tetracycline and Neutropenia

Topics: Agranulocytosis; Bacterial Infections; Carbenicillin; Cross Infection; Gentamicins; Humans; Immunity, Cellular; Leukocyte Count; Mycoses; Neutropenia; Patient Isolators; Phagocytosis; Phosphatidylethanolamines; Tetracycline

This and the accompanying report (DOI: 10.1021/jm201467r ) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP-434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference , Boston, MA , September 12-15, 2010 , poster F1 - 2157 ), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).

Topics: Animals; Anti-Bacterial Agents; Cyclophosphamide; Drug Resistance, Multiple, Bacterial; Escherichia coli Infections; Gram-Negative Bacteria; Gram-Positive Bacteria; Male; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Neutropenia; Pyrrolidines; Rats; Rats, Sprague-Dawley; Ribosomes; Sepsis; Stereoisomerism; Structure-Activity Relationship; Tetracycline Resistance; Tetracyclines

Utilizing a fully synthetic route to tetracycline analogues, the C-9 side-chain of the fluorocyclines was optimized for both antibacterial activity and oral efficacy. Compounds were identified that overcome both efflux (tet(K), tet(A)) and ribosomal protection (tet(M)) tetracycline-resistance mechanisms and are active against Gram-positive and Gram-negative organisms. A murine systemic infection model was used as an oral efficacy screen to rapidly identify compounds with oral bioavailability. Two compounds were identified that exhibit both oral bioavailability in rat and clinically relevant bacterial susceptibility profiles against major respiratory pathogens. One compound demonstrated oral efficacy in rodent lung infection models that was comparable to marketed antibacterial agents.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Biological Availability; Cyclophosphamide; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Lung; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Neutropenia; Rats; Rats, Sprague-Dawley; Respiratory Tract Infections; Ribosomes; Sepsis; Stereoisomerism; Structure-Activity Relationship; Tetracycline Resistance; Tetracyclines

A noninvasive, real-time detection technology was validated for qualitative and quantitative antimicrobial treatment applications. The lux gene cluster of Photorhabdus luminescens was introduced into an Escherichia coli clinical isolate, EC14, on a multicopy plasmid. This bioluminescent reporter bacterium was used to study antimicrobial effects in vitro and in vivo, using the neutropenic-mouse thigh model of infection. Bioluminescence was monitored and measured in vitro and in vivo with an intensified charge-coupled device (ICCD) camera system, and these results were compared to viable-cell determinations made using conventional plate counting methods. Statistical analysis demonstrated that in the presence or absence of antimicrobial agents (ceftazidime, tetracycline, or ciprofloxacin), a strong correlation existed between bioluminescence levels and viable cell counts in vitro and in vivo. Evaluation of antimicrobial agents in vivo could be reliably performed with either method, as each was a sound indicator of therapeutic success. Dose-dependent responses could also be detected in the neutropenic-mouse thigh model by using either bioluminescence or viable-cell counts as a marker. In addition, the ICCD technology was examined for the benefits of repeatedly monitoring the same animal during treatment studies. The ability to repeatedly measure the same animals reduced variability within the treatment experiments and allowed equal or greater confidence in determining treatment efficacy. This technology could reduce the number of animals used during such studies and has applications for the evaluation of test compounds during drug discovery.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Ceftazidime; Cell Count; Cephalosporins; Ciprofloxacin; Diagnostic Imaging; DNA, Bacterial; Escherichia coli; Escherichia coli Infections; Luminescent Measurements; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Muscular Diseases; Neutropenia; Tetracycline

Topics: Antitubercular Agents; Bone Marrow; Chloramphenicol; Drug Hypersensitivity; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Hematopoiesis; Humans; Neutropenia; Nitrofurantoin; Pancytopenia; Penicillins; Phenylbutazone; Phenytoin; Red-Cell Aplasia, Pure; Tetracycline; Thrombocytopenia

Topics: Agranulocytosis; Amidines; Bone Marrow Examination; Dysgammaglobulinemia; Eosinophilia; gamma-Globulins; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologic Deficiency Syndromes; Immunotherapy; Infant; Leukocyte Count; Lymphocyte Activation; Male; Neutropenia; Pedigree; Pharynx; Phenyl Ethers; Pneumonia, Pneumocystis; Streptococcus; Tetracycline

Topics: Agranulocytosis; Ecchymosis; Gingivitis; Gingivitis, Necrotizing Ulcerative; Humans; Isoniazid; Lymphadenitis; Neutropenia; Periodicity; Periodontal Diseases; Prednisone; Splenectomy; Splenomegaly; Tetracycline