scholarly journals Reporting antimicrobial susceptibilities and resistance phenotypes in Staphylococcus spp.: a nationwide proficiency study

2021 ◽  
Author(s):  
Felipe Fernández-Cuenca ◽  
Inmaculada López-Hernández ◽  
Emilia Cercenado ◽  
Carmen Conejo ◽  
Nuria Tormo ◽  
...  
Keyword(s):  
Antimicrobial Agent ◽  
Antimicrobial Agents ◽  
Resistance Mechanisms ◽  
Error Rates ◽  
23S Rrna ◽  
Error Type ◽  
Staphylococcus Capitis ◽  
Gradient Diffusion ◽  
Staphylococcus Spp ◽  
Clinical Category

Abstract Objectives To evaluate the proficiency of microbiology laboratories in Spain in antimicrobial susceptibility testing (AST) of Staphylococcus spp. Materials and methods Eight Staphylococcus spp. with different resistance mechanisms were selected: six Staphylococcus aureus (CC-01/mecA, CC-02/mecC, CC-03/BORSA, CC-04/MLSBi, CC-06/blaZ and CC-07/linezolid resistant, cfr); one Staphylococcus epidermidis (CC-05/linezolid resistant, 23S rRNA mutation); and one Staphylococcus capitis (CC-08/daptomycin non-susceptible). Fifty-one laboratories were asked to report: (i) AST system used; (ii) antimicrobial MICs; (iii) breakpoints used (CLSI or EUCAST); and (iv) clinical category. Minor, major and very major errors (mEs, MEs and VMEs, respectively) were determined. Results The greatest MIC discrepancies found were: (i) by AST method: 19.4% (gradient diffusion); (ii) by antimicrobial agent: daptomycin (21.3%) and oxacillin (20.6%); and (iii) by isolate: CC-07/cfr (48.0%). The greatest error rates were: (i) by AST method: gradient diffusion (4.3% and 5.1% VMEs, using EUCAST and CLSI, respectively); (ii) by breakpoint: 3.8% EUCAST and 2.3% CLSI; (iii) by error type: mEs (0.8% EUCAST and 1.0% CLSI), MEs (1.8% EUCAST and 0.7% CLSI) and VMEs (1.2% EUCAST and 0.6% CLSI); (iii) by antimicrobial agent: VMEs (4.7% linezolid and 4.3% oxacillin using EUCAST); MEs (14.3% fosfomycin, 9.1% tobramycin and 5.7% gentamicin using EUCAST); and mEs (22.6% amikacin using EUCAST). Conclusions Clinical microbiology laboratories should improve their ability to determine the susceptibility of Staphylococcus spp. to some antimicrobial agents to avoid reporting false-susceptible or false-resistant results. The greatest discrepancies and errors were associated with gradient diffusion, EUCAST breakpoints and some antimicrobials (mEs for aminoglycosides; MEs for fosfomycin, aminoglycosides and oxacillin; and VMEs for linezolid and oxacillin).

scholarly journals Relationship between the severity of acne vulgaris and antimicrobial resistance of bacteria isolated from acne lesions in a hospital in Japan

2014 ◽  
Vol 63 (5) ◽  
pp. 721-728 ◽  
Author(s):  
Keisuke Nakase ◽  
Hidemasa Nakaminami ◽  
Yuko Takenaka ◽  
Nobukazu Hayashi ◽  
Makoto Kawashima ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Antimicrobial Agents ◽  
Acne Vulgaris ◽  
Normal Skin ◽  
Resistance Mechanisms ◽  
University Hospital ◽  
23S Rrna ◽  
Rrna Gene ◽  
Severe Acne ◽  
23S Rrna Gene

