BACKGROUND: Given the general unavailability, common adverse effects, and complicated administration of tetracycline, the clinical application of classic bismuth quadruple therapy (BQT) is greatly limited. Whether minocycline can replace tetracycline for Helicobacter pylori ( H . pylori ) eradication is unknown. We aimed to compare the eradication rate, safety, and compliance between minocycline- and tetracycline-containing BQT as first-line regimens. METHODS: This randomized controlled trial was conducted on 434 naïve patients with H . pylori infection. The participants were randomly assigned to 14-day minocycline-containing BQT group (bismuth potassium citrate 110 mg q.i.d., esomeprazole 20 mg b.i.d., metronidazole 400 mg q.i.d., and minocycline 100 mg b.i.d.) and tetracycline-containing BQT group (bismuth potassium citrate/esomeprazole/metronidazole with doses same as above and tetracycline 500 mg q.i.d.). Safety and compliance were assessed within 3 days after eradication. Urea breath test was performed at 4-8 weeks after eradication to evaluate outcome. We used a noninferiority test to compare the eradication rates of the two groups. The intergroup differences were evaluated using Pearson chi-squared or Fisher's exact test for categorical variables and Student's t -test for continuous variables. RESULTS: As for the eradication rates of minocycline- and tetracycline-containing BQT, the results of both intention-to-treat (ITT) and per-protocol (PP) analyses showed that the difference rate of lower limit of 95% confidence interval (CI) was >-10.0% (ITT analysis: 181/217 [83.4%] vs . 180/217 [82.9%], with a rate difference of 0.5% [-6.9% to 7.9%]; PP analysis: 177/193 [91.7%] vs . 176/191 [92.1%], with a rate difference of -0.4% [-5.6% to 6.4%]). Except for dizziness more common (35/215 [16.3%] vs . 13/214 [6.1%], P = 0.001) in minocycline-containing therapy groups, the incidences of adverse events (75/215 [34.9%] vs . 88/214 [41.1%]) and compliance (195/215 [90.7%] vs . 192/214 [89.7%]) were similar between the two groups. CONCLUSION: The eradication efficacy of minocycline-containing BQT was noninferior to tetracycline-containing BQT as first-line regimen for H . pylori eradication with similar safety and compliance. TRIAL REGISTRATION ClinicalTrials.gov, ChiCTR 1900023646.
Humans ; Bismuth/therapeutic use* ; Metronidazole/therapeutic use* ; Esomeprazole/pharmacology* ; Minocycline/pharmacology* ; Helicobacter pylori ; Potassium Citrate/therapeutic use* ; Anti-Bacterial Agents ; Tetracycline/adverse effects* ; Helicobacter Infections/drug therapy* ; Drug Therapy, Combination ; Amoxicillin

Objective To examine the neuroanatomical substrates underlying the effects of minocycline in alleviating lipopolysaccharide (LPS)-induced neuroinflammation. Methods Forty C57BL/6 male mice were randomly and equally divided into eight groups. Over three conse-cutive days, saline was administered to four groups of mice and minocycline to the other four groups. Immediately after the administration of saline or minocycline on the third day, two groups of mice were additionally injected with saline and the other two groups were injected with LPS. Six or 24 hours after the last injection, mice were sacrificed and the brains were removed. Immunohistochemical staining across the whole brain was performed to detect microglia activation via Iba1 and neuronal activation via c-Fos. Morphology of microglia and the number of c-Fo-positive neurons were analyzed by Image-Pro Premier 3D. One-way ANOVA and Fisher's least-significant differences were employed for statistical analyses. Results Minocycline alleviated LPS-induced neuroinflammation as evidenced by reduced activation of microglia in multiple brain regions, including the shell part of the nucleus accumbens (Acbs), paraventricular nucleus (PVN) of the hypothalamus, central nucleus of the amygdala (CeA), locus coeruleus (LC), and nucleus tractus solitarius (NTS). Minocycline significantly increased the number of c-Fo-positive neurons in NTS and area postrema (AP) after LPS treatment. Furthermore, in NTS-associated brain areas, including LC, lateral parabrachial nucleus (LPB), periaqueductal gray (PAG), dorsal raphe nucleus (DR), amygdala, PVN, and bed nucleus of the stria terminali (BNST), minocycline also significantly increased the number of c-Fo-positive neurons after LPS administration. Conclusion Minocycline alleviates LPS-induced neuroinflammation in multiple brain regions, possibly due to increased activation of neurons in the NTS-associated network.
Animals ; Female ; Lipopolysaccharides/toxicity* ; Male ; Mice ; Mice, Inbred C57BL ; Minocycline/pharmacology* ; Neuroinflammatory Diseases ; Solitary Nucleus

