumoniae and potential therapeutic strategies against antibiotic heteroresistant isolates.

Current and novel diagnostics for orthopedic implant biofilm infections: a review.

Biofilm infections involving orthopedic implants are a global problem. They contribute to severe complications and mortality, as well as increased use of antibiotic treatments and development of antibiotic-resistant microorganisms. More than 1 million hip and knee arthroplasties are performed each year in the United States. These hard-to-treat infections lead to patient distress, increased morbidity, and high financial costs to both patients and healthcare systems. There is a need to improve the diagnosis of such biofilm infections to allow for earlier detection and treatment. Current diagnostics rely on clinical signs for infections such as loss of function, fever, rubor, patient history of the predisposing condition, persisting infection, failure of antibiotic treatment, and documentation of antibiotic failure. Below, we present a framework which outlines the data gaps in the conventional laboratory techniques used in clinical diagnostics; we also discuss promising novel diagnostic methods which are currently used solely in research. It is critical to assess these novel infection diagnostic techniques and address the data gaps and clinical hesitance preventing application in a clinical setting. Additionally, the combination of conventional and novel diagnostic technologies would streamline the diagnostic process of biofilm infections associated with orthopedic implants.

Involvement of Small Colony Variant-Related Heme Biosynthesis Genes in Staphylococcus aureus Persister Formation in vitro.

Background: Persisters are important reasons for persistent infections, and they can lead to antibiotic treatment failure in patients and consequently chronic infection. Staphylococcus aureus small colony variants (SCVs) have been shown to be related to persistent infection. Mutations in the genes of the heme biosynthesis pathway lead to the formation of SCVs. However, the relationship between heme production genes and persister has not been tested.Methods:HemA and hemB were knocked out by allelic replacement from S. aureus strain USA500 separately, and then, the heme deficiency was complemented by overexpression of related genes and the addition of hemin. The stress-related persister assay was conducted. RNA-sequencing was performed to find genes and pathways involved in heme-related persister formation, and relative genes and operons were further knocked out and overexpressed to confirm their role in each process.Results: We found that heme biosynthesis deficiency can lead to decreased persister. After complementing the corresponding genes or hemin, the persister levels could be restored. RNA-seq on knockout strains showed that various metabolic pathways were influenced, such as energy metabolism, amino acid metabolism, carbohydrate metabolism, and membrane transport. Overexpression of epiF and operon asp23 could restore USA500∆hemA persister formation under acid stress. Knocking out operon arc in USA500∆hemA could further reduce USA500∆hemA persister formation under acid and oxidative stress.Conclusion: Heme synthesis has a role in S. aureus persister formation.

Isolation of persister cells within the biofilm and relative gene expression analysis of type II toxin/antitoxin system in Pseudomonas aeruginosa isolates in exponential and stationary phases

Chronic infections and treatment failure are concerning issues in patients with Pseudomonas aeruginosa infections. Persister cell formation in biofilm is considered a key reason for antibiotic resistance and treatment failure. In this study, expression of type II toxin/antitoxin (TA) system genes (relBE, Xre-COG5654, vapBC and Xre-GNAT) in persister cells of biofilm was evaluated in the presence of the antibiotics ciprofloxacin and colistin during exponential and stationary phases. The impact of antibiotics on biofilm persister cell formation during exponential and stationary phases of P. aeruginosa strains was examined by colony count at different time intervals in the presence of 5-fold minimum inhibitory concentration (MIC) of ciprofloxacin and colistin. Furthermore, expression of relBE, Xre-COG5654, vapBC and Xre-GNAT genes in P. aeruginosa strains undergoing antibiotic treatment for 3.5 h during exponential and stationary phases was examined by RT-qPCR. Formation of persister cells was observed in biofilms formed by P. aeruginosa strains in the presence of 5×MIC of ciprofloxacin and colistin compared with the control group after 3.5 h of incubation both during exponential and stationary phases. The number of biofilm persister cells was higher in stationary phase than in exponential phase. According to the findings of RT-qPCR, ciprofloxacin and colistin may induce persister cell formation by enhancing the expression of type II TA systems during stationary and exponential phases. The result of this study indicate that ciprofloxacin and colistin have the potential to increase persister cells formation in biofilms by influencing the expression of type II TA systems.

Evaluation of the Treatment of Aspiration Pneumonia in Hospitalized Children.

