Browsing by Subject "Antibiotics"

Now showing 1 - 10 of 23
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    1082. Real-World Experience with Omadacycline for Nontuberculous Mycobacterial Infections: A Multicenter Evaluation
    (Oxford University Press, 2021-12-04) Morrisette, Taylor; Alosaimy, Sara; Lagnf, Abdalhamid M.; Philley, Julie V.; Sigler, Carly; Butt, Saira; Kaip, Emily A.; MacDougall, Conan; Mejia-Chew, Carlos; Bouchard, Jeannette; Frens, Jeremy J.; Gore, Tristan; Hamad, Yasir; Howard, Catessa; Barger, Melissa; Cabanilla, M. Gabriela; Ong, Aaron; Veve, Michael P.; Webb, Andrew J.; Stevens, Ryan W.; Cohen, Keira A.; Rybak, Michael J.; Medicine, School of Medicine
    Background: Nontuberculous mycobacteria (NTM) are resistant to numerous antibiotics and lead to significant morbidity and mortality. Omadacycline (OMC) is an aminomethylcycline antibiotic that is Food and Drug Administration-approved for acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Furthermore, OMC has shown in vitro activity against NTM. Given that real-world evidence is lacking, our primary objective was to evaluate the clinical success and tolerability of OMC when used for a variety of NTM infections. Methods: This was a multicenter, retrospective, observational study conducted from January 2020 to June 2021. We included all patients ≥ 18 years of age that received OMC of any indication for Mycobacterium spp. The primary outcome was clinical success, defined as a lack of all-cause mortality, lack of persistence or re-emergence of infection during or after therapy, and lack of alteration of OMC. Incidence of adverse effects potentially attributable to OMC and reasons for OMC utilization were also analyzed. Results: A total of 31 patients were included from 12 geographically distinct academic health systems (median age: 57 (IQR, 45-63) years; 45% male; 81% Caucasian). The majority of isolated pathogens were Mycobacterium abscessus complex (84%) and of those with subspeciation performed (54%), the majority (86%) were subsp. abscessus. The primary infections were of pulmonary origin (67%) and the median (IQR) duration of OMC therapy was 5.3 (3.2-9.4) months. Most isolates did not have OMC susceptibility conducted (87%), while the majority did for tigecycline (90%). Clinical success was reported in 81% of the population. Most patients were on combination antimicrobial therapy, and 39% of patients reported an adverse effect while on OMC (58% gastrointestinal distress). The majority of patients were prescribed OMC due to ease of administration (61%) and antimicrobial resistance to previous antibiotics (42%). Conclusion: OMC may be a potential option for the therapy of NTM infections. Prospective, randomized clinical trials are needed to confirm our preliminary findings.
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    Alcohol and medication interactions
    (U.S. National Institute on Alcohol Abuse and Alcoholism, 1999) Weathermon, Ron; Crabb, David W.; Medicine, School of Medicine
    Many medications can interact with alcohol, thereby altering the metabolism or effects of alcohol and/or the medication. Some of these interactions can occur even at moderate drinking levels and result in adverse health effects for the drinker. Two types of alcohol-medication interactions exist: (1) pharmacokinetic interactions, in which alcohol interferes with the metabolism of the medication, and (2) pharmacodynamic interactions, in which alcohol enhances the effects of the medication, particularly in the central nervous system (e.g., sedation). Pharmacokinetic interactions generally occur in the liver, where both alcohol and many medications are metabolized, frequently by the same enzymes. Numerous classes of prescription medications can interact with alcohol, including antibiotics, antidepressants, antihistamines, barbiturates, benzodiazepines, histamine H2 receptor antagonists, muscle relaxants, nonnarcotic pain medications and anti-inflammatory agents, opioids, and warfarin. In addition, many over-the-counter and herbal medications can cause negative effects when taken with alcohol.
