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Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy

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A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Bacterial Pathogens".

Deadline for manuscript submissions: closed (20 December 2022) | Viewed by 29379

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Prof. Dr. Seung-Chun Park

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Guest Editor

Department of Pharmacology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea
Interests: combinational antibacterial therapy; antibacterial resistance; pharmacokinetics and pharmacodynamics of antibacterial agents
Special Issues, Collections and Topics in MDPI journals

Dr. Biruk Tesfaye Birhanu

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Laboratory of Veterinary Pharmacokinetics and Pharmacodynamics, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Korea
Interests: mechanism and prevention of antimicrobial resistance; Microbial-host relationship and inhibiting bacterial pathogenetic mechanism; Pharmacokinetics/pharmacodynamics integration

Special Issue Information

Dear Colleagues,

Antibiotics play a significant role in treating and preventing infections caused by microbial agents if used precisely. However, due to the fast development of drug resistance, treatment becomes ineffective and risks the livelihood of humans and animals. To worsen the situation, the invention and production of new antibiotics are alarmingly at a low rate.

Some of the factors which contribute to the development and spread of antimicrobial resistance include the presence of resistant microbial strains in the environment, antimicrobial usage and other related aspects in the community, and antimicrobial use in food-producing animals [1].

Hence, intervention mechanisms should be designed to combat antibacterial resistance globally. Alternatives to the currently available drugs or other means of interventions, including drug combinations [2], are required to limit drug resistance in microbial agents. Furthermore, pharmacokinetic and pharmacodynamic integration studies could play a significant role in increasing the efficacy and potency of currently available drugs.

Hence, the focus of this Special Issue, titled “Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy” in the journal Pathogens is to promote studies that focus on the intervention mechanisms of antimicrobial resistance, provide alternatives to the currently available antimicrobials, study the integration of pharmacokinetics and pharmacodynamics, including the efficacy and dosage formulation of the currently available antibiotics, and combination therapies, which are effective against drug-resistant pathogens.

References

Prestinaci F.; Pezzotti P.; Pantosti A. Antimicrobial resistance: A global multifaceted phenomenon. Pathog. Glob. Health 2015 109, 309–318
Worthington R.J.; Melander C. Combination approaches to combat multidrug-resistant bacteria. Trends Biotechnol. 2013 31, 177–184

Prof. Dr. Seung-Chun Park
Dr. Biruk Tesfaye Birhanu
Guest Editors

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Keywords

Antimicrobial resistance
antimicrobial prudence
combination therapy
pharmacokinetics and pharmacodynamic integration of drugs
AI in antibacterial therapy

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Related Special Issue

Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy (Volume 2) in Pathogens (3 articles)

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12 pages, 2599 KiB

Open AccessArticle

Characterization of Collagen Binding Activity of Clostridium perfringens Strains Isolated from Broiler Chickens

by Zhifeng Sun, Mingmin Lu, Hyun Lillehoj, Youngsub Lee, Doyun Goo, Baohong Yuan, Xianghe Yan and Charles Li

Pathogens 2023, 12(6), 778; https://doi.org/10.3390/pathogens12060778 - 30 May 2023

Cited by 2 | Viewed by 1698

Abstract

Clostridium perfringens is the etiological agent for necrotic enteritis (NE) in broiler chickens, which causes a substantial economic loss of an estimated USD 6 billion annually in the global poultry industry. Collagen adhesion is involved in the NE pathogenesis in poultry. In this study, the binding capabilities of chicken C. perfringens isolates of various genetic backgrounds (netB⁻tpeL⁻, netB⁺tpeL⁻, netB⁺tpeL⁺) to collagen types I–V and gelatin were examined, and the putative adhesin protein cnaA gene was investigated at the genomic level. In total, 28 C. perfringens strains from healthy and NE-inflicted sick chickens were examined. The results on collagen adhesin-encoding gene cnaA by the quantitative-PCR results indicated that netB⁻tpeL⁻ isolates had much lower copies of the detectable cnaA gene than netB⁺ isolates (10 netB⁺tpeL⁻ isolates, 5 netB⁺tpeL⁺ isolates). Most of the virulent C. perfringens isolates demonstrated collagen-binding abilities to types I–II and IV–V, while some strains showed weak or no binding to collagen type III and gelatin. However, the netB⁺tpeL⁺ isolates showed significantly higher binding capabilities to collagen III than netB⁻tpeL⁻ and netB⁺tpeL⁻ isolates. The data in this study suggest that the collagen-binding capability of clinical C. perfringens isolates correlates well with their NE pathogenicity levels, especially for C. perfringens isolates carrying genes encoding crucial virulence factors and virulence-associated factors such as netB, cnaA, and tpeL. These results indicate that the presence of the cnaA gene may be correlated with C. perfringens virulence (particularly for netB⁺ isolates). Full article