Propionibacterium acnes and Staphylococcus epidermidis are normal skin inhabitants that are frequently isolated from lesions caused by acne, and these micro-organisms are considered to contribute to the inflammation of acne. In the present study, we examined the antimicrobial susceptibilities and resistance mechanisms of P. acnes and S. epidermidis isolated from patients with acne vulgaris in a university hospital in Japan from 2009 to 2010. Additionally, we analysed the relationship between the antimicrobial resistance of P. acnes and the severity of acne vulgaris. Some P. acnes strains (18.8 %; 13/69) were resistant to clindamycin. All strains had a mutation in the 23S rRNA gene, except for one strain that expressed erm(X) encoding a 23S rRNA methylase. Tetracycline-resistant P. acnes strains were found to represent 4.3 % (3/69) of the strains, and this resistance was caused by a mutation in the 16S rRNA gene. Furthermore, three strains with reduced susceptibility to nadifloxacin (MIC = 16 µg ml−1) were detected. When analysing the correlation between the antimicrobial resistance of P. acnes and S. epidermidis, more than 80 % of the patients who carried clindamycin-resistant P. acnes also carried clindamycin-resistant S. epidermidis. However, no epidemic strain that exhibited antimicrobial resistance was detected in the P. acnes strains when analysed by PFGE. Therefore, our results suggest that the antimicrobial resistance of P. acnes is closely related to antimicrobial therapy. Additionally, those P. acnes strains tended to be frequently found in severe acne patients rather than in mild acne patients. Consequently, the data support a relationship between using antimicrobial agents and the emergence of antimicrobial resistance.

scholarly journals The epidemiology and molecular characteristics of linezolid-resistant Staphylococcus capitis in Huashan Hospital, Shanghai

2020 ◽  
Vol 69 (8) ◽  
pp. 1079-1088
Author(s):  
Li Ding ◽  
Pei Li ◽  
Yang Yang ◽  
Dongfang Lin ◽  
Xiaogang Xu
Keyword(s):  
Type Species ◽  
Resistance Mechanisms ◽  
23S Rrna ◽  
Molecular Characteristics ◽  
Genetic Characteristics ◽  
Content Type ◽  
Link Type ◽  
Staphylococcus Capitis ◽  
Broth Microdilution Method ◽  
V Region

Introduction. Linezolid-resistant (LZR) Staphylococcus capitis has recently emerged in our hospital, and its potential resistance mechanisms are still not clear. Aim. This study aimed to investigate the epidemiology, clinical and genetic characteristics, resistance mechanisms and biofilm formation capacity of LZR S. capiti s isolated from patients at Huashan Hospital, Shanghai, PR China between 2012 and 2018. Methodology. Strains were subjected to antimicrobial susceptibility testing (AST) with antibiotics using the broth microdilution method according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. The presence of cfr, optrA and poxtA, as well as mutations in the 23S ribosomal (r)RNA and ribosomal proteins, was investigated using PCR and sequencing techniques. The genetic relationship between isolates was analysed using pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing (WGS). Biofilm biomasses were detected by using crystal violet staining. Results. Twenty-one LZR S. capitis strains displayed MICs of 32–512 μg ml−1. All LZR strains showed G2576T and C2104T mutations in the 23S rRNA V region. Besides G2576T and C2104T, no base mutations were detected in the V region. The cfr was detected in 12 strains, while optrA and poxtA were not amplified in 21 S . capitis strains. PFGE showed that the LZR S. capitis strains belonged to a single clone. The phylogenetic tree showed that 20 LZR S. capitis strains were highly similar to LNZR-1, isolated from Harbin (located in the north of China) in 2013, which showed resistance to linezolid. Conclusions. In this research, cfr-negative strains displayed linezolid MICs of 32 μg ml−1. In comparison, cfr-positive strains exhibited linezolid MICs of 128–512 μg ml−1, indicating that high levels of linezolid resistance appear to be related to the presence of cfr. The outbreak of LZR S. capitis in our hospital needs to be monitored closely.

Perceptual Characteristics of Consonant Production in Apraxia of Speech and Aphasia

2019 ◽  
Vol 28 (4) ◽  
pp. 1411-1431 ◽  
Author(s):  
Lauren Bislick ◽  
William D. Hula
Keyword(s):  
Error Rate ◽  
Error Rates ◽  
Group Differences ◽  
Diagnostic Process ◽  
Apraxia Of Speech ◽  
Contextual Variables ◽  
Error Type ◽  
Type Distribution ◽  
Phonetic Features ◽  
Syllable Position

