Individualizing amikacin regimens: accurate method to achieve therapeutic concentrations.

Amikacin's pharmacokinetics and dosage requirements were studied in 98 patients receiving treatment for gram-negative infections. A wide interpatient variation in the kinetic parameters of the drug occurred in all patients and in patients who had normal serum creatinine levels or normal creatinine clearance. The half-life ranged from 0.7 to 14.4 h in 74 patients who had normal serum creatinine levels and from 0.7 to 7.2 h in 37 patients who had normal creatinine clearance. The necessary daily dose to obtain therapeutic serum concentrations ranged from 1.25 to 57 mg/kg in patients with normal serum creatinine levels and from 10 to 57 mg/kg in patients with normal creatinine clearance. In four patients (4%), a significant change in baseline serum creatinine level (greater than 0.5 mg/dl) occurred during or after treatment, which may have been amikacin-associated toxicity. Overt ototoxicity occurred in one patient. The method of individualizing dosage regimens provided a clinically useful means of rapidly attaining therapeutic peak and trough serum concentrations.

Amikacin pharmacokinetics: wide interpatient variation in 98 patients.

The disposition of amikacin was studied in 98 patients receiving treatment for severe gram-negative sepsis. Several factors were identified which were significantly related to the drug's elimination rate. These included renal function (r = .67), age (r = -.55), distribution volume (r = .34), and weight (r = -.31). These variables explain 62% of the variance (R2) in elimination rate constant when combined in a multiple regression model. The drug's half-life demonstrated considerable interpatient variation in patients with a normal serum creatinine (.68-14.4 hrs) or with a normal creatinine clearance (.68-7.2 hrs). The drug's distribution volume ranged from .08 to .48 L/Kg. The drug's clearance varied from 6.5 to 200 mL/hr/kg for patients with a normal serum creatinine and 17.8 to 200 mL/hr/kg for patients with a normal creatinine clearance. The interpatient variation in the drug's kinetic parameters is a concerning clinical problem. Measuring serum amikacin concentrations and adjusting dosage regimens are necessary to achieve desired peak and trough serum concentrations.

Initial dosage regimens of gentamicin in patients with burns.

For 95 patients with burns the gentamicin dosage regimen necessary to achieve optimal serum concentrations was determined. Individual elimination rates and distribution volumes for gentamicin were determined and correlated with renal function parameters and age. In patients with burns who had normal serum creatinine levels (less than 1.5 mg/dl), gentamicin clearance and thus dosage regimens can be stratified by age. Gentamicin's clearance decreased inversely with age. Initial dosage guidelines were calculated for different age groups of patients with normal levels of serum creatinine. The guidelines were developed to assist the clinician in attaining therapeutic concentrations with initial doses of gentamicin. Therapeutic serum concentrations were reached in most patients with burns dosed by these guidelines. Serum gentamicin concentrations should always be monitored during therapy, and dosages should be adjusted to ensure optimal concentrations during the course of therapy.

Blunt trauma in adults and children: a comparative analysis.

Trauma remains the major cause of death in children and young adults. Adult and pediatric patients differ significantly in both mechanism of and physiologic response to injury. We reviewed the records of all consecutive adult and pediatric blunt trauma patients admitted to a major metropolitan trauma center for a 10-year period. An extensive computerized database has been maintained for all patients since 1977. A comparative statistical analysis of mechanism of injury, specific organ injury, and clinical outcome was performed. Altogether, 1,722 adults and 289 children were treated during the study period. Blunt trauma accounted for 82.8% of adult and 94.3% of pediatric injury (p = 0.00005), and only these patients were considered for analysis. Diagnostic peritoneal lavage was performed in 249 children and 1,464 adults, with a respective accuracy of 99.6% and 97.2%. Mechanism of injury was comparable for both groups, although children were far more likely to be injured by falls, bicycle accidents, or struck by an automobile. Comparative analysis of specific injuries demonstrated significantly fewer pediatric chest (p = 0.001), spine (p = 0.03), and pelvic (p = 0.003) injuries. Central nervous system (CNS) injury in children was a strong determinant of outcome: serious pediatric CNS trauma was associated with a tenfold increase in mortality. Mortality for children in the absence of CNS injury was less than 3%. Spinal injury also appeared to be a predictor of poor outcome in the pediatric population, with an associated mortality of greater than 50%. Overall, survival was age independent (82.5% of adults and 85.8% of children were survivors.(ABSTRACT TRUNCATED AT 250 WORDS)

Thermal injury effects on drug disposition: a prospective study with piperacillin.