Tigecycline is a novel glycylcycline antibacterial drug, which shows both antibiotic function and anti-tumor activity. This review summarizes the single and combined use of tigecycline for tumor treatment and the underpinning mechanisms. As an inhibitor for mitochondrial DNA translation, tigecycline affects the proliferation, migration, and invasion of tumor cells mainly through inhibiting mitochondrial protein synthesis and inducing mitochondrial dysfunction. Although the effect of tigecycline monotherapy is controversial, the efficacy of combined use of tigecycline is satisfactory. Therefore, it is important to explore the molecular mechanisms underpinning the anti-tumor activity of tigecycline, with the aim to use it as a cheap and effective new anti-tumor drug.
Anti-Bacterial Agents/pharmacology* ; Humans ; Minocycline/pharmacology* ; Mitochondria ; Neoplasms/drug therapy* ; Tigecycline/pharmacology*

Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been elucidated after determining their physiological structure, but there is still much to learn about the role of this type of cell in NPP and morphine tolerance. Microglia mediate multiple functions in health and disease by controlling damage in the central nervous system (CNS) and endogenous immune responses to disease. Microglial activation can result in altered opioid system activity, and NPP is characterized by resistance to morphine. Here we investigate the regulatory mechanisms of microglia and review the potential of microglial inhibitors for modulating NPP and morphine tolerance. Targeted inhibition of glial activation is a clinically promising approach to the treatment of NPP and the prevention of morphine tolerance. Finally, we suggest directions for future research on microglial inhibitors.
Humans ; Calcitonin Gene-Related Peptide/antagonists & inhibitors* ; Drug Tolerance ; Hypoglycemic Agents/pharmacology* ; Microglia/physiology* ; MicroRNAs/physiology* ; Minocycline/pharmacology* ; Morphine/pharmacology* ; Neuralgia/etiology* ; Plant Extracts/pharmacology* ; Signal Transduction/physiology*

Increasing evidence suggests that spinal microglia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain following intrathecal injection in male and female mice. These modulators were the microglial inhibitors minocycline and ZVEID (a caspase-6 inhibitor) and the astroglial inhibitors L-α-aminoadipate (L-AA, an astroglial toxin) and carbenoxolone (a connexin 43 inhibitor), as well as U0126 (an ERK kinase inhibitor) and D-JNKI-1 (a c-Jun N-terminal kinase inhibitor). We found that spinal administration of minocycline or ZVEID, or Caspase6 deletion, reduced formalin-induced inflammatory and nerve injury-induced neuropathic pain primarily in male mice. In contrast, intrathecal L-AA reduced neuropathic pain but not inflammatory pain in both sexes. Intrathecal U0126 and D-JNKI-1 reduced neuropathic pain in both sexes. Nerve injury caused spinal upregulation of the astroglial markers GFAP and Connexin 43 in both sexes. Collectively, our data confirmed male-dominant microglial signaling but also revealed sex-independent astroglial signaling in the spinal cord in inflammatory and neuropathic pain.
2-Aminoadipic Acid ; toxicity ; Animals ; Anti-Inflammatory Agents ; therapeutic use ; Astrocytes ; pathology ; Carbenoxolone ; pharmacology ; Caspase 6 ; deficiency ; metabolism ; Connexin 43 ; metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Inhibitors ; pharmacology ; Female ; Glial Fibrillary Acidic Protein ; metabolism ; Male ; Mice ; Mice, Transgenic ; Microglia ; pathology ; Minocycline ; therapeutic use ; Neuralgia ; chemically induced ; drug therapy ; pathology ; Pain Measurement ; Phenylurea Compounds ; pharmacology ; Sex Characteristics ; Spinal Cord ; pathology ; Time Factors

