Chlamydial infection showing migratory pulmonary infiltrates.

Intern Med. 2007;46(20):1735-8

Authors: Imokawa S, Yasuda K, Uchiyama H, Sagisaka S, Harada M, Mori K, Kitazawa H, Suda T, Chida K

A 70-year old man was admitted to our hospital because of nonproductive cough, fever and increasing dyspnea associated with alveolar opacities on chest roentgenogram, which later migrated to previously unaffected areas. The diagnosis of Chlamydial pneumonitis was made on serological grounds. Organizing pneumonia was documented by transbronchial lung biopsies and the subsequent course was satisfactory under minocycline therapy. Chlamydial infection should be considered in the differential diagnosis of migratory pulmonary infiltrates.

PMID: 17938530 [PubMed - indexed for MEDLINE]

Antibiotic resistance in an in vitro subgingival biofilm model.

Oral Microbiol Immunol. 2007 Oct;22(5):333-9

Authors: Sedlacek MJ, Walker C

INTRODUCTION: The purpose of this study was to utilize an in vitro biofilm model of subgingival plaque to investigate resistances in subgingival biofilm communities to antibiotics commonly used as adjuncts to periodontal therapy. METHODS: Biofilms were grown on saliva-coated hydroxyapatite supports in trypticase-soy broth for 4 h-10 days and then exposed for 48 h to either increasing twofold concentrations of tetracycline, amoxicillin, clindamycin, and erythromycin or therapeutically achievable concentrations of tetracycline, doxycycline, minocycline, amoxicillin, metronidazole, amoxicillin/clavulanate, and amoxicillin/metronidazole. RESULTS: Concentrations necessary to inhibit bacterial strains in steady-state biofilms were up to 250 times greater than the concentrations needed to inhibit the same strains grown planktonically. In the presence of therapeutically available antibiotic concentrations, significantly higher proportions of the biofilms remained viable as the biofilms reached steady-state growth. The combinations of amoxicillin/clavulanate and amoxicillin/metronidazole were the most effective in suppressing growth. These combinations were particularly effective against biofilms up to and including 7 days of age and inhibited 90% or more of the bacteria present relative to untreated controls. As the biofilms approached steady state, these combinations were less effective with 50-60% of the bacteria retaining viability. CONCLUSION: Most, but not all, species of subgingival bacteria are considerably more resistant in biofilms than in planktonic cultures. Resistance appeared to be age-related because biofilms demonstrated progressive antibiotic resistance as they matured with maximum resistance coinciding with the steady-state phase of biofilm growth.

PMID: 17803631 [PubMed - in process]

Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain.

Brain. 2007 Oct;130(Pt 10):2688-702

Authors: Wallace VC, Blackbeard J, Segerdahl AR, Hasnie F, Pheby T, McMahon SB, Rice AS

A distal symmetrical sensory peripheral neuropathy is frequently observed in people living with Human Immunodeficiency Virus Type 1 (HIV-1). This neuropathy can be associated with viral infection alone, probably involving a role for the envelope glycoprotein gp120; or a drug-induced toxic neuropathy associated with the use of nucleoside analogue reverse transcriptase inhibitors as a component of highly active anti-retroviral therapy. In order to elucidate the mechanisms underlying drug-induced neuropathy in the context of HIV infection, we have characterized pathological events in the peripheral and central nervous system following systemic treatment with the anti-retroviral agent, ddC (Zalcitabine) with or without the concomitant delivery of HIV-gp120 to the rat sciatic nerve (gp120+ddC). Systemic ddC treatment alone is associated with a persistent mechanical hypersensitivity (33% decrease in limb withdrawal threshold) that when combined with perineural HIV-gp120 is exacerbated (48% decrease in threshold) and both treatments result in thigmotactic (anxiety-like) behaviour. Immunohistochemical studies revealed little ddC-associated alteration in DRG phenotype, as compared with known changes following perineural HIV-gp120. However, the chemokine CCL2 is significantly expressed in the DRG of rats treated with perineural HIV-gp120 and/or ddC and there is a reduction in intraepidermal nerve fibre density, comparable to that seen in herpes zoster infection. Moreover, a spinal gliosis is apparent at times of peak behavioural sensitivity that is exacerbated in gp120+ddC as compared to either treatment alone. Treatment with the microglial inhibitor, minocycline, is associated with delayed onset of hypersensitivity to mechanical stimuli in the gp120+ddC model and reversal of some measures of thigmotaxis. Finally, the hypersensitivity to mechanical stimuli was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with amitriptyline. These data suggests that both neuropathic pain models display many features of HIV- and anti-retroviral-related peripheral neuropathy. They therefore merit further investigation for the elucidation of underlying mechanisms and may prove useful for preclinical assessment of drugs for the treatment of HIV-related peripheral neuropathic pain.

PMID: 17761732 [PubMed - indexed for MEDLINE]

Minocycline and sulforaphane inhibited lipopolysaccharide-mediated retinal microglial activation.

Mol Vis. 2007;13:1083-93

Authors: Yang LP, Zhu XA, Tso MO

PURPOSE: To elucidate the inhibitory effect of minocycline and sulforaphane on lipopolysaccharide (LPS)-induced retinal microglial activation and the mechanisms through which they exerted their inhibitory effects. METHODS: Primary retinal microglial cultures were exposed to LPS with or without minocycline and sulforaphane. The mRNA expression of monocyte chemotactic protein (MCP)-1, MCP-3, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, eotaxin, regulated upon activation normal T-cell expressed and secreted (RANTES) protein, and interleukin (IL)-10 were examined by reverse transcription polymerase chain reaction (RT-PCR) assay. The mRNA expression of inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) production were examined by RT-PCR assay and Griess reagent assay. Protein expression of the p65 subunit of nuclear factor-kappaB (NF-kappaB) and p-p38, p-p44/42 and p-JNK mitogen-activated protein kinases (MAPKs) were examined by Western blot and immunofluorescent analysis. RESULTS: Cultured retinal microglial cells were activated following exposure to LPS. The mRNA expression and protein production of eotaxin, RANTES, and IL-10 and the mRNA expression of iNOS and subsequent NO production were upregulated. The protein expression of p-p38, p-JNK, and the p65 subunit of NF-kappaB were also upregulated. However, the protein expression of p-p44/42 was not significantly changed. Pretreatment with minocycline or sulforaphane for 1 h before LPS administration inhibited LPS-induced microglial morphological change and inhibited LPS-induced upregulation of p-p38, but had no effect on the expression of p-p44/42, p-JNK, and the p65 subunit of NF-kappaB. CONCLUSIONS: Minocycline and sulforaphane inhibited LPS-induced retinal microglial activation, Western blot and immunofluorescent studies showed decreased p-p38 MAPK expression. We suggested that the inhibitory effect of minocycline and sulforaphane was partly through a p38 MAPK-dependent mechanism.

PMID: 17653053 [PubMed - indexed for MEDLINE]

Minocycline delayed photoreceptor death in rds mice through iNOS-dependent mechanism.

Mol Vis. 2007;13:1073-82

Authors: Yang LP, Li Y, Zhu XA, Tso MO

PURPOSE: To elucidate the role of activated microglia and nitric oxide (NO) in photoreceptor apoptosis in rds mice, and to investigate the effect of minocycline treatment on rds mice. METHODS: Photoreceptor apoptosis in rds mice was detected by terminal dUTP transferase nick end labeling (TUNEL). Retinal microglial cells were identified by CD11b antibody. The mRNA expression of inducible nitric oxide synthase (iNOS) and chemokines were examined by reverse transcription polymerase chain reaction (RT-PCR) assay. The protein expression of iNOS was examined by immunohistochemistry and Western blotting analysis. The rds mice were treated intra-peritoneally from the second postnatal day (P2) with minocycline. RESULTS: Accompanying photoreceptor degeneration in rds mice, microglia were activated and immigrated from inner retinal layer (IRL) to outer nuclear layer (ONL), and the expression of iNOS was up-regulated. Minocycline treatment reduced the iNOS expression and decreased the initial photoreceptor apoptosis, but did not provide long term ameliorative effect on the photoreceptor cell loss of rds mice. CONCLUSIONS: NO played a major role in the initial photoreceptor apoptosis in rds mice. The migration of activated microglia to the ONL contributed to the subsequent photoreceptor cell death; minocycline treatment ameliorated the photoreceptor apoptosis in rds mice, and this protective effect was partly through iNOS-suppressive mechanism.