Purpose This retrospective analysis examined group differences in error rate across 4 contextual variables (clusters vs. singletons, syllable position, number of syllables, and articulatory phonetic features) in adults with apraxia of speech (AOS) and adults with aphasia only. Group differences in the distribution of error type across contextual variables were also examined. Method Ten individuals with acquired AOS and aphasia and 11 individuals with aphasia participated in this study. In the context of a 2-group experimental design, the influence of 4 contextual variables on error rate and error type distribution was examined via repetition of 29 multisyllabic words. Error rates were analyzed using Bayesian methods, whereas distribution of error type was examined via descriptive statistics. Results There were 4 findings of robust differences between the 2 groups. These differences were found for syllable position, number of syllables, manner of articulation, and voicing. Group differences were less robust for clusters versus singletons and place of articulation. Results of error type distribution show a high proportion of distortion and substitution errors in speakers with AOS and a high proportion of substitution and omission errors in speakers with aphasia. Conclusion Findings add to the continued effort to improve the understanding and assessment of AOS and aphasia. Several contextual variables more consistently influenced breakdown in participants with AOS compared to participants with aphasia and should be considered during the diagnostic process. Supplemental Material https://doi.org/10.23641/asha.9701690

Antimicrobial properties of actively purified secondary metabolites isolated from different marine organisms

2020 ◽  
Vol 21 ◽  
Author(s):  
Nilushi Indika Bamunu Arachchige ◽  
Fazlurrahman Khan ◽  
Young-Mog Kim
Keyword(s):  
Secondary Metabolites ◽  
Pathogenic Bacteria ◽  
Antimicrobial Agents ◽  
Bacterial Species ◽  
Antimicrobial Properties ◽  
Antimicrobial Effect ◽  
Cost Effective ◽  
Resistance Mechanisms ◽  
Marine Organisms ◽  
Antimicrobial Compounds

Background: The treatment of infection caused by pathogenic bacteria becomes one of the serious concerns globally. The failure in the treatment was found due to the exhibition of multiple resistance mechanisms against the antimicrobial agents. Emergence of resistant bacterial species has also been observed due to prolong treatment using conventional antibiotics. To combat these problems, several alternative strategies have been employed using biological and chemically synthesized compounds as antibacterial agents. Marine organisms considered as one of the potential sources for the isolation of bioactive compounds due to the easily available, cost-effective, and eco-friendly. Methods: The online search methodology was adapted for the collection of information related to the antimicrobial properties of marine-derived compounds. These compound has been isolated and purified by different purification techniques, and their structure also characterized. Furthermore, the antibacterial activities have been reported by using broth microdilution as well as disc diffusion assays. Results: The present review paper describes the antimicrobial effect of diverse secondary metabolites which are isolated and purified from the different marine organisms. The structural elucidation of each secondary metabolite has also been done in the present paper, which will help for the in silico designing of the novel and potent antimicrobial compounds. Conclusion: A thorough literature search has been made and summarizes the list of antimicrobial compounds that are isolated from both prokaryotic and eukaryotic marine organisms. The information obtained from the present paper will be helpful for the application of marine compounds as antimicrobial agents against different antibiotic-resistant human pathogenic bacteria.

Development of Peptides that Inhibit Aminoglycoside-Modifying Enzymes and β-Lactamases for Control of Resistant Bacteria

2020 ◽  
Vol 21 (10) ◽  
pp. 1011-1026
Author(s):  
Bruna O. Costa ◽  
Marlon H. Cardoso ◽  
Octávio L. Franco
Keyword(s):  
Drug Target ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Specific Chemical ◽  
Target Interaction ◽  
Multiresistant Bacteria ◽  
Acute Bacterial Infections

: Aminoglycosides and β-lactams are the most commonly used antimicrobial agents in clinical practice. This occurs because they are capable of acting in the treatment of acute bacterial infections. However, the effectiveness of antibiotics has been constantly threatened due to bacterial pathogens producing resistance enzymes. Among them, the aminoglycoside-modifying enzymes (AMEs) and β-lactamase enzymes are the most frequently reported resistance mechanisms. AMEs can inactivate aminoglycosides by adding specific chemical molecules in the compound, whereas β-lactamases hydrolyze the β-lactams ring, preventing drug-target interaction. Thus, these enzymes provide a scenario of multidrug-resistance and a significant threat to public health at a global level. In response to this challenge, in recent decades, several studies have focused on the development of inhibitors that can restore aminoglycosides and β-lactams activity. In this context, peptides appear as a promising approach in the field of inhibitors for future antibacterial therapies, as multiresistant bacteria may be susceptible to these molecules. Therefore, this review focused on the most recent findings related to peptide-based inhibitors that act on AMEs and β-lactamases, and how these molecules could be used for future treatment strategies.