OBJECTIVE: To unravel the underlying mechanism of minocycline in formalin-induced inflammatory pain, and to investigate the effects of minocycline on synaptic transmission in substantia gela-tinosa (SG) neurons of rat spinal dorsal horn. METHODS: Behavioral and immunohistochemistry experiments: 30 male Sprague-Dawley (SD) rats (3-5 weeks old) were randomly assigned to control (n=8 rats), model (n=8 rats), saline treatment model (n=6 rats) and minocycline treatment model (n=8 rats) groups. The control group was subcutaneously injected with normal saline on the right hindpaws. Acute inflammatory pain model was established by injecting 5% (volume fraction) formalin into the right hindpaws. The rats in the latter two groups received intraperitoneal injection of saline and minocycline 1 h before the formalin injection, respectively. The time of licking and lifting was recorded every 5 min within 1 h after the subcutaneous injection of normal saline or formalin for all the groups, which was continuously recorded for 1 h. One hour after the pain behavioral recording, the spinal cord tissue was removed following transcardial perfusion of 4% paraformaldehyde. The expression of c-Fos protein in spinal dorsal horn was observed by immunohistochemistry. Electrophysiological experiment: In vitro whole-cell patch-clamp recordings were performed in spinal cord parasagittal slices obtained from 26 male SD rats (3-5 weeks old). Two to five neurons were randomly selected from each rat for patch-clamp recording. the effects of minocycline, fluorocitrate and doxycycline on spontaneous excitatory postsynaptic currents (sEPSCs) or spontaneous inhibitory postsynaptic currents (sIPSCs) of SG neurons were investigated. RESULTS: Compared with the control group, both the licking and lifting time and the expression of c-Fos protein in ipsilateral spinal dorsal horn of the model group were significantly increased. Intraperitoneal injection of minocycline largely attenuated the second phase of formalin-induced pain responses (t=2.957, P<0.05). Moreover, c-Fos protein expression was also dramatically reduced in both the superficial lamina (I-II) and deep lamina (III-IV) of spinal dorsal horn (t_I-II=3.912, t_III-IV=2.630, P<0.05). On the other side, bath application of minocycline significantly increased the sIPSCs frequency to 220%±10% (P<0.05) of the control but did not affect the frequency (100%±1%, t=0.112, P=0.951) and amplitude (98%±1%, t=0.273, P=0.167) of sEPSCs and the amplitude (105%±3%, t=0.568, P=0.058) of sIPSCs. However, fluorocitrate and doxycycline had no effect on the frequency [(99%±1%, t=0.366, P=0.099); (102%±1%, t=0.184, P=0.146), respectively] and amplitude [(98%±1%, t=0.208, P=0.253); (99%±1%, t=0.129, P=0.552), respectively] of sIPSCs. CONCLUSION Minocycline can inhibit formalin-induced inflammatory pain and the expression of c-Fos protein in spinal dorsal horn. These effects are probably due to its enhancement in inhibitory synaptic transmission of SG neurons but not its effect on microglial activation or antibiotic action.
Animals ; Anti-Bacterial Agents/pharmacology* ; Formaldehyde ; Inflammation/complications* ; Inhibitory Postsynaptic Potentials ; Male ; Minocycline/pharmacology* ; Pain/prevention & control* ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spinal Cord

BACKGROUNDAcinetobacter baumannii has emerged as an important pathogen causing a variety of infections. Using data from the China Surveillance of Antimicrobial Resistance Program conducted biennially, we investigated the secular changes in the resistance of 2917 isolates of A. baumannii from 2004 to 2014 to differ antimicrobial agents.