Aspiration pneumonia (AP) treatment is variable with limited available guidance on optimal antibiotic choice and duration. This study evaluated the impact of antibiotic regimen and duration on treatment failure for AP in children and correlated the effects of antimicrobial stewardship program (ASP) interventions on treatment duration. Hospitalized children who received antibiotics for AP were identified through an existing ASP repository. Diagnosis was confirmed through ASP documentation with either an international classification of diseases 9/10 code or physician diagnosis of AP. Incidence of treatment failure (necrotizing pneumonia, lung abscess, empyema, or retreatment) was compared between patients receiving shorter (≤7 days) vs longer (>7 days) course of antibiotics and between various empiric/final antibiotic regimens utilized. Duration of treatment was evaluated in patients with or without an ASP intervention. Four hundred and nineteen treatment courses for AP were included. Nineteen episodes (4.5%) of treatment failure were identified. No difference in treatment failure was observed between shorter vs longer courses (8 vs 11 episodes). An aminopenicillin plus beta-lactamase inhibitor was most frequently utilized for both empiric (47.2%) and final treatment (67.5%). Treatment failure rates did not differ with length of intravenous therapy nor empiric/final antibiotic regimen chosen. ASP interventions targeting duration were associated with significantly shorter courses (6.28 vs 7.46 days; P = .04). Shorter courses of antibiotics did not result in more treatment failure for AP when compared to longer courses. Neither antibiotic choice nor route impacted treatment failure rates. ASPs may optimize the treatment of pediatric AP.

Salmonella “RecAmends” self-healing

Persistent bacteria contribute to antibiotic treatment failure, potentially fueling resistance. Persisters must survive host defenses while retaining infective capacity after antibiotic cessation. In this issue of Cell Host and Microbe, Hill etal. identify bacterial RecA as a DNA repair factor that allows intracellular bacteria survival, regrowth, and relapse.

THE EFFECT OF INFORMATION BOOKLET ON THE PATIENTS COMPLIANCE WITH ORAL ANTIBIOTIC COURSE IN SEVERAL COMMUNITY HEALTH SERVICE

Inappropriate use of oral antibiotics will contribute to an increase in antibiotic resistance and treatment failure. Compliance with the use of oral antibiotics is one of the things that contributes to the inappropriate use of antibiotics. This study aims to analyze the effect of information booklet reminder media on adherence to short-term antibiotic use conducted in four puskesmas in the Surabaya area. Patients aged 19-50 years who were prescribed short-term antibiotics (<7 days) were included in this study. Patients were then grouped into two groups, namely the intervention group who was given an information booklet, and the control group. Compliance with the use of antibiotics was measured based on the calculation of the remaining antibiotics on the day the antibiotics ran out. A total of 192 people were recruited in this study, 96 people were in the intervention group and 96 people were in the control group. The results of measurement of adherence and analysis showed that 80.21% of patients in the intervention group were obedient in using their antibiotics, while patients in the control group were compliant with 60.42% (p-value 0.003). Based on these results, information booklets can significantly affect patient compliance in the use of short-term oral antibiotics so that information booklets can be used as one of the educational media in increasing adherence to antibiotic use.

Helicobacter pylori eradication by low‐dose rifabutin triple therapy (RHB‐105) is unaffected by high body mass index

Background Helicobacter pylori infection affects ~35% of Americans and may lead to serious sequelae if left untreated, including gastric cancer. Obesity is a significant risk factor for antibiotic treatment failure; however, little work has been done to understand the influence of high body mass index (BMI) on the success rates of H pylori eradication regimens in treatment-naïve and refractory adult patients. Aim This analysis evaluated the association of subject obesity on overall H pylori eradication rates for RHB-105 (rifabutin, amoxicillin, and omeprazole magnesium; Talicia®) and its comparators using data from two Phase 3 clinical trials. Methods A post hoc analysis of the eradication rates of RHB-105 vs comparators in a total of 269 subjects who tested positive for H pylori was conducted. Comparators in the two studies included placebo (placebo comparator) and amoxicillin and omeprazole (active comparator). Subjects were treated for 14 days and returned for follow-up test-of-cure at 28-59 days post-therapy using urea breath testing. Results Subjects receiving RHB-105 with 30 ≤ BMI < 40 or BMI ≥ 40 had pooled modified intent to treat (mITT) eradication rates of 88.1% (95% CI: 81.1-92.8) and 90.9% (95% CI: 72.2-97.5) [P = .707], respectively, compared to active comparator rates of 62.9% (95% CI: 52.5-72.2) and 31.8% (95% CI: 16.4-52.7) [P = .008]. Conclusions Obese patients treated with RHB-105 were associated with efficacy rates comparable to the overall study population. This supports further evaluation of the efficacy of RHB-105 in obese populations, where H pylori is prevalent. ClinTrials.gov # NCT01980095 & NCT031985070.