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    Analogs of nitrofuran antibiotics are potent GroEL/ES inhibitor pro-drugs
    (Elsevier, 2020) Stevens, Mckayla; Howe, Chris; Ray, Anne-Marie; Washburn, Alex; Chitre, Siddhi; Sivinski, Jared; Park, Yangshin; Hoang, Quyen Q.; Chapman, Eli; Johnson, Steven M.; Biochemistry and Molecular Biology, School of Medicine
    In two previous studies, we identified compound 1 as a moderate GroEL/ES inhibitor with weak to moderate antibacterial activity against Gram-positive and Gram-negative bacteria including Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, and SM101 Escherichia coli (which has a compromised lipopolysaccharide biosynthetic pathway making bacteria more permeable to drugs). Extending from those studies, we developed two series of analogs with key substructures resembling those of known antibacterials, nitroxoline (hydroxyquinoline moiety) and nifuroxazide/nitrofurantoin (bis-cyclic-N-acylhydrazone scaffolds). Through biochemical and cell-based assays, we identified potent GroEL/ES inhibitors that selectively blocked E. faecium, S. aureus, and E. coli proliferation with low cytotoxicity to human colon and intestine cells in vitro. Initially, only the hydroxyquinoline-bearing analogs were found to be potent inhibitors in our GroEL/ES-mediated substrate refolding assays; however, subsequent testing in the presence of an E. coli nitroreductase (NfsB) in situ indicated that metabolites of the nitrofuran-bearing analogs were potent GroEL/ES inhibitor pro-drugs. Consequently, this study has identified a new target of nitrofuran-containing drugs, and is the first reported instance of such a unique class of GroEL/ES chaperonin inhibitors. The intriguing results presented herein provide impetus for expanded studies to validate inhibitor mechanisms and optimize this antibacterial class using the respective GroEL/ES chaperonin systems and nitroreductases from E. coli and the ESKAPE bacteria.
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    Antibiotic Discovery Targeting Bacterial GroEL/GroES Chaperonin Systems
    (2018-07-29) Kunkle, Trent A.; Johnson, Steven M.; Georgiadis, Millie M.; Hoang, Quyen Q.
    The Centers for Disease Control (CDC) and World Health Organizations (WHO) have highlighted six species of highly drug-resistant bacteria, commonly termed the ESKAPE pathogens, that new antibacterials are urgently needed to treat). The ESKAPE pathogens account for over two-million infections and have healthcare costs upwards of $20 billion dollars annually. Over the past several decades, pharmaceutical companies have drastically reduced their research programs for developing new antibacterial agents. As well, bacteria are predisposed to rapidly generate resistance against these “me too” drugs, making this strategy a temporary stop-gap in our ability to fight these pathogens. This has left the burden to identify new antibiotics that function through fundamentally unique mechanisms of action to academia. Towards this goal, we are developing a unique antibacterial strategy that functions through targeting the bacterial GroEL chaperonin systems. GroEL is a molecular chaperone that helps fold proteins into their functional states. Being an essential protein, inhibiting GroEL activity leads to global aggregation and bacterial cell death. We previously reported a high-throughput screening effort that identified 235 GroEL inhibitors. A subsequent study with a subset of these inhibitors identified several that kill bacteria. To follow-up, we have synthesized 43 analogs of a hit-to-lead molecule, compound 1, containing systematic deletions of substituents and substructures to determine the essential parts of the scaffold for inhibiting GroEL and killing bacteria. Along with inhibiting GroEL, several compound 1 analogs exhibit >50-fold therapeutic windows between antibacterial efficacy and cytotoxicity to human liver and kidney cells in cell culture. Evaluation of two lead candidates (1 and 11) in a gain-of-resistance assay indicated that MRSA bacteria were not able to easily generate resistance to this compound class. Compound 1 also exhibited the ability to permeate through already established S. aureus biofilms and maintain its bactericidal effects, whereas vancomycin could not. Having established initial structure-activity relationships for the compound 1 substituents and substructures in this study, future efforts will focus on optimizing the antibacterial effects of lead candidates and reducing their off-target toxicity to human cells.
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    Antibiotic prescribing errors generated by the use of an electronic prescribing system in the emergency department: A mixed-method study
    (United Arab Emirates Ministry of Health & Prevention, 2022) Al Meslamani, Ahmad Z.; Abdel-Qader, Derar H.; Ziad, Noura; Al Mazrouei, Nadia; El-Shara, Asma A.; El Sharu, Husam; Ali, Eman Merghani; Al Zahawi, Rand Haider; Ebaed, Samah Bahy Mohammed; Ibrahim, Osama Mohamed; Center for Health Innovation & Implementation Science
    Context: Inappropriate prescribing of antibiotics can result in serious patient harm. Aims: To investigate the incidence, nature, clinical severity, and causes of antibiotic prescribing errors (APEs) in the emergency department (ED) of a large hospital in Jordan. Methods: A mixed-method approach was used to explore the incidence and types of APEs by direct observation of electronic prescriptions (EPS) of antibiotics over four weeks, and to identify causes of errors by semi-structured interviews with ED physicians. The clinical severity of APEs was rated by a committee of experts. SPSS V26 and NVivo 10 were used for the analysis of quantitative and qualitative data, respectively. Results: The incidence of APEs caused by the use of EPS was 4.3%. Wrong quantity (32.62%), wrong dose (15.25%), and duplicate drugs (13.55%) were identified as the most common types of APEs. More than one-third of APEs identified were deemed clinically significant, seven were serious, and one was lethal. Minor and significant antibiotic APEs across physicians who attended workshops on EPS and those who did not were 75.00% versus 46.77% (p = 0.001) and 18.75% versus 52.41% (p = 0.013), respectively. Three major causes of errors were identified: 1) System-related (system crash, drop-down menu), 2) user-related (lack of computer skills), and 3) workplace-related (overcrowding, inadequate staffing). Conclusions: APEs generated by the use of EPS were common in EDs in Jordan, clinically significant, and multifactorial. Further research is required to cover pharmacists' perspectives of this kind of errors.
