Charles A. Bradley

Treatment of Plague with Gentamicin or Doxycycline in a Randomized Clinical Trial in Tanzania

BACKGROUND Over the past 50 years, antibiotics of choice for treatment of plague, including streptomycin, chloramphenicol, and tetracycline, have mostly become outdated or unavailable. To test gentamicin in the treatment of naturally occurring plague and the implications of its use in the treatment of bioterrorist plague, a randomized, comparative, open-label, clinical trial comparing monotherapy with gentamicin or doxycycline was conducted in Tanzania. METHODS Sixty-five adults and children with symptoms of bubonic, septicemic, or pneumonic plague of < or =3 days duration were enrolled in the study. Bubo aspirates and blood were cultured for Yersinia pestis. Acute-phase and convalescent-phase serum samples were tested for antibody against fraction 1 antigen of Y. pestis. Thirty-five patients were randomized to receive gentamicin (2.5 mg/kg intramuscularly every 12 h for 7 days), and 30 patients were randomized to receive doxycycline (100 mg [adults] and 2.2 mg/kg [children] orally every 12 h for 7 days). Serum creatinine concentrations were measured before and after treatment, and peak and trough concentrations of antibiotics were measured. RESULTS Three patients, 2 of whom were treated with gentamicin and 1 of whom was treated with doxycycline, died on the first or second day of treatment, and these deaths were attributed to advanced disease and complications including pneumonia, septicemia, hemorrhage, and renal failure at the start of therapy. All other patients experienced cure or an improved condition after receiving therapy, resulting in favorable response rates of 94% for gentamicin (95% CI, 81.1%-99.0%) and 97% for doxycycline (95% CI, 83.4%-99.8%). Y. pestis isolates obtained from 30 patients belonged to biotype antigua and were susceptible to gentamicin and doxycycline, which had MICs of 0.13 mg/L and 0.25-0.5 mg/L, respectively. Serum concentrations of antibiotics were within therapeutic ranges, and adverse events were infrequent. Patients treated with gentamicin demonstrated a modest increase in the mean serum creatinine concentration after treatment (P<.05, by paired t test). CONCLUSIONS Both gentamicin and doxycycline were effective therapies for adult and pediatric plague, with high rates of favorable responses and low rates of adverse events.

Identification and Activity of Cytosol Creatine Phosphokinase Enzymes in Normal and Diseased Skin

Phosphocreatine molecules (PCR) in skin regenerate adenosine triphosphate and help cutaneous tissue survive ischemia associated with skin flaps, grafts, and hair transplantation procedures. In addition, PCR concentration in psoriasis is elevated many times above normal, indicating either overproduction of PCR by mitochondrial creatine phosphokinase (CPK) enzymes or a defect in cytosol CPK enzymatic activity. Skin CPK isoenzymes, before this study, have not been identified. Herein, for the first time, cytosol CPK enzymatic activity was measured in normal and psoriatic, involved and un-involved skin, skin tumors, and mouse skin and keratinocyte cell cultures. Creatine phosphokinase MM is the major isoenzyme in normal, un-involved psoriatic and mouse skin. Total CPK enzymatic activity was increased in psoriasis and skin tumors. These data clearly indicate that increased PCR concentration in a psoriatic skin is not a result of decreased cytosol CPK enzymatic activity.

Acute Alcohol Intoxication

Patient 2 An intoxicated 50-year-old female was brought to the emergency center by emergency medical service (EMS) personnel. She stated that her husband was not allowing her to drink alcohol so she drank “a lot of mouthwash.” She stated that she could not get alcohol any other way and she just wanted a drink. She denied drinking alcohol as a suicide attempt. The patient had a 1-year history of alcohol abuse. She denied treatment and/or rehabilitation for alcohol abuse.

Alpha-1-antitrypsin: New perspectives and clinical applications

Abstract AAT is a 394-residue single chain glycoprotein and functions as the major protease inhibitor of the human body. In this capacity, it prevents neutrophil elastase and other proteolytic enzymes released during inflammatory reactions and during phagocyte death from destroying normal tissues of the body. An inherited, autosomal recessive disorder of AAT is an important cause of emphysema and childhood cirrhosis in individuals of northern European descent. These disorders have been discovered to result from mutations in the AAT gene, located at q31–32.3 on chromosome 14. More than 75 AAT alleles have been identified, some of which are associated with reduced or absent antiprotease activity. Recently, ATT has served as a model for the treatment of human autosomal recessive disorders. This is presently done through the infusion of purified plasma or recombinant AAT. However, in the near future normal human cells may be genetically engineered to produce and secrete the missing molecule.