(This article belongs to the Special Issue Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy)

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13 pages, 525 KiB

Open AccessArticle

Inhibitory Effect of Select Nitrocompounds and Chlorate against Yersinia ruckeri and Yersinia aleksiciae In Vitro

by Elizabeth A. Latham, Robin C. Anderson, Lauren R. Wottlin, Toni L. Poole, Tawni L. Crippen, Wayne D. Schlosser, Roger B. Harvey and Michael E. Hume

Pathogens 2022, 11(11), 1381; https://doi.org/10.3390/pathogens11111381 - 19 Nov 2022

Cited by 1 | Viewed by 1478

Abstract

Yersinia ruckeri is an important fish pathogen causing enteric redmouth disease. Antibiotics have traditionally been used to control this pathogen, but concerns of antibiotic resistance have created a need for alternative interventions. Presently, chlorate and certain nitrocompounds were tested against Y. ruckeri as well as a related species within the genus, Y. aleksiciae, to assess the effects of these inhibitors. The results reveal that 9 mM chlorate had no inhibitory effect against Y. ruckeri, but inhibited growth rates and maximum optical densities of Y. aleksciciae by 20–25% from those of untreated controls (0.46 h⁻¹ and 0.29 maximum optical density, respectively). The results further reveal that 2-nitropropanol and 2-nitroethanol (9 mM) eliminated the growth of both Y. ruckeri and Y. aleksiciae during anaerobic or aerobic culture. Nitroethane, ethyl nitroacetate and ethyl-2-nitropropionate (9 mM) were less inhibitory when tested similarly. Results from a mixed culture of Y. ruckeri with fish tank microbes and of Y. aleksiciae with porcine fecal microbes reveal that the anti-Yersinia activity of the tested nitrocompounds was bactericidal, with 2-nitropropanol and 2-nitroethanol being more potent than the other tested nitrocompounds. The anti-Yersinia activity observed with these tested compounds warrants further study to elucidate the mechanisms of action and strategies for their practical application. Full article

(This article belongs to the Special Issue Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy)

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13 pages, 1933 KiB

Open AccessArticle

Targeting Host Tyrosine Kinase Receptor EPHA2 Signaling Affects Uropathogen Infection in Human Bladder Epithelial Cells

by Prema S. Prakash, Alexander Kruse, Christian Vogel, Undraga Schagdarsurengin and Florian Wagenlehner

Pathogens 2022, 11(10), 1176; https://doi.org/10.3390/pathogens11101176 - 12 Oct 2022