METHODSPathogen samples were collected from 17 to 20 hospitals located in the eastern, central, and western regions of China. Minimum inhibitory concentrations (MICs) were determined by a 2-fold agar dilution method, and antimicrobial susceptibility was established using the 2014 Clinical Laboratory Standards Institute-approved breakpoints. Isolates not susceptible to all the tested aminoglycosides, fluoroquinolones, β-lactams, β-lactam/β-lactam inhibitors and carbapenems were defined as extensively drug resistant.

RESULTSThe rates of nonsusceptibility to common antimicrobial agents remained high (>65%) over the years with some fluctuations to certain agents. The prevalence of imipenem-resistant A. baumannii (IRAB) increased from 13.3% in 2004 to 70.5% in 2014 and that of extensively drug-resistant A. baumannii (XDRAB) increased from 11.1% in 2004 to 60.4% in 2014. The activity of tigecycline was stable with MIC90 ≤4 mg/L against A. baumannii from 2009 to 2014. Susceptibility to colistin remained high (97.0%) from 2009 to 2014. The prevalence of XDRAB increased in all the three surveillance regions over the years and was significantly higher in Intensive Care Unit (ICU) wards than non-ICU wards.

CONCLUSIONSThis longitudinal multicenter surveillance program revealed the nationwide emergence of A. baumannii in China and showed a significant increase in prevalence from 2004 to 2014. High levels of bacterial resistance were detected among samples collected from clinical settings in China, with IRAB and XDRAB being especially prevalent. This study will help to guide empirical therapy and identify at-risk groups requiring more intense interventional infection control measures, while also helping to focus surveillance efforts.

Acinetobacter baumannii ; drug effects ; Amikacin ; pharmacology ; Anti-Infective Agents ; pharmacology ; Cefoperazone ; pharmacology ; Ceftazidime ; pharmacology ; Cephalosporins ; pharmacology ; China ; Colistin ; pharmacology ; Drug Resistance, Multiple, Bacterial ; Humans ; Imipenem ; pharmacology ; Levofloxacin ; pharmacology ; Microbial Sensitivity Tests ; Minocycline ; pharmacology ; Penicillanic Acid ; analogs & derivatives ; pharmacology ; Piperacillin ; pharmacology ; Sulbactam ; pharmacology

BACKGROUND: Acinetobacter baumannii infections are difficult to treat owing to the emergence of various antibiotic resistant isolates. Because treatment options are limited for multidrug-resistant (MDR) A. baumannii infection, the discovery of new therapies, including combination therapy, is required. We evaluated the synergistic activity of colistin, doripenem, and tigecycline combinations against extensively drug-resistant (XDR) A. baumannii and MDR A. baumannii. METHODS: Time-kill assays were performed for 41 XDR and 28 MDR clinical isolates of A. baumannii by using colistin, doripenem, and tigecycline combinations. Concentrations representative of clinically achievable levels (colistin 2 microg/mL, doripenem 8 microg/mL) and achievable tissue levels (tigecycline 2 microg/mL) for each antibiotic were used in this study. RESULTS: The colistin-doripenem combination displayed the highest rate of synergy (53.6%) and bactericidal activity (75.4%) in 69 clinical isolates of A. baumannii. Among them, thedoripenem-tigecycline combination showed the lowest rate of synergy (14.5%) and bacteri-cidal activity (24.6%). The doripenem-tigecycline combination showed a higher antagonistic interaction (5.8%) compared with the colistin-tigecycline (1.4%) combination. No antagonism was observed for the colistin-doripenem combination. CONCLUSIONS: The colistin-doripenem combination is supported in vitro by the high rate of synergy and bactericidal activity and lack of antagonistic reaction in XDR and MDR A. baumannii. It seems to be necessary to perform synergy tests to determine the appropri-ate combination therapy considering the antagonistic reaction found in several isolates against the doripenem-tigecycline and colistin-tigecycline combinations. These findings should be further examined in clinical studies.
Acinetobacter Infections/drug therapy/microbiology ; Acinetobacter baumannii/*drug effects/genetics/isolation & purification ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; Bacterial Proteins/genetics ; Carbapenems/*pharmacology/therapeutic use ; Colistin/*pharmacology/therapeutic use ; Drug Resistance, Multiple, Bacterial/*drug effects ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Microbial Sensitivity Tests ; Minocycline/*analogs & derivatives/pharmacology/therapeutic use ; Multilocus Sequence Typing ; beta-Lactamases/genetics