scholarly journals Antimicrobial Resistance Profiles and Macrolide Resistance Mechanisms of Campylobacter coli Isolated from Pigs and Chickens

2021 ◽  
Vol 9 (5) ◽  
pp. 1077
Author(s):  
Ji-Hyun Choi ◽  
Dong Chan Moon ◽  
Abraham Fikru Mechesso ◽  
Hee Young Kang ◽  
Su-Jeong Kim ◽  
...  
Keyword(s):  
Nalidixic Acid ◽  
Ribosomal Proteins ◽  
Resistance Mechanisms ◽  
23S Rrna ◽  
Considerable Proportion ◽  
Rrna Gene ◽  
Campylobacter Coli ◽  
Erythromycin Resistance ◽  
Public Health Hazards ◽  
Resistance Rates

We identified 1218 Campylobacter coli isolates from fecal and carcass samples of pigs (n = 643) and chickens (n = 575) between 2010 and 2018. About 99% of the isolates were resistant to at least one antimicrobial agent. The isolates exhibited high resistance rates (>75%) to ciprofloxacin, nalidixic acid, and tetracycline. Azithromycin and erythromycin resistance rates were the highest in isolates from pigs (39.7% and 39.2%, respectively) compared to those of chickens (15.8% and 16.3%, respectively). Additionally, a low-to-moderate proportion of the isolates were resistant to florfenicol, gentamicin, clindamycin, and telithromycin. Multidrug resistance (MDR) was found in 83.1% of the isolates, and profiles of MDR usually included ciprofloxacin, nalidixic acid, and tetracycline. We found point mutation (A2075G) in domain V of the 23S rRNA gene in the majority of erythromycin-resistant isolates. Multilocus sequence typing of 137 erythromycin-resistant C. coli isolates revealed 37 previously reported sequence types (STs) and 8 novel STs. M192I, A103VI, and G74A substitutions were frequently noted in the ribosomal proteins L4 or L22. Further, we identified a considerable proportion (>90%) of erythromycin-resistant isolates carrying virulence factor genes: flaA, cadF, ceuE, and VirB. The prudent use of antimicrobials and regular microbiological investigation in food animals will be vital in limiting the public health hazards of C. coli in Korea.

scholarly journals Silver (I) N-Heterocyclic Carbene Complexes: A Winning and Broad Spectrum of Antimicrobial Properties

2021 ◽  
Vol 22 (5) ◽  
pp. 2497
Author(s):  
Filippo Prencipe ◽  
Anna Zanfardino ◽  
Michela Di Napoli ◽  
Filomena Rossi ◽  
Stefano D’Errico ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Antimicrobial Properties ◽  
Resistance Mechanisms ◽  
Heterocyclic Carbenes ◽  
Significant Activity ◽  
Bacterial Strains ◽  
Development Of Resistance ◽  
Starting Point ◽  
Catalytic Chemistry

The evolution of antibacterial resistance has arisen as the main downside in fighting bacterial infections pushing researchers to develop novel, more potent and multimodal alternative drugs.Silver and its complexes have long been used as antimicrobial agents in medicine due to the lack of silver resistance and the effectiveness at low concentration as well as to their low toxicities compared to the most commonly used antibiotics. N-Heterocyclic Carbenes (NHCs) have been extensively employed to coordinate transition metals mainly for catalytic chemistry. However, more recently, NHC ligands have been applied as carrier molecules for metals in anticancer applications. In the present study we selected from literature two NHC-carbene based on acridinescaffoldand detailed nonclassicalpyrazole derived mono NHC-Ag neutral and bis NHC-Ag cationic complexes. Their inhibitor effect on bacterial strains Gram-negative and positivewas evaluated. Imidazolium NHC silver complex containing the acridine chromophore showed effectiveness at extremely low MIC values. Although pyrazole NHC silver complexes are less active than the acridine NHC-silver, they represent the first example of this class of compounds with antimicrobial properties. Moreover all complexesare not toxic and they show not significant activity againstmammalian cells (Hek lines) after 4 and 24 h. Based on our experimental evidence, we are confident that this promising class of complexes could represent a valuable starting point for developing candidates for the treatment of bacterial infections, delivering great effectiveness and avoiding the development of resistance mechanisms.

