Distribution and drug resistance analysis of pathogenic bacteria in a hospital blood culture, 2018-2022

Objective: To analyze the distribution and drug resistance of pathogenic bacteria in blood culture specimens of patients with bloodstream infections before and after COVID-19 (2018-2019 and 2020-2021), and to provide scientific basis and reference for rational treatment and effective control of bloodstream infections in the post-epidemic period. Methods: Blood culture specimens were collected from patients in Zhongnan Hospital of Wuhan University in the two years before and after the COVID-19 outbreak (2018-2021). The Automated Blood Culture Systems were used to perform blood culture on blood specimens sent for clinical inspection, and the Vitek MS automatic bacterial identification mass spectrometer was used for strain identification and the Vitek 2 automatic bacterial drug susceptibility analyzer was used for drug susceptibility testing and drug resistance analysis. Results: Blood culture specimens were performed on 28 736 patients with suspected bloodstream infection submitted for inspection from January 2018 to December 2019, and a total of 2 181 strains of pathogenic bacteria were detected after removing duplicate strains, with a positive rate of 7.69%, including 1 046 strains of Gram-negative bacteria, accounting for 47.96%. From January 2020 to December 2021, blood culture specimens from 26 083 patients with suspected bloodstream infection were submitted for inspection, and a total of 2 111 strains of pathogenic bacteria were detected after excluding duplicate strains, with a positive rate of 8.09%, including 1 000 strains of Gram-negative bacteria accounted for 47.37%. The drug resistance of Klebsiella pneumoniae was relatively serious, and the sensitivity rate to ertapenem, polymyxin B and tigecycline was more than 90%. The main non-fermentative bacteria Acinetobacter baumannii was more than 50% sensitive to piperacillin/tazobactam, amikacin and polymyxin B. The sensitivity rates of Pseudomonas aeruginosa to piperacillin/tazobactam, ceftazidime, cefepime, amikacin, gentamicin, tobramycin, ciprofloxacin, levofloxacin, piperacillin and meropenem were more than 50%. Conclusions: In the two years before and after COVID-19, there are many types of pathogenic bacteria in bloodstream infection, but the distribution do not differ significantly. The pathogens of bloodstream infection are mainly distributed in ICU, hepatobiliary research institute, and nephrology department. Among them, Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii are the main ones, and different pathogens showed great differences in drug resistance.

Acute pancreatitis - a rare manifestation in scrub typhus

Background: Scrub typhus is an acute febrile illness caused by the bacteria - Orientia tsutsugamushi, transmitted through the bite of an infected chigger. This infection is endemic in tropical countries like India, Pakistan, and Bangladesh. It usually presents with fever, headache, myalgia, nausea, vomiting, abdominal pain, and tender lymphadenopathy. The presence of an eschar clinches the diagnosis clinically. Commonly encountered complications in scrub typhus include acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), acute liver injury, and rarely acute pancreatitis. Case Presentation: We report a case of a 70 year-old teetotaller male, who presented with acute febrile illness and respiratory distress during the peak period of the COVID -19 pandemic. During the course of illness, the patient developed acute pancreatitis as evidenced by elevated serum amylase and lipase as well as features of pancreatitis in the CT abdomen. Common causes of acute pancreatitis were ruled out with necessary investigations. He tested negative for malaria, dengue fever, enteric fever, and leptospirosis, but his IgM and IgG ELISA for scrub typhus were positive with high titres. He also had AKI, ARDS, and acute liver injury. The patient was treated symptomatically and with doxycycline. His condition improved gradually. Conclusion: Even though acute pancreatitis is one of the rare manifestations of scrub typhus, it should be suspected early and treated promptly.

Rescuing Tetracycline Class Antibiotics for the Treatment of Multidrug-Resistant Acinetobacter baumannii Pulmonary Infection.