PMID: 17653052 [PubMed - indexed for MEDLINE]

Serum sickness like reaction with minocycline.

Indian J Dermatol Venereol Leprol. 2004 Jan-Feb;70(1):43-4

Authors: Sarma N, Malakar S, Lahiri K, Banerjee U

PMID: 17642559 [PubMed]

Scleral and conjunctival pigmentation following minocycline therapy.

Can J Ophthalmol. 2007 Aug;42(4):626-7

Authors: McAllum P, Slomovic A

PMID: 17641711 [PubMed - indexed for MEDLINE]

Tigecycline disk diffusion breakpoints of Acinetobacter spp.: a clinical point of view.

J Clin Microbiol. 2007 Jun;45(6):2095; author reply 2095-6

Authors: Curcio D, Fernández F, Jones RN, Ferraro MJ, Reller LB, Schreckenberger PC, Sader HS

PMID: 17548459 [PubMed - indexed for MEDLINE]

[Tigecycline, the first of a new class of antibiotics: the glycylcyclines]

Rev Esp Quimioter. 2007 Mar;20(1):19-35

Authors: Bosó-Ribelles V, Roma-Sánchez E, Salavert-Lletí M, Hernández-Martí V, Poveda-Andrés JL

PMID: 17530033 [PubMed - indexed for MEDLINE]

Validation and reproducibility assessment of tigecycline MIC determinations by Etest.

J Clin Microbiol. 2007 Aug;45(8):2474-9

Authors: Bolmström A, Karlsson A, Engelhardt A, Ho P, Petersen PJ, Bradford PA, Jones CH

A multicenter study was conducted to validate Etest tigecycline compared to the Clinical Laboratory Standards Institute reference broth microdilution and agar dilution methodologies. A large collection of gram-negative (n = 266) and gram-positive (n = 162) aerobic bacteria, a collection of anaerobes (n = 385), and selected collections of nonpneumococcal streptococci (n = 369), Streptococcus pneumoniae (n = 372), and Haemophilus influenzae (n = 372) were tested. Strains with reduced susceptibility to tigecycline were used with all test methods. The Etest showed excellent inter- and intralaboratory reproducibility for all organism groups tested regardless of the test methodology. The essential agreement values with the reference method (+/-1 dilution) were >99% for the collection of gram-negative and gram-positive aerobes; >98% for the S. pneumoniae, H. influenzae, and anaerobe collections; and 100% for the group of nonpneumococcal streptococci. These results validate the performance accuracy and utility of Etest tigecycline and verify the reproducibility of this convenient predefined gradient methodology for tigecycline susceptibility determination.

PMID: 17522277 [PubMed - indexed for MEDLINE]

Papillary thyroid carcinoma in a patient with sarcoidosis treated with minocycline.

Neth J Med. 2007 May;65(5):185-7

Authors: Bruins NA, Oswald JE, Morreau H, Kievit J, Pavel S, Smelt AH

Long-term treatment with minocycline is occasionally associated with the development of black thyroid syndrome in which thyroid cancer is frequently found. Here, we report a patient with cutaneous, pulmonary and thyroid sarcoidosis who developed papillary thyroid carcinoma in the presence of a black thyroid syndrome after being treated with minocycline for 2.5 years.

PMID: 17519514 [PubMed - indexed for MEDLINE]

Minocycline-induced hypersensitivity syndrome presenting with meningitis and brain edema: a case report.

J Med Case Reports. 2007;1:22

Authors: Lefebvre N, Forestier E, Farhi D, Mahsa MZ, Remy V, Lesens O, Christmann D, Hansmann Y

: BACKGROUND: Hypersentivity Syndrome (HS) may be a life-threatening condition. It frequently presents with fever, rash, eosinophilia and systemic manifestations. Mortality can be as high as 10% and is primarily due to hepatic failure. We describe what we believe to be the first case of minocycline-induced HS with accompanying lymphocytic meningitis and cerebral edema reported in the literature. CASE PRESENTATION: A 31-year-old HIV-positive female of African origin presented with acute fever, lymphocytic meningitis, brain edema, rash, eosinophilia, and cytolytic hepatitis. She had been started on minocycline for inflammatory acne 21 days prior to the onset of symptoms. HS was diagnosed clinically and after exclusion of infectious causes. Minocycline was withdrawn and steroids were administered from the second day after presentation because of the severity of the symptoms. All signs resolved by the seventh day and steroids were tailed off over a period of 8 months. CONCLUSION: Clinicians should maintain a high index of suspicion for serious adverse reactions to minocycline including lymphocytic meningitis and cerebral edema among HIV-positive patients, especially if they are of African origin. Safer alternatives should be considered for treatment of acne vulgaris. Early recognition of the symptoms and prompt withdrawal of the drug are important to improve the outcome.

PMID: 17511865 [PubMed - in process]

Minocycline inhibits 5-lipoxygenase activation and brain inflammation after focal cerebral ischemia in rats.

Acta Pharmacol Sin. 2007 Jun;28(6):763-72

Authors: Chu LS, Fang SH, Zhou Y, Yu GL, Wang ML, Zhang WP, Wei EQ

AIM: To determine whether the anti-inflammatory effect of minocycline on postischemic brain injury is mediated by the inhibition of 5-lipoxygenase (5-LOX) expression and enzymatic activation in rats. METHODS: Focal cerebral ischemia was induced for 30 min with middle cerebral artery occlusion, followed by reperfusion. The ischemic injuries, endogenous IgG exudation, the accumulation of neutrophils and macrophage/microglia, and 5-LOX mRNA expression were determined 72 h after reperfusion. 5-LOX metabolites (leukotriene B4 and cysteinyl leukotrienes) were measured 3 h after reperfusion. RESULTS: Minocycline (22.5 and 45 mg/kg, ip, for 3 d) attenuated ischemic injuries, IgG exudation, and the accumulation of neutrophils and macrophage/microglia 72 h after reperfusion. It also inhibited 5-LOX expression 72 h after reperfusion and the production of leukotrienes 3 h after reperfusion. CONCLUSION: Minocycline inhibited postischemic brain inflammation, which might be partly mediated by the inhibition of 5-LOX expression and enzymatic activation.

PMID: 17506934 [PubMed - in process]

Topical minocycline and tetracycline rinses in treatment of recurrent aphthous stomatitis: a randomized cross-over study.

Dermatol Online J. 2007;13(2):1

Authors: Gorsky M, Epstein J, Rabenstein S, Elishoov H, Yarom N

Recurrent aphthous stomatitis (RAS) is a common ulcerative condition of the oral mucosa. We assessed minocycline and tetracycline oral rinses in patients with frequent episodes of RAS in a clinical randomized crossover trial. Seventeen patients with high frequency recurrent minor RAS were randomly allocated to a cross-over topical therapy with 0.2 percent minocycline or 0.25 percent tetracycline aqueous solution mouthwash. The minimum interval between the cross-over was 30 days. The intensity of pain was recorded daily using a visual analogue scale. Minocycline mouthwashes as compared to topical tetracycline rinses resulted in significantly improved pain control, by reducing the severity and duration of pain. Topical minocycline rinse may be a potential treatment for other mucosal diseases that result in mucosal ulceration and pain.

PMID: 17498420 [PubMed - indexed for MEDLINE]

Comparative in vitro antimicrobial activity of tigecycline, a new glycylcycline compound, in freshly prepared medium and quality control.