scholarly journals 1593. Antimicrobial Activity of Ceftazidime-Avibactam and Comparator Agents Against OXA-48 β-lactamase–Producing Enterobacterales Collected in International Medical Centers, Including the United States, in 2017–2018

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S793-S793
Author(s):  
Lynn-Yao Lin ◽  
Dmitri Debabov ◽  
William Chang
Keyword(s):  
Antimicrobial Agents ◽  
The United States ◽  
Resistance Mechanisms ◽  
Clinical Isolates ◽  
Surveillance Program ◽  
Multiple Resistance ◽  
In Vitro Susceptibility ◽  
Medical Centers ◽  
Custom Made

Abstract Background OXA-48 is a carbapenemase with low-level hydrolytic activity toward cephalosporins. This study evaluated in vitro activities of ceftazidime-avibactam (CAZ-AVI), meropenem (MEM), meropenem-vaborbactam (MVB), ceftolozane-tazobactam (C/T), and other antimicrobial agents against 113 OXA-48-producing Enterobacterales with multiple resistance mechanisms collected in a 2017–2018 global surveillance program. Methods Nonduplicate clinical isolates of 113 Enterobacterales were collected from medical centers in 25 countries in 2017–2018. In vitro susceptibility tests were performed by broth microdilution with a custom-made panel consisting of CAZ-AVI, ceftazidime (CAZ), MEM, MVB, C/T, colistin (COL), gentamicin (GEN), levofloxacin (LEV), and amikacin (AMK). Whole genome sequencing or quantitative PCR data were used to analyze resistance mechanisms, such as OXA-48, extended-spectrum β-lactamase (ESBL), original-spectrum β-lactamase (OSBL), and AmpC β-lactamase. Clinical and Laboratory Standards Institute breakpoints were applied for susceptibility interpretations. Results Of 113 OXA-48–producing clinical isolates, 20 carried OXA-48 alone. The remaining 93 isolates carried additional β-lactamases, including 63 with ESBL (CTX-M-15) + OSBL (SHV, TEM), 15 with AmpC (DHA, AAC, CMY) + ESBL (CTX-M-15), and 15 with OSBL (SHV, TEM). 99.1% (all but 1) of all isolates tested were susceptible to CAZ-AVI, whereas 71.7%, 17.7%, and 14.2% were susceptible to MVB, MEM, and C/T, respectively. Among isolates harboring multiple resistance mechanisms (OXA-48 + ESBL + OSBL; n=63), 98.4%, 69.8%, 11.1%, and 7.9% were susceptible to CAZ-AVI, MVB, MEM, and C/T, respectively. Among isolates carrying OXA-48 + AmpC + ESBL + OSBL (n=15), 100%, 66.7%, 13.3%, and 13.3% were susceptible to CAZ-AVI, MVB, MEM, and C/T, respectively (Table). Aminoglycosides (AMK and GEN) and other β-lactams (eg, CAZ) were 20%–90% active against these isolates. COL was the second most effective comparator, inhibiting 83.2% of these isolates. Table Conclusion CAZ-AVI was the most effective agent in this study compared with other antibiotics, including β-lactams, β-lactam–β-lactamase inhibitor combinations, aminoglycosides, and COL, against OXA-48-producing Enterobacterales carrying multiple β-lactamases. Disclosures Lynn-Yao Lin, MS, AbbVie (Employee) Dmitri Debabov, PhD, AbbVie (Employee) William Chang, BS, AbbVie (Employee)

Coumarin-1,2,3-triazole Hybrid Molecules: An Emerging Scaffold for Combating Drug Resistance