Acinetobacter baumannii causes high mortality in ventilator-associated pneumonia patients, and antibiotic treatment is compromised by multidrug-resistant strains resistant to ß-lactams, carbapenems, cephalosporins, polymyxins, and tetracyclines. Among COVID-19 patients receiving ventilator support, a multidrug-resistant A. baumannii secondary infection is associated with a 2-fold increase in mortality. Here, we investigated the use of the 8-hydroxyquinoline ionophore PBT2 to break the resistance of A. baumannii to tetracycline class antibiotics. In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multidrug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. PBT2 and zinc disrupted metal ion homeostasis in A. baumannii, increasing cellular zinc and copper while decreasing magnesium accumulation. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multidrug-resistant A. baumannii infections. IMPORTANCE Within intensive care unit settings, multidrug-resistant (MDR) Acinetobacter baumannii is a major cause of ventilator-associated pneumonia, and hospital-associated outbreaks are becoming increasingly widespread. Antibiotic treatment of A. baumannii infection is often compromised by MDR strains resistant to last-resort ß-lactam (e.g., carbapenems), polymyxin, and tetracycline class antibiotics. During the on-going COVID-19 pandemic, secondary bacterial infection by A. baumannii has been associated with a 2-fold increase in COVID-19-related mortality. With a rise in antibiotic resistance and a reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. Rescuing the efficacy of existing therapies for the treatment of MDR A. baumannii infection represents a financially viable pathway, reducing time, cost, and risk associated with drug innovation.

The improvement of levofloxacin and tetracycline removal from simulated water by thermosensitive flocculant: Mechanisms and simulation

[Display omitted] • P(DAC-NIPAM) significantly improved the removal of levofloxacin and tetracycline. • P(DAC-NIPAM) had strong interaction with antibiotics for its multiple functional groups. • The hydrophobic groups on P(DAC-NIPAM) tightly bridged micelles of antibiotics and SDS. • Compact flocs were formed for shrinkage of P(DAC-NIPAM) molecule at the LCST. • Flocculation simulation further confirmed application feasibility of thermosensitive flocculants. Antibiotics were detected in worldwide natural water especially in COVID-19 period. The common flocculants rarely removed the dissolved antibiotics from natural water and wastewater. The flocculation improvement of organic polymer flocculants might solve the issue of antibiotic pollution or promote the removal efficiencies of antibiotics in water/wastewater treatment plants. Herein, a thermosensitive flocculant, P(DAC-NIPAM), was prepared via one-step method. It was investigated that the relationship between the various functional groups of P(DAC-NIPAM) and its flocculation performances in the treatment of simulated water containing levofloxacin, tetracycline, colloidal particles and natural organic matters. The removal mechanisms were discussed. The results indicated that the rich cationic, hydrophilic and hydrophobic groups of P(DAC-NIPAM) enhanced the interaction between flocculants and pollutants. The bridging of P(DAC-NIPAM) among micelles, charge neutralization, hydrogen bond between P(DAC-NIPAM) and two antibiotics, the shrinkage of P(DAC-NIPAM) molecule and enhancement of hydrophobicity when water temperature was above low critical solution temperature (LCST), co-flocculation and co-settlement of multiple pollutants all contributed to the efficient removal of levofloxacin and tetracycline from water. Flocculation simulation further confirmed that thermosensitive flocculant combined with heating plates was a potential candidate for antibiotic treatment in actual water treatment plants. [ FROM AUTHOR]

Genotyping, virulence genes and drug resistance of MRSA strains isolated from skin and soft tissue infection in Tianjin

OBJECTIVE: To investigate and analyze the genotyping, virulence genes and drug-resistant genes of methicillin resistant Staphylococcus aureus (MRSA) strains isolated from skin and soft tissue infections in this area. METHODS: The skin secretions of 204 patients with skin and soft tissue infections in the Fifth Central Hospital of Tianjin between Jan. 2019 and Dec. 2020 were collected, and MRSA strains identified as non-repetitive strains were isolated. The Staphylococcal cassette chromosome mec (SCCmec) and Staphylococcal protein A gene (spa) genotyping and Panton-valentine leukocidin (PVL) gene carrying status were analyzed among the MRSA strains, and their relationship with drug resistance was analyzed. RESULTS: Totally 82 strains of S. aureus were isolated from the skin secretions of 204 patients with skin and soft tissue infections, including 44 strains of MRSA (53.66%). The most common SCCmec genotype was genotype III (accounting for 84.09%) and the most common spa genotype was genotype t030 (accounting for 84.09%). PVL genes encoding virulence factors were amplified in 5 strains (11.36%). The drug resistance rates of 44 MRSA strains to vancomycin and compound sulfamethoxazole were 0.00%, and all the strains were drug-resistant to penicillin. Different SCCmec and spa genotypes were highly resistant to erythromycin, cefazolin, clindamycin and levofloxacin, but the differences in drug resistance rates of different SCCmec genotypes to clindamycin and levofloxacin were significant (P < 0.05). The resistance rates of strains with PVL positive genes to chloramphenicol, gentamicin and tetracycline were significantly higher than those with PVL negative genes (P < 0.05). CONCLUSION: Strains carrying SCCmec III and spa t030 genotypes may be the dominant strains of MRSA in skin and soft tissue infections in this area. Spa genotypes and PVL gene have certain impact on drug resistance of MRSA, and the isolated MRSA strains are all sensitive to vancomycin and compound sulfamethoxazole, which can provide a reference for anti-MRSA treatment in this area.