J Clin Microbiol. 2007 Jul;45(7):2173-9

Authors: Brown SD, Traczewski MM

The in vitro spectra of activity of tigecycline and tetracycline were determined for 2,490 bacterial isolates representing 50 different species or phenotypic groups. All isolates were tested simultaneously by broth microdilution using freshly prepared Mueller-Hinton broth and by disk diffusion. Portions of these data were submitted to the Food and Drug Administration (FDA) in support of the sponsor's application for new drug approval. In a separate study, MIC and disk diffusion quality control ranges were determined. The tigecycline MICs at which 50%/90% of bacteria were inhibited were (in microg/ml) as follows: for Streptococcus spp., 0.06/0.12; for Moraxella catarrhalis, 0.06/0.12; for Staphylococcus spp., 0.12/0.25; for Enterococcus spp., 0.12/0.25; for Listeria monocytogenes, 0.12/0.12; for Neisseria meningitidis, 0.12/0.25; for Haemophilus spp., 0.25/0.5; for Enterobacteriaceae, 0.05/2.0; for non-Enterobacteriaceae, 0.5/8.0. Tigecycline was consistently more potent than tetracycline against all species studied. The data from this study confirm the FDA-approved MIC and disk diffusion breakpoints for tigecycline for Streptococcus spp. other than Streptococcus pneumoniae, enterococci, and Enterobacteriaceae. Provisional breakpoints for Haemophilus spp. and S. pneumoniae are proposed based on the data from this study. The following MIC and/or disk diffusion quality control ranges are proposed: Staphylococcus aureus ATCC 29213, 0.03 to 0.25 microg/ml; S. aureus ATCC 25923, 20 to 25 mm; Escherichia coli ATCC 25922, 0.03 to 0.25 microg/ml and 20 to 27 mm; Pseudomonas aeruginosa ATCC 27853, 9 to 13 mm, Enterococcus faecalis ATCC 29212, 0.03 to 0.12 microg/ml; S. pneumoniae ATCC 49619, 0.015 to 0.12 microg/ml and 23 to 29 mm; Haemophilus influenzae ATCC 49247, 0.06 to 0.5 microg/ml and 23 to 31 mm; and Neisseria gonorrhoeae ATCC 49226, 30 to 40 mm.

PMID: 17494717 [PubMed - indexed for MEDLINE]

Relapsing Campylobacter coli bacteremia with reactive arthritis in a patient with X-linked agammaglobulinemia.

Intern Med. 2007;46(9):605-9

Authors: Arai A, Kitano A, Sawabe E, Kanegane H, Miyawaki T, Miura O

A patient genetically diagnosed with X-linked agammaglobulinemia repeatedly developed bacteremia due to Campylobacter coli (C. coli) for one year and seven months in spite of immunoglobulin replacement therapy. Throughout the clinical course, C. coli with identical genetic patterns was repeatedly isolated from both blood and stool cultures, thus indicating that the patient had latent intestinal infection. The bacteremia was always accompanied by reactive arthritis. Since the immunoglobulin level was extremely low with severe B cell deficiency, the reactive arthritis must have been induced in a humoral immunity-independent manner. Adding oral minocycline following intravenous meropenem was very effective; the stool cultures became negative and the patient has been well for more than one year without relapse of bacteremia.

PMID: 17473499 [PubMed - indexed for MEDLINE]

Minocycline-induced acute eosinophilic pneumonia: controversial results of lymphocyte stimulation test and re-challenge test.

Intern Med. 2007;46(9):593-5

Authors: Ono E, Miyazaki E, Matsuno O, Nureki S, Okubo T, Ando M, Kumamoto T

We report an instructive case of minocycline-induced eosinophilic pneumonia confirmed by re-challenge test, in which a preceding lymphocyte-stimulation test indicated acetaminophen as the etiologic agent. A 55-year-old woman developed high fever and lung infiltrates with pulmonary eosinophilia after exposure to minocycline, acetaminophen, theophylline and procaterol. All of the medicines were discontinued, resulting in prompt improvement. The lymphocyte stimulation tests provided a positive result for acetaminophen, but not for the other medicines; however, a negative result was given by a re-challenge test with acetaminophen. In contrast, symptoms and hypoxemia reappeared when minocycline was re-administered. We would like to emphasize that lymphocyte stimulation test results need to be carefully interpreted for individual drugs.

PMID: 17473496 [PubMed - indexed for MEDLINE]

Synergistic antimicrobial effect of cefotaxime and minocycline on proinflammatory cytokine levels in a murine model of Vibrio vulnificus infection.

J Microbiol Immunol Infect. 2007 Apr;40(2):123-33

Authors: Chiang SR, Tang HJ, Chang PC, Cheng KC, Ko WC, Chen CH, Chuang YC

BACKGROUND AND PURPOSE: Vibrio vulnificus causes primary bacteremia and necrotizing wound infection, leading to high morbidity and mortality in humans. This study aimed to evaluate the antimicrobial effect of cefotaxime and minocycline on proinflammatory cytokine levels in a murine model of V. vulnificus infection. METHODS: We investigated the dynamics of proinflammatory cytokines and their modulation by antimicrobial agents using a murine model of V. vulnificus infection. The change in cytokine levels was followed over a time course to identify the antimicrobial activity of the drugs against V. vulnificus. BALB/c female mice were challenged with an intraperitoneal infection using a clinical invasive isolate of Vv05191, and their cytokine levels were assayed over various time points. RESULTS: Serum levels of tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-6 post-infection were found to be inoculum dose-dependent and positively correlated to the subsequent fatality rate in the infected mice. With an inoculum of 6.6 x 10(6) colony-forming units and intraperitoneal administration of cefotaxime, minocycline, or both, the serum and peritoneal fluid cytokine levels increased and then declined gradually. Comparison of the 3 antimicrobial regimens revealed that the magnitude of reduction in cytokine levels was greatest in mice treated with cefotaxime-minocycline combination. Moreover, the peritoneal fluid cytokine level in the combination group was significantly lower than that in the groups treated with minocycline or cefotaxime alone. CONCLUSIONS: The current results support the superiority of the combination therapy in treating invasive V. vulnificus infections.

PMID: 17446960 [PubMed - indexed for MEDLINE]

Tigecycline Efflux as a Mechanism for Nonsusceptibility in Acinetobacter baumannii.

Antimicrob Agents Chemother. 2007 Jun;51(6):2065-9

Authors: Peleg AY, Adams J, Paterson DL

Tigecycline has an extended spectrum of in vitro antimicrobial activities, including that against multidrug-resistant Acinetobacter. After identifying bloodstream isolates of Acinetobacter with reduced susceptibilities to tigecycline, we performed a study to assess tigecycline efflux mediated by the resistance-nodulation-division-type transporter AdeABC. After exposure of two tigecycline-nonsusceptible isolates to the efflux pump inhibitor phenyl-arginine-beta-naphthylamide (PABN), a fourfold reduction in the tigecycline MIC was observed. Both tigecycline-susceptible and -nonsusceptible isolates were found to carry the gene coding for the transmembrane component of the AdeABC pump, adeB, and the two-component regulatory system comprising adeS and adeR. Previously unreported point mutations were identified in the regulatory system in tigecycline-nonsusceptible isolates. Real-time PCR identified 40-fold and 54-fold increases in adeB expression in the two tigecycline-nonsusceptible isolates compared to that in a tigecycline-susceptible isolate. In vitro exposure of a tigecycline-susceptible clinical strain to tigecycline caused a rapid rise in the MIC of tigecycline from 2 microg/ml to 24 microg/ml, which was reversible with PABN. A 25-fold increase in adeB expression was observed in a comparison between this tigecycline-susceptible isolate and its isogenic tigecycline-nonsusceptible mutant. These results indicate that an efflux-based mechanism plays a role in reduced tigecycline susceptibility in Acinetobacter.

PMID: 17420217 [PubMed - indexed for MEDLINE]

Therapy with minocycline aggravates experimental rabies in mice.

J Virol. 2007 Jun;81(12):6248-53

Authors: Jackson AC, Scott CA, Owen J, Weli SC, Rossiter JP

Minocycline is a tetracycline derivative with antiapoptotic and anti-inflammatory properties, and the drug has been shown to have beneficial effects in a variety of models of neurological disorders. The potentially neuroprotective role of minocycline was assessed in experimental in vitro and in vivo models of rabies virus infection. In this study, 5 nM minocycline did not improve the viability of embryonic mouse cortical and hippocampal neurons infected in vitro with the attenuated SAD-D29 strain of rabies virus, based on assessments using trypan blue exclusion. Two-day-old ICR mice were inoculated in the right hind limb thigh muscle with SAD-D29, and they received daily subcutaneous injections of either 50 mg/kg minocycline or vehicle (phosphate-buffered saline). Infected minocycline-treated mice experienced an earlier onset of neurologic signs and greater mortality (83% versus 50%) than those receiving vehicle (log rank test, P=0.002 and P=0.003, respectively). Immunohistochemical analysis of rabies virus antigen distribution was performed at early time points and in moribund mice. There were greater numbers of infected neurons in the regional brain areas of minocycline-treated mice than in vehicle-treated mice, which was significant in the CA1 region of the hippocampus. There was less apoptosis (P=0.01) and caspase 3 immunostaining (P=0.0008) in the midbrains of mice treated with minocycline than in mice treated with vehicle, consistent with a neuroprotective role of neuronal apoptosis that may have had a mild effect of inhibiting viral spread. Reduced infiltration of CD3+ T cells was observed in the pons/medulla of moribund mice that received minocycline therapy (P=0.008), suggesting that the anti-inflammatory actions of minocycline may intensify the neurologic disease. These findings indicate that minocycline has important detrimental effects in the therapy of experimental rabies. Empirical therapy with minocycline should therefore be approached with caution in cases of human rabies and possibly other viral encephalitides until more experimental data become available.