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    Antibiotic Safety and Effectiveness in Premature Infants With Complicated Intraabdominal Infections
    (Wolters Kluwer, 2021) Smith, Michael J.; Boutzoukas, Angelique; Autmizguine, Julie; Hudak, Mark L.; Zinkhan, Erin; Bloom, Barry T.; Heresi, Gloria; Lavery, Adrian P.; Courtney, Sherry E.; Sokol, Gregory M.; Cotten, C. Michael; Bliss, Joseph M.; Mendley, Susan; Bendel, Catherine; Dammann, Christiane E. L.; Weitkamp, Jörn-Hendrik; Saxonhouse, Matthew A.; Mundakel, Gratias T.; Debski, Julie; Sharma, Gaurav; Erinjeri, Jinson; Gao, Jamie; Benjamin, Daniel K., Jr.; Hornik, Christoph P.; Smith, P. Brian; Cohen-Wolkowiez, Michael; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee; Pediatrics, School of Medicine
    Background: In premature infants, complicated intraabdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens have not been established in this population. Methods: Infants ≤33 weeks gestational age and <121 days postnatal age with cIAI were randomized to ≤10 days of ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3) at doses stratified by postmenstrual age. Due to slow enrollment, a protocol amendment allowed eligible infants already receiving study regimens to enroll without randomization. The primary outcome was mortality within 30 days of study drug completion. Secondary outcomes included adverse events, outcomes of special interest, and therapeutic success (absence of death, negative cultures, and clinical cure score >4) 30 days after study drug completion. Results: One hundred eighty infants [128 randomized (R), 52 nonrandomized (NR)] were enrolled: 63 in group 1 (45 R, 18 NR), 47 in group 2 (41 R, 6 NR), and 70 in group 3 (42 R, 28 NR). Thirty-day mortality was 8%, 7%, and 9% in groups 1, 2, and 3, respectively. There were no differences in safety outcomes between antibiotic regimens. After adjusting for treatment group and gestational age, mortality rates through end of follow-up were 4.22 [95% confidence interval (CI): 1.39-12.13], 4.53 (95% CI: 1.21-15.50), and 4.07 (95% CI: 1.22-12.70) for groups 1, 2, and 3, respectively. Conclusions: Each of the antibiotic regimens are safe in premature infants with cIAI.
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    Antibiotics in the pipeline: a literature review (2017–2020)
    (Springer, 2021-10-04) Al-Tawfiq, Jaffar A.; Momattin, Hisham; Al-Ali, Anfal Y.; Eljaaly, Khalid; Tirupathi, Raghavendra; Haradwala, Mohamed Bilal; Areti, Swetha; Alhumaid, Saad; Rabaan, Ali A.; Al Mutair, Abbas; Schlagenhauf, Patricia; Medicine, School of Medicine
    Introduction Antimicrobial resistance (AMR) is an emerging global threat. It increases mortality and morbidity and strains healthcare systems. Health care professionals can counter the rising AMR by promoting antibiotic stewardship and facilitating new drug development. Even with the economic and scientific challenges, it is reassuring that new agents continue to be developed. Methods This review addresses new antibiotics in the pipeline. We conducted a review of the literature including Medline, Clinicaltrials.org, and relevant pharmaceutical companies for approved and in pipeline antibiotics in phase 3 or new drug application (NDA). Results We found a number of new antibiotics and reviewed their current development status, mode of action, spectra of activity, and indications for which they have been approved. The included studies from phase 3 clinical trials were mainly utilized for the treatment of acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia, and pneumonia acquired in the healthcare settings. The number of these agents is limited against high priority organisms. The identified antibiotics were based mainly on previously known molecules or pre-existing antimicrobial agents. Conclusion There are a limited number of antibiotics against high priority organisms such as multi-drug-resistant Pseudomonas aeruginosa, and carbapenem-resistant Enterobacteriaceae. New antimicrobial agents directed against the top priority organisms as classified by the World Health Organization are urgently needed.