The disposition of piperacillin was prospectively evaluated in nine severely burned patients who had normal renal and hepatic function. Wide interpatient variations were demonstrated in the drug's distribution volume, half-life, and clearance, with mean (+/- SD) values of 55.0 (+/- 44.2) liters, 3.6 (+/- 5.2) hours, and 14.9 (+/- 6.3) liters/hour, respectively. Piperacillin clearance was best explained by patient factors other than age, renal function, and the percentage of body surface area burns. Piperacillin disposition was related to the patients' serum albumin, total bilirubin, blood urea nitrogen, and the amount of urea nitrogen excreted daily in urine. Altered piperacillin disposition thus appeared to occur secondary to changes in the patients' physiologic and metabolic state caused by injury-related stress and fluid therapy. The patient's physiologic and metabolic response to injury, along with age and renal function, should be considered when instituting treatment with piperacillin or other agents cleared from the body in a similar manner.

Effects of treatment and the metabolic response to injury on drug clearance: a prospective study with piperacillin.

The disposition of piperacillin was prospectively evaluated in 11 critically ill surgical patients who had no evidence of pre-existing renal and hepatic disease. Interpatient variations were demonstrated in the drug's half-life, distribution volume, and clearance, with values of 1.50 +/- 2.05 (SD) h, 25.0 +/- 17.2 L, and 23.8 +/- 17.2 L/h, respectively. Variations in piperacillin disposition were best explained by serum concentrations of albumin, total protein, and bilirubin, and the amount of urea nitrogen excreted daily in urine. Age and renal function were moderately associated with piperacillin elimination rate and clearance. Altered piperacillin disposition thus appeared to occur as secondary to changes in the patients' physiologic and metabolic state caused by injury-related stress and fluid/colloid therapy. These alterations may necessitate dosage modifications to achieve optimal patient response when treating patients with piperacillin as well as with other similar drugs eliminated via renal and nonrenal routes.

An unusual cause of massive non-surgical pneumoperitoneum: case report.

A case of pneumoperitoneum due to cocaine abuse is presented. Although most commonly associated with surgical disease, pneumoperitoneum may actually be a manifestation of non-surgical intrathoracic pathology. In this patient percutaneous diagnostic peritoneal lavage resulted in return of a large quantity of air and was negative for bleeding or contamination.

Laser Doppler flowmetry and cardiac output in critically ill surgical patients.

Laser Doppler flowmetry (LDF) accurately measures cutaneous microcirculatory blood flow. We compared change in LDF flow to change in thermodilution cardiac output in ten critically ill surgical patients. A subset analysis of three patients with low cardiac output (cardiac index less than 2 L/min X m2) showed no correlation. We conclude that, under these study conditions, LDF microcirculatory flow did not reflect macrocirculatory flow. We conjecture that overcoming cutaneous vasoregulation with thermal vasodilation may obviate these results.

Comparison of radioimmunoassay and fluorescent polarization immunoassay for quantitative determination of vancomycin concentrations in serum.

A new fluorescent polarization immunoassay (Abbott Laboratories, Diagnostics Division, North Chicago, Ill.) was compared with a standard radioimmunoassay (American Diagnostics Corp., Newport Beach, Calif.) in 34 patients being treated with vancomycin. A total of 123 serum samples were divided and quantitatively analyzed for vancomycin by both assay methods. The results obtained indicated that the two assay methods are comparable (y = 1.01x - 0.81; r = 0.99).

Blunt injury to the colon and rectum.

One hundred nine patients suffering blunt injury to the colon or rectum were treated between 1 January 1970 and 31 December 1980. Vehicular accidents accounted for 90% of the injuries and 91% of the fatalities. Multiple system injury predominated, with survivors averaging 1.9 and nonsurvivors 3.8 injuries/patient. Six cases were complicated by abdominal sepsis directly related to their colon injury. There were no deaths and no episodes of colon-related abdominal sepsis among patients with isolated colon trauma. Of the 32 patients not surviving, four (3.7%), died as a direct result of their colon injury. Three of the four deaths appear to have been preventable.

Clinical use of a one-compartment model for determining netilmicin pharmacokinetic parameters and dosage recommendations.