PMID: 17409147 [PubMed - indexed for MEDLINE]

Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid.

J Neurosci. 2007 Mar 21;27(12):3057-63

Authors: Fan R, Xu F, Previti ML, Davis J, Grande AM, Robinson JK, Van Nostrand WE

Cerebral microvascular amyloid beta protein (Abeta) deposition and associated neuroinflammation is increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease and related cerebral amyloid angiopathy disorders. Transgenic mice expressing the vasculotropic Dutch/Iowa (E693Q/D694N) mutant human Abeta precursor protein in brain (Tg-SwDI) accumulate abundant cerebral microvascular fibrillar amyloid deposits and exhibit robust neuroinflammation. In the present study, we investigated the effect of the anti-inflammatory drug minocycline on Abeta accumulation, neuroinflammation, and behavioral deficits in Tg-SwDI mice. Twelve-month-old mice were treated with saline or minocycline by intraperitoneal injection every other day for a total of 4 weeks. During the final week of treatment, the mice were tested for impaired learning and memory. Brains were then harvested for biochemical and immunohistochemical analysis. Minocycline treatment did not alter the cerebral deposition of Abeta or the restriction of fibrillar amyloid to the cerebral microvasculature. Similarly, minocycline-treated Tg-SwDI mice exhibited no change in the levels of total Abeta, the ratios of Abeta40 and Abeta42, or the amounts of soluble, insoluble, or oligomeric Abeta compared with the saline-treated control Tg-SwDI mice. In contrast, the numbers of activated microglia and levels of interleukin-6 were significantly reduced in minocycline-treated Tg-SwDI mice compared with saline-treated Tg-SwDI mice. In addition, there was a significant improvement in behavioral performance of the minocycline-treated Tg-SwDI mice. These finding suggest that anti-inflammatory treatment targeted for cerebral microvascular amyloid-induced microglial activation can improve cognitive deficits without altering the accumulation and distribution of Abeta.

PMID: 17376966 [PubMed - indexed for MEDLINE]

Reevaluation of Clinical and Laboratory Standards Institute disk diffusion breakpoints for tetracyclines for testing Enterobacteriaceae.

J Clin Microbiol. 2007 May;45(5):1640-3

Authors: Sader HS, Ferraro MJ, Reller LB, Schreckenberger PC, Swenson JM, Jones RN

We reevaluated Enterobacteriaceae disk diffusion breakpoints for the tetracyclines published in the Clinical and Laboratory Standards Institute (CLSI) document M100-S16, which were (susceptible/resistant) >or=19 mm/<or=14 mm for tetracycline, >or=16 mm/<or=12 mm for doxycycline, and >or=19 mm/<or=14 mm for minocycline. A collection of 504 recent clinical isolates of Enterobacteriaceae were tested against these tetracycline compounds by disk diffusion and broth microdilution methods according to CLSI guidelines. Regression line and scattergram plot analyses determined intermethod accuracy for current disk diffusion breakpoints and showed excellent r values of 0.91 to 0.95. However, error rates (minor/major [false-resistant]/very major [false-susceptible]) were 14.9/0.8/0.0% for tetracycline, 11.5/0.4/0.0% for doxycycline, and 30.6/0.7/0.0% for minocycline and only 4.4/0.0/0.0% for tetracycline, 5.6/0.0/0.2% for doxycycline, and 8.3/0.0/0.3% for minocycline when proposed breakpoints were modified to (susceptible/resistant) >or=15 mm/<or=11 mm for tetracycline, >or=14 mm/<or=10 mm for doxycycline, and >or=16 mm/<or=12 mm for minocycline. Listed modifications were recently approved by the CLSI (M100-S17).

PMID: 17360844 [PubMed - indexed for MEDLINE]

Comparative activities of daptomycin, linezolid, and tigecycline against catheter-related methicillin-resistant Staphylococcus bacteremic isolates embedded in biofilm.

Antimicrob Agents Chemother. 2007 May;51(5):1656-60

Authors: Raad I, Hanna H, Jiang Y, Dvorak T, Reitzel R, Chaiban G, Sherertz R, Hachem R

In the setting of catheter-related bloodstream infections, intraluminal antibiotic lock therapy could be useful for the salvage of vascular catheters. In this in vitro study, we investigated the efficacies of the newer antibiotics daptomycin, linezolid, and tigecycline, in comparison with those of vancomycin, minocycline, and rifampin, against methicillin-resistant Staphylococcus aureus (MRSA) embedded in biofilm. We also assessed the emergence of MRSA strains resistant to these antibiotics, alone or in combination with rifampin, after 4-hour daily use for catheter lock therapy. Minocycline, daptomycin, and tigecycline were more efficacious in inhibiting MRSA in biofilm than linezolid, vancomycin, and the negative control (P < 0.001) after the first day of exposure to these antibiotics, with minocycline being the most active, followed by daptomycin and then tigecycline, and with vancomycin and linezolid lacking activity, similar to the negative control. After 3 days of 4-hour daily exposures, daptomycin was the fastest in eradicating MRSA from biofilm, followed by minocycline and tigecycline, which were faster than linezolid, rifampin, and vancomycin (P < 0.001). When rifampin was used alone, it was the least effective in eradicating MRSA from biofilm after 5 days of 4-hour daily exposures, as it was associated with the emergence of rifampin-resistant MRSA. However, when rifampin was used in combination with other antibiotics, the combination was significantly effective in eliminating MRSA colonization in biofilm more rapidly than each of the antibiotics alone. In summary, daptomycin, minocycline, and tigecycline should be considered further for antibiotic lock therapy, and rifampin should be considered for enhanced antistaphylococcal activity but not as a single agent.

PMID: 17353249 [PubMed - indexed for MEDLINE]

Exposure-response analyses of tigecycline efficacy in patients with complicated skin and skin-structure infections.

Antimicrob Agents Chemother. 2007 Jun;51(6):1939-45

Authors: Meagher AK, Passarell JA, Cirincione BB, Van Wart SA, Liolios K, Babinchak T, Ellis-Grosse EJ, Ambrose PG

Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecycline in the treatment of complicated skin and skin-structure infections, where Staphylococcus aureus and streptococci are the predominant pathogens. A prospective method was developed to create homogeneous patient populations for PK-PD analyses. Evaluable patients from three clinical trials were pooled for analysis. Patients received a tigecycline 100-mg loading dose/50 mg every 12 h or a 50-mg loading dose/25 mg every 12 h. At the test-of-cure visit, microbiologic and clinical responses were evaluated. Patients were prospectively evaluated and classified into cohorts based on baseline pathogens: S. aureus only (cohort 1), monomicrobial S. aureus or streptococci (cohort 2), two gram-positive pathogens (cohort 3), polymicrobial (cohort 4), or other monomicrobial infections (cohort 5). A prospective procedure for combining cohorts was used to increase the sample size. Logistic regression evaluated steady-state 24-h area under the concentration-time curve (AUC(24))/MIC ratio as a predictor of response, and classification and regression tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with pooled cohorts 2 and 3, the focus of these analyses, and included 35 patients with 40 S. aureus and/or streptococcal pathogens. CART analyses identified a significant AUC/MIC breakpoint of 17.9 (P = 0.0001 for microbiological response and P = 0.0376 for clinical response). The continuous AUC/MIC ratio was predictive of microbiological response based on sample size (P = 0.0563). Analysis of all pathogens combined decreased the ability to detect exposure-response relationships. The prospective approach of creating homogeneous populations based on S. aureus and streptococci pathogens was critical for identifying exposure-response relationships.

PMID: 17353238 [PubMed - indexed for MEDLINE]

Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury.