Cited by 2 | Viewed by 1957

Abstract

Urinary tract infections (UTIs) affect a major proportion of the world population but have limited non-antibiotic-based therapeutic and preventative strategies against UTIs. Facultative intracellular uropathogens such as strains of uropathogenic E. coli, K. pneumoniae, E. faecalis, E. cloacae are well-known uropathogens causing UTIs. These pathogens manipulate several host-signaling pathways during infection, which contributes to recurrent UTIs and inappropriate antibiotic application. Since host cell receptor tyrosine kinases (RTKs) are critical for the entry, survival and replication of intracellular pathogens, we investigated whether different uropathogens require host EPHA2 receptors for their intracellular survival using a cell culture model of intracellular infection in human bladder epithelial cells (BECs). Infection of BECs with seven different uropathogens enhanced the expression levels and activation of EPHA2. The significance of EPHA2 signaling for uropathogen infection was investigated by silencing EPHA2 expression using RNA interference or by inhibiting the kinase activity of EPHA2 using small-molecule compounds such as dasatinib or ALW-II-41-27. Both preventive and therapeutic tyrosine kinase inhibition significantly reduced the intracellular bacterial load. Thus, our results demonstrate the involvement of host cell EPHA2 receptor during intracellular uropathogen infection of BECs, and targeting RTK activity is a viable non-antibiotic therapeutic strategy for managing recurrent UTIs. Full article

(This article belongs to the Special Issue Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy)

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13 pages, 1093 KiB

Open AccessArticle

Cobalt (II) Chloride Regulates the Invasion and Survival of Brucella abortus 544 in RAW 264.7 Cells and B6 Mice

by Tran X. N. Huy, Trang T. Nguyen, Alisha W. B. Reyes, Heejin Kim, WonGi Min, Hu J. Lee, John H. Lee and Suk Kim

Pathogens 2022, 11(5), 596; https://doi.org/10.3390/pathogens11050596 - 18 May 2022

Cited by 2 | Viewed by 2537

Abstract

The effects of Cobalt (II) chloride (CoCl₂) in the context of Brucella abortus (B. abortus) infection have not been evaluated so far. Firstly, we found that CoCl₂ treatment inhibited the phagocytosis of B. abortus into RAW 264.7 cells. The inhibition of bacterial invasion was regulated by F-actin formation and associated with a reduction in the phosphorylation of ERK1/2 and HIF-1α expression. Secondly, the activation of trafficking regulators LAMP1, LAMP2, and lysosomal enzyme GLA at the transcriptional level activated immune responses, weakening the B. abortus growth at 4 h post-infection (pi). The silencing of HIF-1α increased bacterial survival at 24 h pi. At the same time, CoCl₂ treatment showed a significant increase in the transcripts of lysosomal enzyme HEXB and cytokine TNF-α and an attenuation of the bacterial survival. Moreover, the enhancement at the protein level of HIF-1α was induced in the CoCl₂ treatment at both 4 and 24 h pi. Finally, our results demonstrated that CoCl₂ administration induced the production of serum cytokines IFN-γ and IL-6, which is accompanied by dampened Brucella proliferation in the spleen and liver of treated mice, and reduced the splenomegaly and hepatomegaly. Altogether, CoCl₂ treatment contributed to host resistance against B. abortus infection with immunomodulatory effects. Full article

(This article belongs to the Special Issue Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy)

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9 pages, 1320 KiB

Open AccessCommunication

Antimicrobial Synergy between Aminoglycosides and Licorice Extract in Listeria monocytogenes

by Myungseo Park, Liz Horn, Victoria Lappi, Dave Boxrud, Craig Hedberg and Byeonghwa Jeon

Pathogens 2022, 11(4), 440; https://doi.org/10.3390/pathogens11040440 - 6 Apr 2022

Cited by 6 | Viewed by 2549

Abstract

Listeria monocytogenes is a foodborne pathogen that can develop serious invasive infections. Among foodborne pathogens, L. monocytogenes exhibits the highest case fatality despite antibiotic treatment, suggesting the current therapy should be improved. Although ampicillin and gentamicin are used as a combination therapy to treat listeriosis, our results showed there is no synergy between the two antibiotics. We discovered that aqueous extract of licorice generated significant antimicrobial synergy when combined with aminoglycosides, such as gentamicin, in L. monocytogenes. In the presence of 1 mg/mL licorice extract, for instance, the minimum inhibitory concentration (MIC) of gentamicin was reduced by 32-fold. Moreover, antimicrobial synergy with licorice extract made gentamicin-resistant clinical isolates of L. monocytogenes susceptible to gentamicin. Given the common use of licorice as a food sweetener in Western countries and a herb in Oriental medicine, our findings suggest that licorice extract can be potentially used as an antibiotic adjuvant to improve the efficacy of antimicrobial treatment of listeriosis. Full article