To determine netilmicin pharmacokinetic parameters and to evaluate the use of a one-compartment pharmacokinetic model, 32 patients receiving netilmicin for suspected gram-negative sepsis were enrolled in our study protocol. Dose and dosage interval for each patient were determined by one-compartment pharmacokinetic analysis of six postinfusion netilmicin serum samples (0.16, 0.33, 0.5, 1, 2, and 3 h) measured by radioimmunoassay. In patients with a normal serum creatinine, mean (+/- SD) half-life and distribution volume were 1.9 +/- 1.1 h and 0.2 +/- 0.8 L/kg, respectively. The average daily dose and mean days of therapy were 5.1 +/- 1.9 mg/kg/day for 7.3 +/- 2.8 days. Serum creatinine changes of greater than 0.5 mg% occurred in 2 of 28 (7%) patients. Substantial variability in half-life and distribution volume occurred in patients. Initial dosages of 5-7 mg/kg/day in divided dosages seem appropriate for adult patients with normal renal function. Monitoring of serum levels and adjustment of dose and dosage interval are necessary to maintain therapeutic antibiotic concentrations. As with other aminoglycosides, the one-compartment pharmacokinetic model proved to be an acceptable method for measuring netilmicin pharmacokinetic parameters and individualizing therapy.

Wide interpatient variations in gentamicin dose requirements for geriatric patients.

Substantial interpatient variations were demonstrated in the daily doses required to obtain therapeutic gentamicin sulfate serum concentrations in 417 elderly patients. Dosages ranged from 0.3 to 22.0 mg/kg/day in patients with a normal serum creatinine level. Twenty-five percent of these patients required daily doses higher than the standard regimen of 5 mg/kg/day, and 33% required less than 3 mg/kg/day. The drug half-lives in these patients ranged from 0.3 to 32.7 hours, compared with previous reports of 2.5 to four hours. The distribution volumes of these patients ranged from 0.07 to 0.53 L/kg, compared with reported values of 0.20 to 0.25 L/kg. These wide variations in kinetic variables in elderly patients and the need to obtain narrow ranges in serum concentrations required measuring serum concentrations and individually calculating each patient's dosage requirement early in the treatment course. Doing this consistently produced optimal peak and trough serum levels. Ototoxicity did not occur in any of the patients, and nephrotoxicity may have been drug related in 2% of the elderly patients.

Gentamicin pharmacokinetics in 1,640 patients: method for control of serum concentrations.

The pharmacokinetics and dosage requirements of gentamicin were studied in 1,640 patients receiving treatment for gram-negative infections. A wide interpatient variation in the kinetic parameters of the drug occurred in all patients and in patients who had normal serum creatinine or normal creatinine clearance. The half-life ranged from 0.4 to 32.7 h in 331 patients who had normal creatinine clearance. The factors related to the elimination rate constant were creatinine clearance, age, distribution volume, weight, gender, and hematocrit. The daily dose necessary to obtain therapeutic serum concentrations ranged from 0.5 to 25.8 mg/kg in patients with normal serum creatinine and from 0.7 to 25.8 mg/kg in patients with normal creatinine clearance. In 13 patients (0.9%), a significant change in base-line serum creatinine (greater than or equal to 0.5 mg/dl) occurred during or after treatment, which may have been gentamicin-associated toxicity. Overt cochlear or vestibular toxicity did not occur in these patients. The method of individualizing dosage regimens provided a clinically useful means of rapidly attaining therapeutic peak and trough serum concentrations.

Increased burn patient survival with individualized dosages of gentamicin.

The clinical effect of measuring serum gentamicin concentrations and individualizing each patient's dosage regimen was determined 105 burn patients with severe gram-negative sepsis. Thirty-nine patients (conventionally dosed group) received the recommended dosage regimen of 3 to 5 mg/kg/day from 1972 to 1974. From 1974 to 1976, serum concentrations were measured in 66 patients (individually dosed group), and each patient's dose was individually calculated to obtain therapeutic serum concentrations. All patients had normal renal function prior to initiation of gentamicin therapy. For each group, 16 independent variables were compared that may have influenced treatment response. The patients in the individually dosed group required an average dose of 7.4 mg/kg/day to achieve therapeutic concentrations, compared to the average dose of 4.4 mg/kg/day for the patients receiving conventional doses (P less than 0.001). An abrupt increase in patient survival occurred with the implementation of individualized regimens. Patient survival rates for the entire hospital course were 33% and 64% for the conventionally dosed and individually dosed groups, respectively (P less than 0.005). Survival rates for the first septic episode were 51.3% and 86.4%, respectively (P less than 0.001). Individualized gentamicin regimens, age, percent burn, and sex were the statistically significant variables related to patient survival for the first episode of sepsis. Age, percent burn, individualized dosing, complications during hospitalization, and a positive blood culture were significant factors related to patient survival for the entire hospital course. These data confirm the need for measuring serum gentamicin concentrations and adjusting dosages to ensure therapeutic levels and maximal efficacy of gentamicin in burn patients.