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    The application of antibiotics and other drugs to infected dental pulps of monkeys
    (1970) Epstein, David Weiss, 1941-; Van Huysen, Grant; Whitten, Jack; Garner, La Forrest Dean, 1933-
    The pulps of 112 permanent teeth of monkeys were surgically exposed and left open to the oral environment for 25 to 27 hours. Then one-third of the exposed, infected pulps were capped with a paste of calcium hydroxide and tap water; one-third were treated with an antibiotic paste compased of erythromycin estolate 10 per cent, streptomycin sulfate 10 per cent, and starch q.s. as the vehicle; and one-third were treated with a paste of zinc oxide powder, one drop of eugenol and one drop of formocresol. The teeth were extracted after one and two years post-operative intervals and were microscopically evaluated. The calcium hydroxide treated teeth had the highest percentage of satisfactory pulpal responses (91.6 per cent). The antibiotic treated teeth were considered to have had satisfactory pulpal responses in 87.5 per cent and the zinc oxide, eugenol and formocresol treated teeth showed satisfactory pulpal response in only 58.0 per cent of the teeth treated with this paste. After two years, several of the antibiotic teeth were considered to have had a satisfactory pulp response even though the calcific bridges were incomplete. The histologic findings were encouraging with calcium hydroxide and the antibiotic paste and warrant clinical investigations.
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    Dynamic modulation of spleen germinal center reactions by gut bacteria during Plasmodium infection
    (Cell Press, 2021-05-11) Mandal, Rabindra K.; Denny, Joshua E.; Namazzi, Ruth; Opoka, Robert O.; Datta, Dibyadyuti; John, Chandy C.; Schmidt, Nathan W.; Pediatrics, School of Medicine
    Gut microbiota educate the local and distal immune system in early life to imprint long-term immunological outcomes while maintaining the capacity to dynamically modulate the local mucosal immune system throughout life. It is unknown whether gut microbiota provide signals that dynamically regulate distal immune responses following an extra-gastrointestinal infection. We show here that gut bacteria composition correlated with the severity of malaria in children. Using the murine model of malaria, we demonstrate that parasite burden and spleen germinal center reactions are malleable to dynamic cues provided by gut bacteria. Whereas antibiotic-induced changes in gut bacteria have been associated with immunopathology or impairment of immunity, the data demonstrate that antibiotic-induced changes in gut bacteria can enhance immunity to Plasmodium. This effect is not universal but depends on baseline gut bacteria composition. These data demonstrate the dynamic communications that exist among gut bacteria, the gut-distal immune system, and control of Plasmodium infection.
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    Effects of ciprofloxacin-containing antimicrobial scaffolds on dental pulp stem cell viability-In vitro studies
    (Elsevier, 2015-08) Kamocki, Krzysztof; Nör, Jacques E.; Bottino, Marco C.; Department of Restorative Dentistry, School of Dentistry
    OBJECTIVE: A combination of antibiotics, including but not limited to metronidazole (MET) and ciprofloxacin (CIP), has been indicated to eradicate bacteria in necrotic immature permanent teeth prior to regenerative procedures. It has been shown clinically that antibiotic pastes may lead to substantial stem cell death. The aim of this study was to synthesise scaffolds containing various concentrations of CIP to enhance cell viability while preserving antimicrobial properties. DESIGN: Polydioxanone (PDS)-based electrospun scaffolds were processed with decreasing CIP concentrations (25-1 wt.%) and morphologically evaluated using scanning electron microscopy (SEM). Cytotoxicity assays were performed to determine whether the amount of CIP released from the scaffolds would lead to human dental pulp stem cell (hDPSC) toxicity. Similarly, WST-1 assays were performed to evaluate the impact of CIP release on hDPSC proliferation. Pure PDS scaffolds and saturated double antibiotic solution MET/CIP (DAP) served as both positive and negative controls, respectively. Antibacterial efficacy against E. faecalis (Ef) was tested. RESULTS: A significant decrease in hDPSC' viability at concentrations 5-25 wt.% was observed. However, concentrations below 5wt.% did not impair cell viability. Data from the WST-1 assays indicated no detrimental impact on cell proliferation for scaffolds containing 2.5 wt.% CIP or less. Significant antimicrobial properties were seen for CIP-scaffolds at lower concentrations (i.e., 1 and 2.5 wt.%). CONCLUSION: The obtained data demonstrated that a reduced concentration of CIP incorporated into PDS-based scaffolds maintains its antimicrobial properties while enhancing viability and proliferation of dental pulp stem cells.