Acinetobacter baumannii strains grown in endotracheal aspirate culture in Samsun Bafra State Hospital intensive care units and the effect of COVID-19 on Acinetobacter baumannii strains (2019-2020)

INTRODUCTION: Acinetobacter baumannii is an important causative agent of ventilation-associated pneumonia capable of long-term survival in the hospital setting. Increasing resistance to antibiotics effective against this pathogen is of concern. In this study, the antibiotic resistance profiles of A. baumannii strains grown in endotracheal aspirate (ETA) cultures in intensive care units and the effect of the COVID-19 pandemic on the resistance profiles in our province where the highest number of cases were observed in our country for a long time were investigated. METHODS: Our study included 74 A. baumannii isolates isolated from ETA samples that was sent to our laboratory from the intensive care units of Bafra State Hospital between January 2019 and December 2020. Bacteria were identified using conventional methods and a semi automatic bacterial identification system Vitek-2 (bioMerieux, France). The antibiotic susceptibility tests of the isolated strains were studied in accordance with the European Committee for Antimicrobial Susceptibility Testing (EUCAST) standards. Antibiotic susceptibility of A. baumannii strains was tested with Vitek-2 system. RESULTS: The mean age and standard deviations of 18 patients before the COVID-19 pandemic and 56 patients after the pandemic were found to be 83.0 +or- 8.3 and 70.5 +or- 14.9 (p < 0.001), respectively. A statistically significant difference was found between the distributions of gender by years (p=0.025). While 55.6% of the patients were female in 2019, 73.2% of the patients in 2020 were male. There was no difference between the two periods in terms of death rates (p=0.628) and respiratory support needs (p=0.191). It was determined that the pandemic increased the number of isolated A. baumannii by 311%. For the two periods, resistance was greatest for piperacillin/tazobactam, ceftazidime, ciprofloxacin and against imipenem. Examinig the two periods, amikacin resistance was seen to a lesser extent in 2020. A statistically significant difference was found between tigecycline resistance rates according to years (p < 0.001). While the tigecycline susceptibility of strains was 88.9% in 2019, it was found to be 26.8% in 2020.11.1% of the strains in 2019 and 64.3% in 2020 were found to be moderately susceptible. In this study, colistin resistance was observed in one (1.4%) of all isolates, while tigecycline resistance was detected in five isolates (6.8%). One isolate (1.4%) was susceptible to all antibiotics except ceftazidime. When the multi-antibiotic resistance of 73 A. baumannii isolates was examined, multidrug resistant (MDR) was 22.9% (n: 17), extensive drug resistance (XDR) was 74.3% (n: 55), pandrug resistance (PDR) was 1.4% (n: 1). Although there was a statistical difference in amikacin, meropenem and tigecycline resistances before and after the pandemic, no difference was found between the resistance patterns (p=0.281). DISCUSSION AND CONCLUSION: It has been observed that the most effective antibiotics against A. baumannii are colistin and tigecycline. It was determined that the COVID-19 pandemic did not change the resistance pattern rates. It is thought that success in fighting this infection will increase when each hospital determines its own resistance patterns, updates empirical treatment protocols based on their results, and clinicians use appropriate antibiotics early.

Repurposing tetracyclines for acute respiratory distress syndrome (ARDS) and severe COVID-19: a critical discussion of recent publications.

INTRODUCTION: Drug repurposing can be a successful approach to deal with the scarcity of cost-effective therapies in situations such as the COVID-19 pandemic. Tetracyclines have previously shown efficacy in preclinical acute respiratory distress syndrome (ARDS) models and initial predictions and experimental reports suggest a direct antiviral activity against SARS-CoV2. Furthermore, a few clinical reports indicate their potential in COVID-19 patients. In addition to the scarcity and limitations of the scientific evidence, the effectiveness of tetracyclines in experimental ARDS has been proven extensively, counteracting the overt inflammatory reaction and fibrosis sequelae due to a synergic combination of pharmacological activities. AREAS COVERED: This paper discusses the scientific evidence behind the application of tetracyclines for ARDS/COVID-19. EXPERT OPINION: The benefits of their multi-target pharmacology and their safety profile overcome the limitations, such as antibiotic activity and low commercial interest. Immunomodulatory tetracyclines and novel chemically modified non-antibiotic tetracyclines have therapeutic potential. Further drug repurposing studies in ARDS and severe COVID-19 are necessary.