J Neurosci. 2007 Feb 28;27(9):2357-68

Authors: Zhao P, Waxman SG, Hains BC

Many patients with traumatic spinal cord injury (SCI) report pain that persists indefinitely and is resistant to available therapeutic approaches. We recently showed that microglia become activated after experimental SCI and dynamically maintain hyperresponsiveness of spinal cord nociceptive neurons and pain-related behaviors. Mechanisms of signaling between microglia and neurons that help to maintain abnormal pain processing are unknown. In this study, adult male Sprague Dawley rats underwent T9 spinal cord contusion injury. Four weeks after injury when lumbar dorsal horn multireceptive neurons became hyperresponsive and when behavioral nociceptive thresholds to mechanical and thermal stimuli were decreased, we tested the hypothesis that prostaglandin E2 (PGE2) contributes to signaling between microglia and neurons. Immunohistochemical data showed specific localization of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream regulator of PGE2 release, to microglial cells and a neuronal localization of the PGE2 receptor E-prostanoid 2 (EP2). Enzyme immunoassay analysis showed that PGE2 release was dependent on microglial activation and ERK1/2 phosphorylation. Pharmacological antagonism of PGE2 release was achieved with the mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] and the microglial inhibitor minocycline. Cyclooxygenase-2 expression in microglia was similarly reduced by MEK1/2 inhibition. PD98059 and EP2 receptor blockade with AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) resulted in a decrease in hyperresponsiveness of dorsal horn neurons and partial restoration of behavioral nociceptive thresholds. Selective targeting of dorsal horn microglia with the Mac-1-SAP immunotoxin, a chemical conjugate of mouse monoclonal antibody to CD11b and the ribosome-inactivating protein saporin, resulted in reduced microglia staining, reduction in PGE2 levels, and reversed pain-related behaviors [corrected]. On the basis of these observations, we propose a PGE2-dependent, ERK1/2-regulated microglia-neuron signaling pathway that mediates the microglial component of pain maintenance after injury to the spinal cord.

PMID: 17329433 [PubMed - indexed for MEDLINE]

In vitro activities of various antimicrobials alone and in combination with tigecycline against carbapenem-intermediate or -resistant Acinetobacter baumannii.

Antimicrob Agents Chemother. 2007 May;51(5):1621-6

Authors: Scheetz MH, Qi C, Warren JR, Postelnick MJ, Zembower T, Obias A, Noskin GA

The activities of tigecycline alone and in combination with other antimicrobials are not well defined for carbapenem-intermediate or -resistant Acinetobacter baumannii (CIRA). Pharmacodynamic activity is even less well defined when clinically achievable serum concentrations are considered. Antimicrobial susceptibility testing of clinical CIRA isolates from 2001 to 2005 was performed by broth or agar dilution, as appropriate. Tigecycline concentrations were serially increased in time-kill studies with a representative of the most prevalent carbapenem-resistant clone (strain AA557; imipenem MIC, 64 mg/liter). The in vitro susceptibility of the strain was tested by time-kill studies in duplicate against the average free serum steady-state concentrations of tigecycline alone and in combination with various antimicrobials. Ninety-three CIRA isolates were tested and were found to have the following antimicrobial susceptibility profiles: tigecycline, MIC(50) of 1 mg/liter and MIC(90) of 2 mg/liter; minocycline, MIC(50) of 0.5 mg/liter and MIC(90) of 8 mg/liter; doxycycline, MIC(50) of 2 mg/liter and MIC(90) of > or =32 mg/liter; ampicillin-sulbactam, MIC(50) of 48 mg/liter and MIC(90) of 96 mg/liter; ciprofloxacin, MIC(50) of > or =16 mg/liter and MIC(90) of > or =16 mg/liter; rifampin, MIC(50) of 4 mg/liter and MIC(90) of 8 mg/liter; polymyxin B, MIC(50) of 1 mg/liter and MIC(90) of 1 mg/liter; amikacin, MIC(50) of 32 mg/liter and MIC(90) of > or =32 mg/liter; meropenem, MIC(50) of 16 mg/liter and MIC(90) of > or =128 mg/liter; and imipenem, MIC(50) of 4 mg/liter and MIC(90) of 64 mg/liter. Among the tetracyclines, the isolates were more susceptible to tigecycline than minocycline and doxycycline, according to FDA breakpoints (95%, 88%, and 71% of the isolates were susceptible to tigecycline, minocycline, and doxycycline, respectively). Concentration escalation studies with tigecycline revealed a maximal killing effect near the MIC, with no additional extent or rate of killing at concentrations 2x to 4x the MIC for tigecycline. Time-kill studies demonstrated indifference for tigecycline in combination with the antimicrobials tested. Polymyxin B, minocycline, and tigecycline are the most active antimicrobials in vitro against CIRA. Concentration escalation studies demonstrate that tigecycline may need to approach concentrations higher than those currently achieved in the bloodstream to adequately treat CIRA bloodstream infections. Future studies should evaluate these findings in vivo.

PMID: 17307973 [PubMed - indexed for MEDLINE]

Hyperpigmentation associated with minocycline therapy.

CMAJ. 2007 Jan 30;176(3):321-2

Authors: Chatterjee S

PMID: 17261828 [PubMed - indexed for MEDLINE]

In vitro activity of aurein 1.2 alone and in combination with antibiotics against gram-positive nosocomial cocci.

Antimicrob Agents Chemother. 2007 Apr;51(4):1494-6

Authors: Giacometti A, Cirioni O, Riva A, Kamysz W, Silvestri C, Nadolski P, Della Vittoria A, &#x141;ukasiak J, Scalise G

This study was performed to evaluate the in vitro activity of the amphibian peptide aurein 1.2 and to investigate its interaction with six antibiotics against nosocomial gram-positive cocci. All isolates were inhibited at concentrations of 1 to 16 mg/liter. Synergy was demonstrated when aurein 1.2 was combined with clarithromycin and minocycline.

PMID: 17220421 [PubMed - indexed for MEDLINE]

Combination of tigecycline and N-acetylcysteine reduces biofilm-embedded bacteria on vascular catheters.

Antimicrob Agents Chemother. 2007 Apr;51(4):1556-8

Authors: Aslam S, Trautner BW, Ramanathan V, Darouiche RO

To assess the efficacy of an antibiofilm/antimicrobial agent combination, we incubated catheter segments colonized with one of six studied bacterial organisms in N-acetylcysteine, tigecycline, N-acetylcysteine-tigecycline, or saline. Segments were washed, sonicated, and cultured. N-acetylcysteine-tigecycline significantly decreased all viable biofilm-associated bacteria and was synergistic for methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis.

PMID: 17220399 [PubMed - indexed for MEDLINE]

Clonal diversity and resistance mechanisms in tetracycline-nonsusceptible Streptococcus pneumoniae isolates in Poland.

Antimicrob Agents Chemother. 2007 Apr;51(4):1155-63

Authors: Izdebski R, Sadowy E, Fiett J, Grzesiowski P, Gniadkowski M, Hryniewicz W

The frequency of tetracycline resistance in Streptococcus pneumoniae isolates in Poland is one of the highest in Europe. The aim of this study was to analyze the clonal diversity and resistance determinants of tetracycline-nonsusceptible S. pneumoniae isolates identified in Poland and to investigate the effect of tetracycline resistance on their susceptibilities to tigecycline, doxycycline, and minocycline. We have analyzed 866 pneumococcal isolates collected from 1998 to 2003 from patients with respiratory tract diseases, and 242 of these (27.9%) were found to be resistant to tetracycline. All of the resistant isolates were characterized by testing of their susceptibilities to other antimicrobials, serotyping, pulsed-field gel electrophoresis (PFGE), and identification of tetracycline resistance genes and transposons. Selected isolates representing the main PFGE types were analyzed by multilocus sequence typing. Among the isolates investigated, 27 serotypes and 146 various PFGE patterns, grouped into 90 types, were discerned. The most common PFGE type, corresponding to serotype 19F and sequence type 423, was represented by 22.3% of all of the tetracycline-resistant isolates. The tet(M) gene was the sole resistance gene in the group of isolates studied, and in over 96% of the isolates, the Tn916 family of tet(M)-containing conjugative transposons was detected. Several isolates contained specific variants of the transposons, the Tn1545-like, Tn3872-like, or Tn2009-like element. The correlation between the MICs of tetracycline, doxycycline, and minocycline was revealed, whereas no cross-resistance to tetracycline and tigecycline was observed.

PMID: 17210772 [PubMed - indexed for MEDLINE]

In vitro activities of tigecycline and eight other antimicrobials against different Nocardia species identified by molecular methods.