Single-Cell Technologies to Study Phenotypic Heterogeneity and Bacterial Persisters.

Antibiotic persistence is a phenomenon in which rare cells of a clonal bacterial population can survive antibiotic doses that kill their kin, even though the entire population is genetically susceptible. With antibiotic treatment failure on the rise, there is growing interest in understanding the molecular mechanisms underlying bacterial phenotypic heterogeneity and antibiotic persistence. However, elucidating these rare cell states can be technically challenging. The advent of single-cell techniques has enabled us to observe and quantitatively investigate individual cells in complex, phenotypically heterogeneous populations. In this review, we will discuss current technologies for studying persister phenotypes, including fluorescent tags and biosensors used to elucidate cellular processes; advances in flow cytometry, mass spectrometry, Raman spectroscopy, and microfluidics that contribute high-throughput and high-content information; and next-generation sequencing for powerful insights into genetic and transcriptomic programs. We will further discuss existing knowledge gaps, cutting-edge technologies that can address them, and how advances in single-cell microbiology can potentially improve infectious disease treatment outcomes.

Tubo‐ovarian abscess: A proposed new scoring system to guide clinical management

AbstractObjectiveTo create a risk scoring system comprised of clinical and radiological characteristics that can predict the likelihood of antibiotic treatment failure of tubo‐ovarian abscesses. The score should guide clinicians in identifying patients to whom early intervention should be offered instead of a prolonged trial of antibiotics.MethodsA multicenter, retrospective cohort study carried out between January 1, 2013 and September 30, 2019, identified consecutive patients with tubo‐ovarian abscess. Using a chronological split, patients were allocated to two groups for the development and subsequent validation of the postulated scoring system. Univariate and bivariate analyses were performed to identify statistically significant variables for the failure of intravenous antibiotic treatment.ResultsIn total, 214 consecutive patients with tubo‐ovarian abscesses were identified. Data from the first 150 patients were used for the development of the postulated scoring system; data from the subsequent 64 patients were used for validation. Statistically significant clinical features between those having successful and unsuccessful management were: temperature (median = 37.1℃ vs 38.2℃, P = 0.0001), C‐reactive protein (151 mg/L vs 243 mg/L, P = 0.0001), and tubo‐ovarian abscess diameter (6.0 cm vs 8.0 cm, P = 0.0001). These parameters were used to create a risk prediction score. A score of four or more was predictive of requiring surgical/radiological intervention of tubo‐ovarian abscess (P &lt; 0.001). The score had a sensitivity of 69% and a specificity of 88%, with area under the curve (AUC) = 0.859.ConclusionCurrently, there is no guidance for clinicians on when to operate on a tubo‐ovarian abscess. Our prediction score is simple, using only three easily obtained clinical characteristics.

816 Managing Acute Appendicitis During the First Wave of the COVID-19 Pandemic: A Single-Centre Retrospective Study

IntroductionThe COVID-19 pandemic provoked a change to normal surgical practice and led to a higher proportion of acute appendicitis (AA) patients being treated conservatively with antibiotics. We aim to analyse patients presenting with AA during the first wave of the pandemic, comparing surgically and conservatively managed patients.MethodAll patients presenting to our centre with AA between March and July 2020 were included. Six-month follow-up data was collected retrospectively using electronic records. Patients were categorised into surgically and conservatively managed groups. The primary outcome was the complication rate (post-operative complications vs failure of antibiotic treatment) and the secondary outcome was length of hospital stay.ResultsFifty-seven patients (n = 57) were admitted with AA, 45.6% (n = 26) managed conservatively compared to 54.4% (n = 31) treated surgically. Higher complication rates were observed amongst the conservatively managed group, although not statistically significant (16% vs 35%; p = 0.131). There was no significant difference in length of hospital stay observed between the two groups (surgical: median, 2; interquartile range, 2-3 vs conservative: median, 3; interquartile range, 2-4). White cell count (WCC) and Alvarado score were higher on admission in the surgical group with statistical significance (p = 0.012 and p = 0.028 respectively).ConclusionsStratification criteria, such as Alvarado score and WCC may identify patients more suitable for conservative management. Longer term follow-up will be carried out, which may alter complication rates in either group. We suggest all patients treated conservatively should undergo computerised tomography (CT) to exclude complicated appendicitis. Further UK-based studies will add to the evidence-base surrounding management of AA during the COVID-19 pandemic.