2021 ◽  
Vol 21 ◽  
Author(s):  
Harish C. Upadhyay
Keyword(s):  
Drug Resistance ◽  
Antimicrobial Agents ◽  
Plant Secondary Metabolites ◽  
Cost Effective ◽  
Resistance Mechanisms ◽  
Biologically Active ◽  
Multidrug Therapy ◽  
Diverse Range ◽  
Development Of Resistance ◽  
Hybrid Molecules

: No doubt antibiotics have saved billions of lives, but lack of novel antibiotics, development of resistance mechanisms in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria hamper the successful treatment of infections. Due to widespread emergence of resistance, even the new families of antimicrobial agents have a short life expectancy. Drugs acting on single target often lead to drug resistance and are associated with various side effects. To overcome this problem either multidrug therapy or single drug acting on multiple targets may be used. The later are called ‘hybrid molecules’ which are formed by clubbing two biologically active pharmacophores together with or without an appropriate linker. In this rapidly evolving era, the development of natural product-based hybrid molecules may be a super-alternative to multidrug therapy to combat drug resistance caused by various bacterial and fungal strains. Coumarins (benzopyran-2-one) are one of the earliest reported plant secondary metabolites having clinically proven diverse range of pharmacological properties. On the other hand, 1,2,3-triazole is a common pharmacophore in many drugs responsible for polar interactions improving the solubility and binding affinity to biomolecular targets. In this review we discuss recent advances in Coumarin-1,2,3-triazole hybrids as potential antibacterial agents aiming to provide a useful platform for the exploration of new leads with broader spectrum, more effectiveness, less toxicity with multiple modes of action for the development of cost-effective and safer drugs in the future.

Resistance to nitrofurantoin is an indicator of extensive drug-resistant (XDR) Enterobacteriaceae

2021 ◽  
Vol 70 (4) ◽  
Author(s):  
Balaram Khamari ◽  
Prakash Kumar ◽  
Bulagonda Eswarappa Pradeep
Keyword(s):  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Treatment Options ◽  
Strong Association ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Drug Resistant ◽  
Content Type ◽  
Link Type

Introduction. Nitrofurantoin is one of the preferred antibiotics in the treatment of uropathogenic multidrug-resistant (MDR) infections. However, resistance to nitrofurantoin in extensively drug-resistant (XDR) bacteria has severely limited the treatment options. Gap statement. Information related to co-resistance or collateral sensitivity (CS) with reference to nitrofurantoin resistant bacteria is limited. Aim. To study the potential of nitrofurantoin resistance as an indicator of the XDR phenotype in Enterobacteriaceae . Methods. One hundred (45 nitrofurantoin-resistant, 21 intermediately resistant and 34 nitrofurantoin-susceptible) Enterobacteriaceae were analysed in this study. Antibiotic susceptibility testing (AST) against nitrofurantoin and 17 other antimicrobial agents across eight different classes was performed by using the Vitek 2.0 system. The isolates were screened for the prevalence of acquired antimicrobial resistance (AMR) and efflux pump genes by PCR. Results. In total, 51 % of nitrofurantoin-resistant and 28 % of intermediately nitrofurantoin resistant isolates exhibited XDR characteristics, while only 3 % of nitrofurantoin-sensitive isolates were XDR (P=0.0001). Significant co-resistance was observed between nitrofurantoin and other tested antibiotics (β-lactam, cephalosporin, carbapenem, aminoglycoside and tetracycline). Further, the prevalence of AMR and efflux pump genes was higher in the nitrofurantoin-resistant strains compared to the susceptible isolates. A strong association was observed between nitrofurantoin resistance and the presence of bla PER-1, bla NDM-1, bla OXA-48, ant(2) and oqxA-oqxB genes. Tigecycline (84 %) and colistin (95 %) were the only antibiotics to which the majority of the isolates were susceptible. Conclusion. Nitrofurantoin resistance could be an indicator of the XDR phenotype among Enterobacteriaceae , harbouring multiple AMR and efflux pump genes. Tigecycline and colistin are the only antibiotics that could be used in the treatment of such XDR infections. A deeper understanding of the co-resistance mechanisms in XDR pathogens and prescription of AST-based appropriate combination therapy may help mitigate this problem.

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