Antimicrob Agents Chemother. 2007 Mar;51(3):1102-4

Authors: Cercenado E, Mar&#xED;n M, Sánchez-Martínez M, Cuevas O, Martínez-Alarcón J, Bouza E

The in vitro activities of tigecycline and other antimicrobials against 51 isolates of Nocardia spp. were evaluated. MIC(90)s and MIC ranges were as follows: tigecycline, 4 and < or =0.06 to 8 mg/liter, respectively; minocycline, 2 and < or =0.06 to 2 mg/liter, respectively; linezolid, 1 and < or =0.06 to 2 mg/liter, respectively; moxifloxacin, 2 and < or =0.06 to >64 mg/liter, respectively; ertapenem, 32 and < or =0.06->64 mg/liter, respectively; imipenem, 2 and < or =0.06 to >64 mg/liter, respectively; meropenem, 8 and < or =0.06 to >64 mg/liter, respectively; amikacin, 1 and < or =0.06 to 32 mg/liter, respectively; and trimethoprim-sulfamethoxazole, 1/19 and < or =0.5/9.5 to >2/38 mg/liter, respectively.

PMID: 17194827 [PubMed - indexed for MEDLINE]

Inhibition of caspase-1/interleukin-1beta signaling prevents degeneration of retinal capillaries in diabetes and galactosemia.

Diabetes. 2007 Jan;56(1):224-30

Authors: Vincent JA, Mohr S

The proinflammatory cytokine, interleukin (IL)-1beta, is known to induce vascular dysfunction and cell death. We investigated the role of IL-1beta and caspase-1 (the enzyme that produces it) in diabetes-induced degeneration of retinal capillaries. Caspase-1 activity is increased in retinas of diabetic and galactosemic mice and diabetic patients. First, we investigated the effect of agents known to inhibit caspase-1 (minocycline and tetracycline) on IL-1beta production and retinal capillary degeneration in diabetic and galactose-fed mice. Second, we examined the effect of genetic deletion of the IL-1beta receptor on diabetes-induced caspase activities and retinal capillary degeneration. Diabetic and galactose-fed mice were injected intraperitoneally with minocycline or tetracycline (5 mg/kg). At 2 months of diabetes, minocycline inhibited hyperglycemia-induced caspase-1 activity and IL-1beta production in the retina. Long-term administration of minocycline prevented retinal capillary degeneration in diabetic (6 months) and galactose-fed (13 months) mice. Tetracycline inhibited hyperglycemia-induced caspase-1 activity in vitro but not in vivo. Mice deficient in the IL-1beta receptor were protected from diabetes-induced caspase activation and retinal pathology at 7 months of diabetes. These results indicate that the caspase-1/IL-1beta signaling pathway plays an important role in diabetes-induced retinal pathology, and its inhibition might represent a new strategy to inhibit capillary degeneration in diabetic retinopathy.

PMID: 17192486 [PubMed - indexed for MEDLINE]

Characteristics of Streptococcus suis isolated from patients in Japan.

Jpn J Infect Dis. 2006 Dec;59(6):397-9

Authors: Chang B, Wada A, Ikebe T, Ohnishi M, Mita K, Endo M, Matsuo H, Asatuma Y, Kuramoto S, Sekiguchi H, Yamazaki M, Yoshikawa H, Watabe N, Yamada H, Kurita S, Imai Y, Watanabe H

Seven cases of Streptococcus suis infection in Japan during 1994 and 2006 were summarized. All cases had porcine exposure and five of them had hand skin injury during the exposure. Five cases presented symptoms of meningitis, three presented symptoms of sepsis, and one resulted in sudden death. All of the isolated S. suis belonged to Lancefield's group D and to serotype 2. They were susceptible to penicillin G, ampicillin, cefotaxime, and ciprofloxacin. However, six of them were resistant to both erythromycin and clindamycin, and four were also resistant to minocycline. Multilocus sequence typing of six isolates showed that they belonged to sequence type (ST) 1, and their pulsed-field gel electrophoresis (PFGE) patterns were similar. The remaining isolate was ST28 and its PFGE pattern was distinct from those of the others.

PMID: 17186962 [PubMed - indexed for MEDLINE]

Effect of synthetic matrix metalloproteinase inhibitors on lipopolysaccharide-induced blood-brain barrier opening in rodents: Differences in response based on strains and solvents.

Brain Res. 2007 Feb 16;1133(1):186-92

Authors: Rosenberg GA, Estrada EY, Mobashery S

Matrix metalloproteinase inhibitors (MMPIs) reduce blood-brain barrier (BBB) disruption and prevent cell death. Animal models of multiple sclerosis, cerebral ischemia and hemorrhage, and bacterial meningitis respond to treatment with MMPIs. We have used the intracerebral injection of lipopolysaccharide (LPS) in rat, which induces MMP production and results in a delayed opening of the BBB, to screen MMPIs to identify therapeutic agents. We hypothesized that the mouse would respond similarly to LPS and that the mouse/LPS model of BBB damage would be more useful for screening of MMPIs. Therefore, we adapted the rat LPS model to the mouse and compared the response to LPS and treatment with MMPIs. Wistar-Kyoto rats (WKY) and three strains of mice had stereotactic injections of LPS into the caudate. (14)C-sucrose was used to measure permeability of the BBB 24 h after injection. Initially, we tested three broad-spectrum MMPIs in the rat, BB-1101, BB-94, and BB-2293, and a MMP-2 selective inhibitor, IW449; both BB-1101 and BB-94 significantly suppressed LPS-induced BBB damage (p<0.05). In the 3 mouse strains, C57/BL6, C57/BL10, and C57/BL10HIIIR2, LPS significantly opened the BBB in C57/BL6, and it was the only strain that showed a reduction in BBB permeability with BB-94. Treatment with methylprednisolone and several broad-spectrum MMPIs, including BB-1101, was ineffective in the C57/BL6. There was a significant reduction in BBB permeability seen with 10% dimethyl sulfoxide (DMSO) alone, which was used to dissolve the selective MMP-2 and-9 inhibitor, SB-3CT. The tetracycline derivative, minocycline, reduced the BBB injury in mouse by blocking the production of MMP-9. Our results show variability in rats and mice to LPS and MMPIs, which most likely is based on genetic make-up. Understanding these differences may provide important clues that could guide selection of MMPIs in treatment of neurological diseases.

PMID: 17184743 [PubMed - indexed for MEDLINE]

Prurigo pigmentosa: an underdiagnosed disease?

Indian J Dermatol Venereol Leprol. 2006 Nov-Dec;72(6):405-9

Authors: Boer A, Asgari M

Prurigo pigmentosa is a distinctive inflammatory disease first described by the Japanese dermatologist Masaji Nagashima in 1971. It is typified by recurrent, pruritic erythematous macules, papules and papulovesicles that resolve leaving behind netlike pigmentation. The disease is rarely diagnosed outside Japan, because clinicians outside Japan are not well conversant with the criteria for its diagnosis. Only one patient from India has been published previously under the diagnosis of prurigo pigmentosa, a hint that the disease may be under-recognized in India. We present an account of our observations in patients diagnosed with prurigo pigmentosa who were of five different nationalities, namely, Japanese, German, Indonesian, Turkish and Iranian. With this article we seek to increase awareness for the condition among dermatologists in India and we provide criteria for its diagnosis, both clinically and histopathologically.

PMID: 17179613 [PubMed - indexed for MEDLINE]

Severe Japanese spotted fever successfully treated with fluoroquinolone.

Intern Med. 2006;45(22):1323-6

Authors: Seki M, Ikari N, Yamamoto S, Yamagata Y, Kosai K, Yanagihara K, Kakugawa T, Kurihara S, Izumikawa K, Miyazaki Y, Higashiyama Y, Hirakata Y, Tashiro T, Kohno S

A 77 years old woman who had a bite with eschar on her left arm, was admitted to emergency ward in our hospital, because of high fever, severe malaise, skin eruption, and consciousness disturbance beginning 5 days previously. She was diagnosed as Japanese spotted fever by seropositive of Rickettsia japonica (R. japonica) antibody, and successfully treated with fluoroquinolone, after minocycline hydrochloride had been proven ineffective. R. japonica-specific DNA was detected by PCR from the tick: Haemaphysalis hystricis larvae collected from a mountainous location in Fukuoka, Japan where the patient had been bitten.