(This article belongs to the Special Issue Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy)

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12 pages, 10210 KiB

Open AccessArticle

Prevalence of Bacterial Species in Skin, Urine, Diarrheal Stool, and Respiratory Samples in Cats

by Dong Chan Moon, Ji-Hyun Choi, Naila Boby, Su-Jeong Kim, Hyun-Ju Song, Ho-Sung Park, Min-Chan Gil, Soon-Seek Yoon and Suk-Kyung Lim

Pathogens 2022, 11(3), 324; https://doi.org/10.3390/pathogens11030324 - 7 Mar 2022

Cited by 10 | Viewed by 3836

Abstract

Bacterial infections are a significant cause of illness and death in different animals. However, these bacterial infections could be a source of human disease or illness if these pathogenic bacteria are present in companion animals. This study aimed to investigate the prevalence of pathogenic bacteria associated with different site infections in cats in the Republic of Korea. For this purpose, samples were collected from the skin/ear, urine, respiratory, and diarrheal stool origins of cats obtained between 2018 and 2019 from seven different laboratories and centers participating in the Korean Veterinary Antimicrobial Resistance Monitoring System. These samples were subjected to analysis for the identification and isolation of associated bacterial species using a bacterial culture approach. A total of 609 isolates were identified in four different cat samples. Among them, 267, 184, 57, and 101 were extracted from diarrheal stool, skin, urine, and respiratory samples, respectively. The findings of this study showed that Escherichia coli was the most prevalent species among isolated bacterial species of diarrheal stool and urine origin. Staphylococcus felis and Pasteurella multocida were most prevalent in the skin and respiratory tract, respectively. However, there was no significant difference in bacterial distribution among the different age groups in all samples. This is the first nationwide surveillance report that associates bacterial prevalence with their site of origin and helps in the prevention of bacterial infections in cats. Moreover, the pattern of bacterial prevalence could provide sufficient guidance for the selection of empirical antimicrobial therapy against infections in cats. Full article

(This article belongs to the Special Issue Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy)

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12 pages, 5342 KiB

Open AccessArticle

Prophylactic Catechin-Rich Green Tea Extract Treatment Ameliorates Pathogenic Enterotoxic Escherichia coli-Induced Colitis

by Jeong-Won Kim, Chang-Yeop Kim, Jin-Hwa Kim, Ji-Soo Jeong, Je-Oh Lim, Je-Won Ko and Tae-Won Kim

Pathogens 2021, 10(12), 1573; https://doi.org/10.3390/pathogens10121573 - 2 Dec 2021

Cited by 13 | Viewed by 3031

Abstract

In this study, we explored the potential beneficial effects of green tea extract (GTE) in a pathogenic Escherichia coli (F18:LT:STa:Stx2e)-induced colitis model. The GTE was standardized with catechin and epigallocatechin-3-gallate content using chromatography analysis. Ten consecutive days of GTE (500 and 1000 mg/kg) oral administration was followed by 3 days of a pathogenic E. coli challenge (1 × 10⁹ CFU/mL). In vitro antibacterial analysis showed that GTE successfully inhibited the growth of pathogenic E. coli, demonstrating over a 3-fold reduction under time- and concentration-dependent conditions. The in vivo antibacterial effect of GTE was confirmed, with an inhibition rate of approximately 90% when compared to that of the E. coli alone group. GTE treatment improved pathogenic E. coli-induced intestinal injury with well-preserved epithelial linings and villi. In addition, the increased expression of annexin A1 in GTE-treated jejunum tissue was detected, which was accompanied by suppressed inflammation-related signal expression, including TNFA, COX-2, and iNOS. Moreover, proliferation-related signals such as PCNA, CD44, and Ki-67 were enhanced in the GTE group compared to those in the E. coli alone group. Taken together, these results indicate that GTE has an antibacterial activity against pathogenic E. coli and ameliorates pathogenic E. coli-induced intestinal damage by modulating inflammation and epithelial cell proliferation. Full article