Genistein Inhibits the Pathogenesis of Aeromonas hydrophila by Disrupting Quorum Sensing Mediated Biofilm Formation and Aerolysin Production.

Aeromonas hydrophila is an opportunistic pathogen that is responsible for a variety of infectious diseases both in human and animals, particularly aquatic animals. Moreover, the pathogen has become a foodborne pathogen by transmitting from seafood to human. The abuse of antibiotics in aquaculture results in the emergence of antibiotic resistance and treatment failure. Therefore, novel approaches are urgently needed for managing resistant A. hydrophila associated infections. Aerolysin, an essential virulence factor of pathogenic A. hydrophila strain, has been identified as target developing novel drugs against pathogenesis of A. hydrophila. In the present study, genistein, without anti-A. hydrophila activity, was identified that could decrease the production of aerolysin and biofilm formation at a dose-dependent manner. Transcription of aerolysin encoding gene aerA and quorum sensing related genes ahyI and ahyR was significantly down-regulated when co-cultured with genistein. Cell viability studies demonstrated that genistein could significantly improve aerolysin mediated A549 cell injury. Furthermore, genistein could provide a remarkable protection to channel catfish infected with A. hydrophila. These findings indicate that targeting quorum sensing and virulence can be a useful approach developing drugs against A. hydrophila infections in aquaculture. Moreover, genistein can be chosen as a promising candidate in developing drugs against A. hydrophila.

Value of pneumococcal vaccination in controlling the development of antimicrobial resistance (AMR): Case study using DREAMR in Ethiopia

BackgroundAntimicrobial resistance (AMR) poses an imminent threat to global health security. Pneumococcal vaccination reduces disease incidence, prevents antibiotic use, and decreases antibiotic-resistant infections. However, the benefit of vaccination in reducing AMR has been poorly quantified to date. MethodsWe developed an agent-based model, DREAMR (Dynamic Representation of the Economics of AMR) to evaluate the economic value of childhood immunization with the pneumococcal conjugate vaccine (PCV) in mitigating the development of AMR. Our model incorporates vaccination coverage, disease incidence, care seeking, and antibiotic use. Accumulation of AMR is simulated based on antibiotic exposure through pharmacokinetics and resulting pharmacodynamics. The model was applied to Ethiopia. ResultsIntroduction of PCV vaccination has helped slow the development of AMR by 14.77% for amoxicillin and 0.59% for ceftriaxone in Ethiopia since 2011. In addition to the benefit of reduction in disease incidence, PCV vaccination has averted approximately 718,100 antibiotic treatment failures and 9,520 AMR-related deaths (27.8% reduction) in Ethiopia between 2011 and 2017, resulting in savings of $32.7 million. Maintaining current PCV immunization coverage will contribute an additional $7.67 million in annual AMR cost savings over five years compared to no vaccination scenario, which could increase to $11.43 million by increasing PCV coverage to 85% by 2022. ConclusionsThis study is the first to demonstrate the broader economic value of pneumococcal vaccination in controlling the development of AMR in Africa. Vaccination not only saves lives by preventing illnesses, but also benefits society by reducing antibiotic utilization and treatment failures due to AMR.

SURGICAL VERSUS CONSERVATIVE MANAGEMENT OF ACUTE APPENDICITIS DURING THE COVID-19 PANDEMIC

Background: We aim to analyse the management of patients presenting with AA to our institution during the first wave of the pandemic, comparing surgically and conservatively managed patients&#x0D; Method: Patients were categorised into surgically and conservatively managed groups. The primary outcome was the complication rate (post-operative complications vs failure of antibiotic treatment) and the secondary outcomes were length of hospital stay and Alvarado score.&#x0D; Results: Higher complication rates were observed amongst the conservatively managed group, although not found to be statistically significant (16.67% vs 34.78%; p=&gt;0.05). There was no significant difference in length of hospital stay observed between the two groups (surgical: 2.31±1.02 days vs conservative: 2.62±1.12 days).&#x0D; Conclusions: COVID-19 has led to a significant cohort of conservatively managed AA patients. We propose a stratification pathway based on clinical severity, Alvarado score and imaging to facilitate safe selection for conservative management of AA, in order to reduce failure of treatment rates in this patient group.&#x0D; Keywords: Appendicectomy, Appendicitis, Conservative, Coronavirus