PMID: 17170509 [PubMed - indexed for MEDLINE]

Antimicrobial susceptibility and synergy studies of Burkholderia cepacia complex isolated from patients with cystic fibrosis.

Antimicrob Agents Chemother. 2007 Mar;51(3):1085-8

Authors: Zhou J, Chen Y, Tabibi S, Alba L, Garber E, Saiman L

Susceptibility (18 antimicrobial agents including high-dose tobramycin) and checkerboard synergy (23 combinations) studies were performed for 2,621 strains of Burkholderia cepacia complex isolated from 1,257 cystic fibrosis patients. Minocycline, meropenem, and ceftazidime were the most active, inhibiting 38%, 26%, and 23% of strains, respectively. Synergy was rarely noted (range, 1% to 15% of strains per antibiotic combination).

PMID: 17158942 [PubMed - indexed for MEDLINE]

In vitro minocycline activity on superinfecting microorganisms isolated from chronic periodontitis patients.

Braz Oral Res. 2006 Jul-Sep;20(3):202-6

Authors: de Oliveira LF, Jorge AO, Dos Santos SS

Chronic periodontitis is the most common type of periodontitis and it is associated with various species of microorganisms. Enteric rods, Pseudomonas, Staphyloccocus and Candida have been retrieved from periodontal pockets of patients with chronic periodontitis and correlated to cases of superinfection. Local or systemic antibiotic therapy is indicated to reinforce the effects of the conventional mechanical therapy. Minocycline has been suggested as one of the most effective drugs against periodontal pathogens. The aim of this work was to evaluate the minimal inhibitory concentration (MIC) of minocycline on superinfecting microorganisms isolated from the periodontal pocket and the oral cavity of individuals with chronic periodontitis. Isolates of Enterobacteriaceae (n = 25), Staphylococcus spp. (n = 25), Pseudomonas aeruginosa (n = 9) and Candida spp. (n = 25) were included in the study. Minimal inhibitory concentrations (MIC) of minocycline were determined using the M&#xFC;eller-Hinton agar dilution method. Staphylococcus spp. isolates were the most sensitive to minocycline with a MIC of 8 microg/mL, followed by Enterobacteriaceae with a MIC of 16 microg/mL. The concentration of 16 microg/mL inhibited 96% of Candida spp. isolates. The MIC for 88.8% of the isolates of Pseudomonas aeruginosa was 128 microg/mL. A concentration of 1,000 microg/mL was not enough to inhibit 100% of the tested isolates.

PMID: 17119701 [PubMed - indexed for MEDLINE]

A requirement for microglial TLR4 in leukocyte recruitment into brain in response to lipopolysaccharide.

J Immunol. 2006 Dec 1;177(11):8103-10

Authors: Zhou H, Lapointe BM, Clark SR, Zbytnuik L, Kubes P

To study the mechanisms involved in leukocyte recruitment induced by local bacterial infection within the CNS, we used intravital microscopy to visualize the interaction between leukocytes and the microvasculature in the brain. First, we showed that intracerebroventricular injection of LPS could cause significant rolling and adhesion of leukocytes in the brain postcapillary venules of wild-type mice, while negligible recruitment was observed in TLR4-deficient C57BL/10ScCr mice and CD14 knockout mice, suggesting recruitment is mediated by TLR4/CD14-bearing cells. Moreover, we observed reduced but not complete inhibition of recruitment in MyD88 knockout mice, indicating both MyD88-dependent and -independent pathways are involved. The leukocyte recruitment responses in chimeric mice with TLR4-positive microglia and endothelium, but TLR4-negative leukocytes, were comparable to normal wild-type mice, suggesting either endothelium or microglia play a crucial role in the induction of leukocyte recruitment. LPS injection induced both microglial and endothelial activation in the CNS. Furthermore, minocycline, an effective inhibitor of microglial activation, completely blocked the rolling and adhesion of leukocytes in the brain and blocked TNF-alpha production in response to LPS in vivo. Minocycline did not affect activation of endothelium by LPS in vitro. TNFR p55/p75 double knockout mice also exhibited significant reductions in both rolling and adhesion in response to LPS, indicating TNF-alpha signaling is critical for the leukocyte recruitment. Our results identify a TLR4 detection system within the blood-brain barrier. The microglia play the role of sentinel cells detecting LPS thereby inducing endothelial activation and leading to efficient leukocyte recruitment to the CNS.

PMID: 17114485 [PubMed - indexed for MEDLINE]

[Bacterial resistance and a new antibiotic: tigecycline]

Rev Esp Quimioter. 2006 Sep;19(3):209-19

Authors: Gobernado M

PMID: 17099789 [PubMed - indexed for MEDLINE]

Nigrostriatal dopaminergic neurodegeneration in the weaver mouse is mediated via neuroinflammation and alleviated by minocycline administration.

J Neurosci. 2006 Nov 8;26(45):11644-51

Authors: Peng J, Xie L, Stevenson FF, Melov S, Di Monte DA, Andersen JK

The murine mutant weaver (gene symbol, wv) mouse, which carries a mutation in the gene encoding the G-protein inwardly rectifying potassium channel Girk2, exhibits a diverse range of defects as a result of postnatal cell death in several different brain neuron subtypes. Loss of dopaminergic nigrostriatal neurons in the weaver, unlike cerebellar granule neuronal loss, is via a noncaspase-mediated mechanism. Here, we present data demonstrating that degeneration of midbrain dopaminergic neurons in weaver is mediated via neuroinflammation. Furthermore, in vivo administration of the anti-inflammatory agent minocycline attenuates nigrostriatal dopaminergic neurodegeneration. This has novel implications for the use of the weaver mouse as a model for Parkinson's disease, which has been associated with increased neuroinflammation.

PMID: 17093086 [PubMed - indexed for MEDLINE]

Multicenter studies of tigecycline disk diffusion susceptibility results for Acinetobacter spp.

J Clin Microbiol. 2007 Jan;45(1):227-30

Authors: Jones RN, Ferraro MJ, Reller LB, Schreckenberger PC, Swenson JM, Sader HS

Acinetobacter sp. isolates having multidrug resistance (MDR) patterns have become common in many medical centers worldwide, limiting therapeutic options. A five-center study tested 103 contemporary clinical Acinetobacter spp., including MDR strains, by reference broth microdilution and disk diffusion (15-mug disk content) methods against tigecycline. Applying U.S. Food and Drug Administration tigecycline breakpoint criteria for Enterobacteriaceae (susceptibility at < or =2 microg/ml [< or =1 microg/ml by the European Committee on Antimicrobial Susceptibility Testing]; disk diffusion breakpoints at > or =19 mm and < or =14 mm) to Acinetobacter spp. led to an unacceptable error rate (23.3%). However, an adjustment of tigecycline disk diffusion breakpoints (susceptible/resistant) to > or =16/ < or =12 mm reduced intermethod errors to an acceptable level (only 9.7%, all minor).

PMID: 17093026 [PubMed - indexed for MEDLINE]

Solodyn (Minocycline HCl, USP) extended-release tablets.

Skinmed. 2006 Nov-Dec;5(6):291-2

Authors: Gupta AK, Gover MD, Abramovits W, Perlmutter A

PMID: 17085996 [PubMed - indexed for MEDLINE]

Optimal antimicrobial catheter lock solution, using different combinations of minocycline, EDTA, and 25-percent ethanol, rapidly eradicates organisms embedded in biofilm.

Antimicrob Agents Chemother. 2007 Jan;51(1):78-83

Authors: Raad I, Hanna H, Dvorak T, Chaiban G, Hachem R

Antimicrobial lock solutions may be needed to salvage indwelling catheters in patients requiring continuous intravenous therapy. We determined the activity of minocycline, EDTA, and 25% ethanol, alone or in combination, against methicillin-resistant Staphylococcus aureus and Candida parapsilosis catheter-related bloodstream infection strains in two established models of biofilm colonization. Biofilm-colonized catheter segments from a modified Robbins device and a silicone disk biofilm colonization model were exposed to these antimicrobial agents for 15 or 60 min, respectively. After exposure, segments were sonicated and cultured. To determine regrowth after incubation at 37 degrees C, following the brief exposure to the antimicrobial agents, an equal number of segments were washed, reincubated for 24 h, and then sonicated and cultured. The triple combination of minocycline-EDTA (M-EDTA) in 25% ethanol was the only antimicrobial lock solution that completely eradicated S. aureus and C. parapsilosis in biofilm of all segments tested in the two models, and it completely prevented regrowth. In addition, M-EDTA in 25% ethanol was significantly more effective in rapidly eradicating the growth or regrowth of methicillin-resistant S. aureus and C. parapsilosis biofilm colonization in the two models than the other solutions--minocycline, EDTA, M-EDTA, 25% ethanol, and EDTA in ethanol. We conclude that M-EDTA in 25% ethanol is highly effective at rapidly eradicating S. aureus and C. parapsilosis embedded in biofilm adhering to catheter segments.