(This article belongs to the Special Issue Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy)

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13 pages, 2710 KiB

Open AccessArticle

Colistin Induces Resistance through Biofilm Formation, via Increased phoQ Expression, in Avian Pathogenic Escherichia coli

by Na-Hye Park, Seung-Jin Lee, Eon-Bee Lee, Biruk Tesfaye Birhanu and Seung-Chun Park

Pathogens 2021, 10(11), 1525; https://doi.org/10.3390/pathogens10111525 - 22 Nov 2021

Cited by 5 | Viewed by 3051

Abstract

This study aimed to optimize the colistin-based antibacterial therapy to prevent antimicrobial resistance related to biofilm formation in avian pathogenic Escherichia coli (APEC) in chicken. Of all the bacterial isolates (n = 136), 69 were identified as APEC by polymerase chain reaction (PCR). Through a series of antibiotic susceptibility tests, susceptibility to colistin (<2 μg/mL) was confirmed in all isolates. Hence, a mutant selection window (MSW) was determined to obtain colistin-induced resistant bacteria. The minimum inhibitory concentration (MIC) of colistin against the colistin-induced resistant APEC strains ranged from 8 to 16 μg/mL. To identify the inhibitory activity of colistin against the resistant strains, the mutant prevention concentration (MPC) was investigated for 72 h, and the single and multi-dose colistin activities were determined through the time-kill curve against APEC strains. Bacterial regrowth occurred after 12 h at a double MIC₅₀ concentration (1.00 μg/mL), and regrowth was not inhibited even during multiple exposures. However, upon exposure to 8 μg/mL—a concentration that was close to the MPC—the growth of APEC was inhibited, including in the resistant strains. Additionally, colistin-induced resistant strains showed a slower growth compared with the susceptible ones. Colistin-induced resistant APEC strains did not show colistin resistance gene (mcr-1). However, the expression of higher mgrB and phoQ levels was observed in the resistant strains. Furthermore, these strains showed increased formation of biofilm. Hence, the present study indicated that colistin could induce resistance through the increased formation of biofilm in APEC strains by enhancing the expression of phoQ. Full article

(This article belongs to the Special Issue Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy)

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14 pages, 1634 KiB

Open AccessArticle

Pharmacokinetic/Pharmacodynamic Modeling of Spiramycin against Mycoplasma synoviae in Chickens

by Sara T. Elazab, Nahla S. Elshater, Yousreya H. Hashem, Nayera M. Al-Atfeehy, Eon-Bee Lee, Seung-Chun Park and Walter H. Hsu

Pathogens 2021, 10(10), 1238; https://doi.org/10.3390/pathogens10101238 - 25 Sep 2021

Cited by 6 | Viewed by 3668

Abstract

This research aimed to assess the pharmacokinetics/pharmacodynamics (PK/PD) and tissue residues of spiramycin in chickens. The PK of spiramycin were determined in 12 chickens using a parallel study design in which each group of chickens (n = 6) received a single dose of spiramycin at 17 mg/kg intravenously (IV) or orally. Plasma samples were collected at assigned times for up to 48 h to measure spiramycin concentrations. Additionally, a tissue depletion study was performed in 42 chickens receiving spiramycin at 17 mg/kg/day orally for 7 days. The area under the plasma concentration–time curve values were 29.94 ± 4.74 and 23.11 ± 1.83 µg*h/mL after IV and oral administrations, respectively. The oral bioavailability was 77.18%. The computed withdrawal periods of spiramycin were 11, 10, and 7 days for liver, muscle, and skin and fat, respectively. The minimum inhibitory concentration for spiramycin against Mycoplasma synoviae (M. synoviae) strain 1853 was 0.0625 µg/mL. Using the PK/PD integration, the appropriate oral dose of spiramycin against M. synoviae was estimated to be 15.6 mg/kg. Thus, we recommend an oral dose of 15.6 mg spiramycin/kg against M. synoviae in chickens and a withdrawal period of 11 days following oral treatment with 17 mg spiramycin/kg/day for 7 days. Full article

