In Vitro Activity of Ceftaroline and Comparators against Bacterial Isolates Collected Globally from Patients with Skin and Soft Tissue Infections: ATLAS Program 2019–2020

The objective of this study was to assess the in vitro activity of ceftaroline and a panel of comparator agents against isolates causing skin and soft tissue infections (SSTIs) collected in Africa/Middle East, Asia–Pacific, Europe, and Latin America from 2019–2020. Minimum inhibitory concentrations (MIC) were determined using European Committee on Antimicrobial Susceptibility Testing criteria. All the methicillin-susceptible Staphylococcus aureus (MSSA) isolates were susceptible to ceftaroline. Across all regions, ceftaroline demonstrated potent activity against methicillin-resistant S. aureus (MRSA, susceptibility 89.5–93.7%) isolates. Susceptibility to vancomycin, daptomycin, linezolid, teicoplanin, trimethoprim sulfamethoxazole, and tigecycline was ≥94.1% in MSSA and MRSA isolates. Against β-hemolytic streptococci isolates, ceftaroline demonstrated very potent activity (MIC90 0.008–0.03 mg/L) across all regions. All β-hemolytic streptococci isolates were susceptible to linezolid, penicillin, and vancomycin (MIC90 0.06–2 mg/L). Among the extended-spectrum β-lactamases (ESBL)-negative Enterobacterales tested (E. coli, K. pneumoniae, and K. oxytoca), susceptibility to ceftaroline was high (88.2–98.6%) in all regions. All ESBL-negative Enterobacterales were susceptible to aztreonam. Potent activity was observed for amikacin, cefepime, and meropenem (94.1–100%) against these isolates. Overall, ceftaroline showed potent in vitro activity against isolates of pathogens causing SSTIs. Continuous surveillance of global and regional susceptibility patterns is needed to guide appropriate treatment options against these pathogens.


Introduction
Skin and soft tissue infections (SSTIs) are among the major causes of hospitalizations and emergency department visits and are associated with considerable morbidity [1,2].SSTIs include a range of infections, and the clinical presentation ranges from mild infections such as cellulitis to life-threatening, necrotizing infections of soft tissue [3].Complicated SSTIs (cSSTIs) require hospitalization and include infections of deeper soft tissues such as necrotizing infections, major abscesses, ulcers, and burns [3,4].According to the US Food and Drugs Administration (FDA), acute bacterial skin and skin structure infection (ABSSI) includes cellulitis, erysipelas, wound infections, and major cutaneous abscesses with a lesion surface area ≥75 cm 2 [3].According to a Global Burden of Disease (GBD) study , there was a 46.8% increase in incidence and a 40.2% increase in years lived with disability for skin and subcutaneous diseases between 1990 and 2017 [5].A systematic analysis in the GBD study in 2017 estimated a total of 76,000 deaths (48,700-95,600) attributed to bacterial skin diseases with an increase of 45.5% (36.8-54.9%)from 2007-2017 [6].Another systematic analysis based on data from the GBD database conducted in 2019 revealed an annual increase of 7.38% (7.06-7.67)for age-standardized incidence of bacterial skin disease from 1990-2019 [7].
The treatment of SSTIs has been complicated by increasing incidence of MRSA which has led to antibiotic misuse [12,[16][17][18][19][20][21][22].Furthermore, in SSTIs caused by drug-resistant Gram-negative bacilli, treatment options are limited [10].As the incidence of skin infections and antimicrobial resistance is on the rise [5,12,23], it is essential to monitor the global longitudinal trends of antimicrobial susceptibility for ceftaroline and other agents among SSTI isolates for understanding emerging resistance mechanisms to guide appropriate antimicrobial therapy.Previously, a study by Piérard et al. assessed the antimicrobial activity of ceftaroline and comparators in SSTI isolates collected across regions including Africa/Middle East, Asia-Pacific, Europe, and Latin America as part of the Antimicrobial Testing Leadership and Surveillance (ATLAS) surveillance program, from 2015-2018 [24].Considering that antimicrobial resistance is annually monitored to evaluate the changes in susceptibility patterns of antimicrobials and complications of treatment of SSTIs, we conducted this study with the aim of examining the antimicrobial activity of ceftaroline and a panel of comparator agents against SSTI isolates collected in Africa/Middle East (AfME), Asia-Pacific (APAC), Europe, and Latin America (LATAM) from 2019-2020 as part of the ATLAS program.