PMID: 17074799 [PubMed - indexed for MEDLINE]

Antimicrobial susceptibility patterns and staphylococcal cassette chromosome mec types of, as well as Panton-Valentine leukocidin occurrence among, methicillin-resistant Staphylococcus aureus isolates from children and adults in middle Tennessee.

J Clin Microbiol. 2006 Dec;44(12):4436-40

Authors: Kilic A, Li H, Stratton CW, Tang YW

Antimicrobial susceptibility patterns, Panton-Valentine leukocidin (PVL) occurrence, and staphylococcal cassette chromosome mec (SCCmec) types in methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from children and adults at Vanderbilt University Medical Center during a 12-month period were evaluated. A total of 1,315 MRSA isolates were collected, of which 748 (36.7%) were recovered from children. Among all isolates, 448 (34.1%) were SCCmec-II, and 847 (64.4%) were SCCmec-IV. More SCCmec-IV isolates were recovered from children than SCCmec-II isolates (424 [50.1%] versus 50 [11.2%]; odds ration [OR]=7.98; P<0.000001). The PVL gene was detected in 93.6% of SCCmec-IV isolates, in contrast to 0.2% in SCCmec-II isolates. Within SCCmec-IV isolates, a statistically higher PVL occurrence was noticed in children (98.1%) than in adults (89.1%) (OR=6.34; P<0.000001). Overall, SCCmec-II strains showed greater resistance than SCCmec-IV strains to clindamycin, erythromycin, levofloxacin, gentamicin, rifampin, minocycline, and trimethoprim-sulfamethoxazole. Both SCCmec-II and SCCmec-IV strains recovered from adults were more resistant to these antibiotics than those recovered from children. SCCmec-II strains were predominantly recovered from the respiratory tract, whereas SCCmec-IV strains were predominantly recovered from skin, soft tissue, abscesses, and surgical wounds. These data indicate that SCCmec-IV MRSA isolates frequently infect children in middle Tennessee and are likely to harbor the PVL gene.

PMID: 17065272 [PubMed - indexed for MEDLINE]

Successful salvage therapy with tigecycline after linezolid failure in a liver transplant recipient with MRSA pneumonia.

Liver Transpl. 2006 Nov;12(11):1689-92

Authors: Saner FH, Heuer M, Rath PM, Gensicke J, Radtke A, Dr&#xFC;he N, Rüngeler EM, Nadalin S, Malagó M, Broelsch CE

Pulmonary infections are a significant cause of morbidity and mortality after liver transplantation. Infections with methicillin-resistant Staphylococcus aureus (MRSA) have increased in the last 10 years. Mortality may exceed 80% in liver transplant recipients who develop MRSA pneumonia. A 57-year-old male following living-donor liver transplantation developed a right-sided MRSA pneumonia 6 weeks after transplantation, which required artificial ventilation for 14 weeks. Initially, pneumonia was treated with linezolid. However, after 12 days under current therapy, the infection spread out to both lungs. At that time. we initiated the treatment with tigecycline. Under this therapy, the patient could be cured from MRSA pneumonia and was extubated. We detected no tigecycline related hepatotoxic effect. In conclusion, this case suggests that tigecycline may be useful in the salvage therapy of pneumonia due to MRSA after linezolid failure.

PMID: 17058251 [PubMed - indexed for MEDLINE]

Susceptibility of acinetobacter strains isolated from deployed U.S. military personnel.

Antimicrob Agents Chemother. 2007 Jan;51(1):376-8

Authors: Hawley JS, Murray CK, Griffith ME, McElmeel ML, Fulcher LC, Hospenthal DR, Jorgensen JH

The susceptibilities of 142 Acinetobacter baumannii-calcoaceticus complex isolates (95 from wounded U.S. soldiers deployed overseas) to 13 antimicrobial agents were determined by broth microdilution. The most active antimicrobial agents (> or =95% of isolates susceptible) were colistin, polymyxin B, and minocycline.

PMID: 17043112 [PubMed - indexed for MEDLINE]

Activity of tigecycline against ESBL-producing and AmpC-hyperproducing Enterobacteriaceae from south-east England.

J Antimicrob Chemother. 2006 Dec;58(6):1312-4

Authors: Hope R, Warner M, Potz NA, Fagan EJ, James D, Livermore DM

PMID: 17035342 [PubMed - indexed for MEDLINE]

Tigecycline does not induce proliferation or cytotoxin production by epidemic Clostridium difficile strains in a human gut model.

J Antimicrob Chemother. 2006 Nov;58(5):1062-5

Authors: Baines SD, Saxton K, Freeman J, Wilcox MH

OBJECTIVES: Data on the risk of Clostridium difficile infection (CDI) associated with specific antibiotics are difficult to obtain because of confounding clinical factors. It is particularly important to evaluate the propensity of new antibiotics to induce CDI. We have examined the propensity of tigecycline to induce CDI using a human gut model. METHODS: We used a three-stage chemostat human gut model to study the effects of tigecycline on indigenous gut microflora and C. difficile. Two epidemic C. difficile were studied in separate experiments: PCR ribotype 001 (UK, CD001) and PCR ribotype 027 (North America, CD027). Tigecycline MICs for 39 C. difficile representing 19 distinct PCR ribotypes were also determined. RESULTS: Tigecycline MICs were 0.06 mg/L for all the C. difficile strains. Peak tigecycline concentrations in the gut model were 10.9 and 11.7 mg/L in CD027 and CD001 experiments, respectively. Tigecycline instillation invoked marked decreases in numbers of bacteroides and bifidobacteria (10(7)-10(8) cfu/mL) and lesser reductions in facultative anaerobes. Despite markedly altered gut microflora, CD001 and CD027 remained as spores for the duration of the experiment, with no evidence of proliferation or cytotoxin production. CONCLUSIONS: Tigecycline exposure did not induce C. difficile proliferation or cytotoxin production despite reduced competing microflora. The potency of tigecycline against C. difficile may contribute to the low risk of CDI induction. Factors other than gut microflora colonization resistance may be important in preventing C. difficile spore germination, proliferation and cytotoxin production.

PMID: 17030519 [PubMed - indexed for MEDLINE]

Occurrence of carbapenem-resistant Acinetobacter baumannii clones at multiple hospitals in London and Southeast England.

J Clin Microbiol. 2006 Oct;44(10):3623-7

Authors: Coelho JM, Turton JF, Kaufmann ME, Glover J, Woodford N, Warner M, Palepou MF, Pike R, Pitt TL, Patel BC, Livermore DM

From late 2003 to the end of 2005, the Health Protection Agency's national reference laboratories received approximately 1,600 referrals of Acinetobacter spp., including 419 and 58 examples, respectively, of two carbapenem-resistant Acinetobacter baumannii lineages, designated OXA-23 clones 1 and 2. Representatives of these clones were obtained from 40 and 8 hospitals, respectively, in London or elsewhere in Southeast England. Both clones had blaOXA-23-like genes, as well as the intrinsic (but downregulated) blaOXA-51-like carbapenemase genes typical of A. baumannii. Both were highly multiresistant: only colistin and tigecycline remained active versus OXA-23 clone 1 isolates; OXA-23 clone 2 isolates were also susceptible to amikacin and minocycline. These lineages increase the burden created by the southeast (SE) clone, a previously reported A. baumannii lineage with variable carbapenem resistance contingent on upregulation of the blaOXA-51-like gene. Known since 2000, the SE clone had been referred from over 40 hospitals by the end of 2005, with 627 representatives received by the reference laboratories. The OXA-23 clone 2 is now in decline, but OXA-23 clone 1 continues to be referred from new sites, as does the SE clone. Their spread is forcing the use of unorthodox therapies, principally colistin and tigecycline, although the optimal regimens remain uncertain.

PMID: 17021090 [PubMed - indexed for MEDLINE]