COVID management and prophylaxis among rural, hilly and tribal population of India

The Covid-19 pandemic has been around us for more than a year now, with millions of confirmed cases and related deaths around the World. Recently, during second wave in India we observed a large number of infected cases with high mortality and scarcity of health infrastructure and manpower. The worst hit states were Rajasthan, Maharashtra, Uttar Pradesh, Karnataka, Andhra Pradesh and Kerala. The uncertainty and hopelessness of the disease is more exaggerated in remote rural, hilly and tribal areas of our country because of scarcity and inefficiency of health care facilities. A streamlined treatment and prophylaxis protocol is the need of the hour. Uttar Pradesh was the first State in India that issued a Government order for Ivermectin prophylaxis to household contacts, health care workers and to treat mild to moderate cases of Covid-19 with combination of Ivermectin and Doxycycline. This author was one of the external experts who was behind the formulation of this Government order. He further observed the miraculous effect of combination of ivermectin and doxycycline which became the backbone of the treatment protocol designed by him for the people living in remote areas of the country. Author's concept is just the simplified version, mainly based on Indian Council for Medical Research (ICMR) protocol and the Government order issued by Uttar Pradesh which is more applicable and feasible and accessible in such resource poor localities of our country. Author's strategy for such areas is simply based on COVID symptoms and pulse oximetry measurement to diagnose, categorise and treat the mild and moderate cases of COVID. This innovative strategy can be very helpful for rapid and prompt treatment of Covid-19 in remote areas considering the scarcity of COVID testing, health infrastructure and difficult connectivity and transport facilities in these areas.

Doxycycline Inhibition of a Pseudotyped Virus Transduction Does Not Translate to Inhibition of SARS-CoV-2 Infectivity.

The rapid spread of the pandemic caused by the SARS-CoV-2 virus has created an unusual situation, with rapid searches for compounds to interfere with the biological processes exploited by the virus. Doxycycline, with its pleiotropic effects, including anti-viral activity, has been proposed as a therapeutic candidate for COVID-19 and about twenty clinical trials have started since the beginning of the pandemic. To gain information on the activity of doxycycline against SARS-CoV-2 infection and clarify some of the conflicting clinical data published, we designed in vitro binding tests and infection studies with a pseudotyped virus expressing the spike protein, as well as a clinically isolated SARS-CoV-2 strain. Doxycycline inhibited the transduction of the pseudotyped virus in Vero E6 and HEK-293 T cells stably expressing human receptor angiotensin-converting enzyme 2 but did not affect the entry and replication of SARS-CoV-2. Although this conclusion is apparently disappointing, it is paradigmatic of an experimental approach aimed at developing an integrated multidisciplinary platform which can shed light on the mechanisms of action of potential anti-COVID-19 compounds. To avoid wasting precious time and resources, we believe very stringent experimental criteria are needed in the preclinical phase, including infectivity studies with clinically isolated SARS-CoV-2, before moving on to (futile) clinical trials.

Pleiotropic Effects of Tetracyclines in the Management of COVID-19: Emerging Perspectives.

Coronavirus disease 2019 (COVID-19) is a global infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Approximately 15% of severe cases require an intensive care unit (ICU) admission and mechanical ventilation due to development of acute respiratory distress syndrome (ARDS). Tetracyclines (TCs) are a group of bacteriostatic antibiotics, like tetracycline, minocycline, and doxycycline, effective against aerobic and anaerobic bacteria as well as Gram-positive and Gram-negative bacteria. Based on available evidences, TCs may be effective against coronaviruses and thus useful to treat COVID-19. Thus, this review aims to provide a brief overview on the uses of TCs for COVID-19 management. SARS-CoV-2 and other coronaviruses depend mainly on the matrix metalloproteinases (MMPs) for their proliferation, cell adhesion, and infiltration. The anti-inflammatory mechanisms of TCs are linked to different pathways. Briefly, TCs inhibit mitochondrial cytochrome c and caspase pathway with improvement of lymphopenia in early COVID-19. Specifically, minocycline is effective in reducing COVID-19-related complications, through attenuation of cytokine storm as apparent by reduction of interleukin (IL)-6, IL-1, and tumor necrosis factor (TNF)-α. Different clinical trials recommend the replacement of azithromycin by minocycline in the management of COVID-19 patients at high risk due to two main reasons: 1) minocycline does not prolong the QT interval and even inhibits ischemia-induced arrhythmia; 2) minocycline displays synergistic effect with chloroquine against SARS-CoV-2. Taken together, the data presented here show that TCs, mainly doxycycline or minocycline, may be potential partners in COVID-19 management, derived pneumonia, and related complications, such as acute lung injury (ALI) and ARDS.