PURPOSE: Tigecycline is one of the drugs used to treat multi-drug resistant Klebsiella pneumoniae (K. pneumoniae) infections, including complicated skin and soft tissue infections, complicated intra-abdominal infection, and community-acquired pneumonia in the Republic of Korea. However, since its commercial release, K. pneumoniae resistance against tigecycline has been reported, and there is a serious concern about the spread of tigecycline resistant bacteria. MATERIALS AND METHODS: In this study, we collected and analyzed 342 isolates from 23 hospitals in the Republic of Korea to determine the mechanisms of tigecycline susceptibility and their clonal types. The hospitals include several from each province in the Republic of Korea, except Jeju, an island province, and nonsusceptibility among the isolates was tested by the disk diffusion method. In our lab, susceptibility was checked again using the broth dilution method, and clonal types were determined using the multilocus sequence typing protocol. Real-time PCR was performed to measure the ramR mutation in the isolates nonsusceptible to tigecycline, which would suggest an increased expression of the AcrAB multidrug pump. RESULTS: Fifty-six K. pneumoniae isolates were found to be nonsusceptible, 16% of the 342 collected. Twenty-seven and nine isolates of the tigecycline nonsusceptible isolates had mutations in the ramR and rpsJ genes, respectively; while 18 nonsusceptible isolates harbored the tetA gene. Comparison of isolates with and without ramR mutation showed a significant statistical difference (p<0.05) for expression of AcrAB. Moreover, the most common clonal types, as observed in our study, appear to be ST11 and ST789. CONCLUSION: Several dominate clonal types infer tigecycline resistance to K. pneumoniae, including ST11, ST768, ST15, ST23, ST48, and ST307. There does not seem to be a transferrable medium, such as plasmid, for the resistance yet, although mutation of the ramR gene may be a common event, accounting for 48% of the nonsusceptibility in this study.
Anti-Bacterial Agents/*pharmacology/therapeutic use ; Bacterial Proteins ; *Drug Resistance, Bacterial ; Humans ; Klebsiella Infections/*drug therapy ; Klebsiella pneumoniae/*drug effects/genetics/*isolation & purification ; Microbial Sensitivity Tests ; Minocycline/*analogs & derivatives/pharmacology/therapeutic use ; Multilocus Sequence Typing ; Plasmids ; Polymerase Chain Reaction ; Real-Time Polymerase Chain Reaction ; Republic of Korea

Scrub typhus is a zoonosis caused by Orientia tsutsugamushi (O. tsutsugamushi) occurring mainly in autumn in Korea. The need of new antibiotics has arisen with a report on strains resistant to antibiotics and chronic infection. This study aims to identify susceptibility of tigecycline in-vitro as a new therapeutic option for O. tsutsugamushi. Antibacterial activity of tigecycline against the O. tsutsugamushi was compared with doxycycline using flow cytometry assay. The inhibitory concentration 50 (IC50) was 3.59×10(-3) µg/mL in doxycycline-treated group. Whereas in 0.71×10(-3) µg/mL tigecycline-treated group. These findings indicate that tigecycline may be a therapeutic option for the treatment of scrub typhus.
Anti-Bacterial Agents/*pharmacology/therapeutic use ; Drug Resistance, Bacterial/drug effects ; Humans ; Inhibitory Concentration 50 ; Minocycline/*analogs & derivatives/pharmacology/therapeutic use ; Orientia tsutsugamushi/*drug effects/physiology ; Scrub Typhus/drug therapy