(This article belongs to the Special Issue Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy)

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12 pages, 1701 KiB

Open AccessSystematic Review

Global Prevalence of Colistin Resistance in Klebsiella pneumoniae from Bloodstream Infection: A Systematic Review and Meta-Analysis

by Leonard Ighodalo Uzairue, Ali A. Rabaan, Fumilayo Ajoke Adewumi, Obiageli Jovita Okolie, Jamiu Bello Folorunso, Muhammed A. Bakhrebah, Mohammed Garout, Wadha A. Alfouzan, Muhammad A. Halwani, Aref A. Alamri, Shaima A. Halawani, Fatimah S. Alshahrani, Abdulkarim Hasan, Abbas Al Mutair, Saad Alhumaid, Johnson Etafo, Idorenyin Utip, Ikenna Maximillian Odoh and Nkolika S. Uwaezuoke

Pathogens 2022, 11(10), 1092; https://doi.org/10.3390/pathogens11101092 - 24 Sep 2022

Cited by 27 | Viewed by 4219

Abstract

Background: Among gram-negative bacteria, Klebsiella pneumoniae is one of the most common causes of healthcare-related infection. Bloodstream infections (BSIs) caused by Klebsiella pneumoniae are notorious for being difficult to treat due to resistance to commonly used antimicrobials. Klebsiella pneumoniae isolates from bloodstream infections are becoming increasingly resistant to carbapenems. In the fight against carbapenem-resistant Klebsiella pneumoniae, colistin [polymyxin E] is the antimicrobial of choice and is thus widely used. Objective: This study aimed to determine the global prevalence of colistin resistance amongst Klebsiella pneumoniae isolates from bloodstream infections. Methods: PubMed, Medline, Scopus, and the Cochrane Library were searched for published articles without restricting the search period. Studies meeting the predefined inclusion and exclusion criteria were included, and quality was assessed using Joanna Briggs Institute Checklist. We used a statistical random effect model to analyze data with substantial heterogeneity (I² > 50%) in the meta-analysis. Results: A total of 10 studies out of 2873 search results that met the inclusion criteria were included in the final synthesis for this study. A pooled prevalence of colistin resistance was 3.1%, 95% CI (1.5–4.7%). The highest colistin resistance pooled prevalence was recorded in isolates studied in 2020 and beyond 12.90% (4/31), while Klebsiella pneumoniae isolates studied in 2015 and before and in 2016–2019 showed a pooled colistin resistance rate of 2.89% (48/1661) and 2.95% (28/948), respectively. The highest colistin resistance was found in Klebsiella pneumoniae isolates from Thailand (19.2%), while the least pooled resistance was in Klebsiella pneumoniae from South Korea (0.8%). The pooled prevalence of the multidrug-resistant (MDR) of Klebsiella pneumoniae from bloodstream infection ranged from 80.1%, 95% CI (65.0–95.2%), and the resistance prevalence of other antibiotics by Klebsiella pneumoniae from bloodstream infections were as follows; ciprofloxacin (45.3%), ertapenem (44.4%), meropenem (36.1%), imipenem (35.2%), gentamicin (33.3%), amikacin (25.4%) and tigecycline (5.1%). Klebsiella pneumoniae recovered from the intensive care unit (ICU) showed higher colistin resistance, 11.5% (9/781%), while non-ICU patients showed 3.03% (80/2604) pooled colistin resistance. Conclusion: This study showed low colistin resistance in Klebsiella pneumoniae isolates from global bloodstream infections. However, significant colistin resistance was observed in isolates collected from 2020 and beyond. Significant colistin resistance was also observed in Klebsiella pneumoniae isolates in bloodstream infections from the intensive care unit (ICU) compared to those from non-ICUs. As a result, there is a need to institute colistin administration stewardship in the ICU in clinical settings. Full article

(This article belongs to the Special Issue Antibiotics, Antibiotic Alternatives, and Combination Antimicrobial Therapy)

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