The Emerging Role of Epigenetic Mechanisms in the Causation of Aberrant MMP Activity during Human Pathologies and the Use of Medicinal Drugs.

Matrix metalloproteinases (MMPs) cleave extracellular matrix proteins, growth factors, cytokines, and receptors to influence organ development, architecture, function, and the systemic and cell-specific responses to diseases and pharmacological drugs. Conversely, many diseases (such as atherosclerosis, arthritis, bacterial infections (tuberculosis), viral infections (COVID-19), and cancer), cholesterol-lowering drugs (such as statins), and tetracycline-class antibiotics (such as doxycycline) alter MMP activity through transcriptional, translational, and post-translational mechanisms. In this review, we summarize evidence that the aforementioned diseases and drugs exert significant epigenetic pressure on genes encoding MMPs, tissue inhibitors of MMPs, and factors that transcriptionally regulate the expression of MMPs. Our understanding of human pathologies associated with alterations in the proteolytic activity of MMPs must consider that these pathologies and their medicinal treatments may impose epigenetic pressure on the expression of MMP genes. Whether the epigenetic mechanisms affecting the activity of MMPs can be therapeutically targeted warrants further research.

Computational insights into tetracyclines as inhibitors against SARS-CoV-2 Mpro via combinatorial molecular simulation calculations.

The COVID-19 pandemic raised by SARS-CoV-2 is a public health emergency. However, lack of antiviral drugs and vaccine against human coronaviruses demands a concerted approach to challenge the SARS-CoV-2 infection. Under limited resource and urgency, combinatorial computational approaches to identify the potential inhibitor from known drugs could be applied against risen COVID-19 pandemic. Thereof, this study attempted to purpose the potent inhibitors from the approved drug pool against SARS-CoV-2 main protease (Mpro). To circumvent the issue of lead compound from available drugs as antivirals, antibiotics with broad spectrum of viral activity, i.e. doxycycline, tetracycline, demeclocycline, and minocycline were chosen for molecular simulation analysis against native ligand N3 inhibitor in SARS-CoV-2 Mpro crystal structure. Molecular docking simulation predicted the docking score >-7 kcal/mol with significant intermolecular interaction at the catalytic dyad (His41 and Cys145) and other essential substrate binding residues of SARS-CoV-2 Mpro. The best ligand conformations were further studied for complex stability and intermolecular interaction profiling with respect to time under 100 ns classical molecular dynamics simulation, established the significant stability and interactions of selected antibiotics by comparison to N3 inhibitor. Based on combinatorial molecular simulation analysis, doxycycline and minocycline were selected as potent inhibitor against SARS-CoV-2 Mpro which can used in combinational therapy against SARS-CoV-2 infection.

Tetracyclines in COVID-19 patients quarantined at home: Literature evidence supporting real-world data from a multicenter observational study targeting inflammatory and infectious dermatoses.

Tetracyclines (TetraC) are widely used in dermatology for both inflammatory and infectious dermatoses; recently both in vivo and in vitro studies started to suggest also a potential antiviral effect. During COVID-19 outbreak, several dermatological patients contracted SARS-CoV-2 experiencing only mild symptoms, but no protocol were approved. A multicenter prospective observational study that enrolled COVID-19 patients visited with teledermatology and undergoing TetraC was performed. About 38 adult outpatients (M/F: 20/18, age 42.6 years [21-67]) were enrolled. During the TetraC treatment, symptoms resolved in all patients within 10 days. Remarkably, ageusia and anosmia disappeared in the first week of TetraC treatment. TetraC seem a promising drug to treat COVID-19 outpatients with mild symptoms.