Discussion
This study evaluated the in vitro antimicrobial susceptibilities of ceftaroline and a panel of comparator agents against SSTI isolates collected in AfME, APAC, Europe, and LATAM from 2019-2020.
Among the ESBL-negative Enterobacterales isolates, ceftaroline demonstrated potent activity against E. coli across all regions (MIC 90 0.5-1 mg/L).In contrast, the previous global ATLAS study (2015)(2016)(2017)(2018)) demonstrated moderate ceftaroline activity in APAC (MIC 90 128 mg/L) compared with other regions (MIC 90 0.5-4 mg/L) [24].These data suggest an increase in activity for ceftaroline in APAC compared with previous years.In the current study, ceftaroline demonstrated potent activity against K. pneumoniae in Europe (MIC 90 1 mg/L) and very potent activity against those collected in APAC (MIC 90 0.25 mg/L).Notably, the previous global ATLAS study from 2015-2018 reported moderate activity (MIC 90 16 mg/L) for ceftaroline in Europe and APAC [24].In the current study, ceftaroline demonstrated very potent activity against K. oxytoca isolates in Europe (MIC 90 0.5 mg/L).In contrast, the global ATLAS study from 2015-2018 reported good activity for ceftaroline against K. oxytoca in Europe (MIC 90 2 mg/L) [24].Overall, the results in this study suggest that ceftaroline is potent against ESBL-negative Enterobacterales and could be a good treatment option against these isolates.In the current study, all ESBLnegative Enterobacterales isolates were susceptible to aztreonam (MIC 90 0.12-0.5 mg/L).However, the previous global ATLAS study reported variable activity for aztreonam across regions and organisms (MIC 90 0.25-32 mg/L) [24].The current study also reported potent activity for amikacin, cefepime, and meropenem across all regions (MIC 90 ≤ 0.06-8 mg/L).Interestingly, the previous global ATLAS study noted variation in activity for these agents across regions and organisms (MIC 90 0.06-8 mg/L) [24].
This study has a few limitations.Approximately half of the isolates collected were from Europe, which could skew the overall data patterns towards those seen in Europe.However, for MRSA, the isolate distribution was well balanced across most regions except AfME.The distribution of participating centers varied across countries and years of the study period, as a result of which all countries and regions are not equally represented within the dataset.A pre-defined number of isolates were collected from each site, so the results of this study cannot be interpreted as prevalence or used for epidemiological data.The low number of samples for some species in this study should be taken into consideration while interpreting the findings.ATLAS is a global surveillance platform focusing on the susceptibility rates of a panel of antimicrobials against clinical isolates from hospitalized patients with various infections including SSTIs, and does not capture biochemical analyses, serology, morbidity and mortality rates, nor clinical outcomes associated with these isolates.Hence, such analyses were not included in this surveillance study which focuses only on the susceptibility rates against pathogens associated with SSTIs.As the current study is an extension of the previous study by Pierard et al. (2015Pierard et al. ( -2018) ) [24], the number of isolates collected in this study could be lower due to a shorter recruitment period (2019-2020) and the COVID-19 outbreak during 2020.Data for ceftriaxone were unavailable among ESBLnegative Enterobacterales isolates as ceftriaxone was not tested post 2017 in these isolates as part of the ATLAS program.Lastly, tigecycline susceptibility data were unavailable for K. pneumoniae and K. oxytoca isolates as EUCAST breakpoints for tigecycline are not available for Klebsiella species.
In conclusion, this study demonstrates that ceftaroline has potent in vitro activity against Gram-positive and Gram-negative isolates associated with cSSTI collected from AfME, APAC, Europe, and LATAM.Among MRSA isolates, the activity of ceftaroline was slightly lower in APAC compared with other regions, and this trend has been maintained over the years.Among ESBL-negative E. coli isolates, an increase in susceptibility to ceftaroline was observed in APAC compared with previous years.Among the comparator agents, our study also identified vancomycin, daptomycin, linezolid, teicoplanin, and tigecycline to be highly active against MSSA and MRSA isolates, whereas linezolid, penicillin, and vancomycin demonstrated very potent activity among β-hemolytic streptococci isolates.Against the Gram-negative isolates, amikacin, aztreonam, cefepime, and meropenem exhibited potent activity.With polymicrobial SSTIs often requiring empirical and broad-spectrum treatment, surveillance of global and regional susceptibility patterns and resistance mechanisms is warranted for ensuring the use of appropriate treatment options and limiting antimicrobial resistance.

Bacterial Isolates
In this study, non-duplicate clinical isolates (single isolate per patient) of S. aureus, S. agalactiae, S. dysgalactiae, S. pyogenes, E. coli, K. pneumoniae, and K. oxytoca were collected between 2019-2020 from hospitalized patients with skin and soft tissue infections from AfME, APAC, Europe, and LATAM, as part of ATLAS [36], a global surveillance program implemented in 2004 that provides antimicrobial activity data for different classes of antimicrobials against isolates collected worldwide.North America was not included in this study as this region was not part of the global ATLAS program sponsored by Pfizer.This program collected a predefined set of isolates from each participating center annually, across selected bacterial species and infection types.Isolates were limited to one patient every year and accepted independently of the patient's hospital location.Bacterial isolates were collected from abscess, bone, burn, carbuncle, cellulitis, decubitus, exudate, furuncle, hair, impetiginous lesions, integumentary (skin, nail, hair), muscle, nails, skin, synovial fluid, tissue fluid, ulcer, wound, other skin, and other skeletal specimen sources.Isolates Informed Consent Statement: Not applicable.