Increased gentamicin dosage requirements: rapid elimination in 249 gynecology patients.

Wide interpatient variations were demonstrated in gentamicin elimination rate and dosage requirements for 249 gynecology patients with normal renal function. These variations combined with the need to obtain narrow ranges in serum levels necessitated measuring serum concentrations and individually calculating each patient's dose and dosing interval. Optimal peak and trough serum concentrations were reliably and rapidly achieved by means of this method. Required dosage regimens ranged from 1.9 to 14.0 mg/kg/day. Ototoxicity and nephrotoxicity did not occur in these patients. These results further emphasize the need to measure serum concentrations and make necessary dosage adjustments to ensure therapeutic levels. However, because of the wide interpatient variation, these increased dosages are not routinely suggested without previously measuring serum concentrations and calculating each patient's dosage regimen.

Rapid gentamicin elimination in obstetric patients.

Wide interpatient variation in gentamicin elimination rates and dosage requirements was demonstrated in 67 obstetric patients with normal serum creatinine levels. A poor correlation occurred between the elimination rate of gentamicin and creatinine clearance (r = .23). A higher correlation was found between the drug's elimination rate and distribution volume (r = -.62), which suggests that the changing fluid status associated with pregnancy affects the kinetic parameters of gentamicin. Gentamicin dosage regimens were systematically calculated for each patient from serum concentration-time data to obtain desired serum levels. These individualized regimens demonstrated considerable variability, ranging from 3.0 to 11.6 mg/kg/day. Clinical ototoxicity and nephrotoxicity were not observed. Because of the wide interpatient variation, these increased dosages are not routinely suggested unless serum concentrations are previously measured and each patient's regimen is calculated. These results emphasize the need to measure serum concentrations and make necessary dosage adjustments to ensure therapeutic levels in obstetric patients.

Systematically individualizing tobramycin dosage regimens.

Tobramycin dosage regimens were individually calculated from serum concentration-time data in 64 patients. Tobramycin pharmacokinetic parameters and dosage requirements demonstrated wide interpatient variation. The tobramycin half-life varied from 0.5 to 8.6 hours in patients with normal serum creatinines. The mean (+/- S.D.) distribution volume was 0.22 (+/- 0.09) liter/kg for all patients. Dosage requirements were higher for the younger patients, however, considerable variability existed within age groups. In patients with normal serum creatinines, an 8-hour dosing interval was optimal in only 17 of the 46 patients. A multiple regression model using age, weight, and creatinine clearance could explain only 44.2% of the variance in tobramycin clearance. Measured steady-state peak and trough concentrations compared favorably with desired peak and trough concentrations. The mean (+/- S.D.) desired peak was 7.2 (+/- 1.8) microgram/ml, and the mean (+/- S.D.) measured peak was 7.1 (+/- 2.0) microgram/ml. The mean (+/- S.D.) desired trough was 1.1 (+/- 0.9) microgram/ml, and the mean (+/- S.D.) measured trough was 1.3 (+/- 0.8) microgram/ml. Many patients required dosage regimens exceeding those commonly recommended; however, no cases of ototoxicity or nephrotoxicity were encountered. This model proved successful in calculating dosage regimens of tobramycin to obtain optimal serum concentrations.

Hospital acquired gram-negative pneumonias: response rate and dosage requirements with individualized tobramycin therapy.

Individualized tobramycin therapy was systemically evaluated in 26 patients with gram-negative pneumonias involving Pseudomonas aeruginosa and other multiple antibiotic-resistant pathogens. Patient prognoses were classified by underlying diseases, and response was determined according to previously established criteria. Twenty-three patients (88%), including all 11 cases involving multiple antibiotic-resistant pathogens and 12 of 15 cases involving Pseudomonas aeruginosa, successfully responded to individualized tobramycin therapy. Tobramycin daily dosages and pharmacokinetic parameters demonstrated a wide interpatient variability. Measured peak and trough serum concentrations resulting from individualized dosage regimens closely matched desired peak and trough concentrations. Clinical ototoxicity or nephrotoxicity were not observed. Individualizing dosage regimens was an important factor in obtaining therapeutic serum concentrations that may influence treatment response to tobramycin therapy.

The management of human bite injuries of the hand.

Three hundred twenty-seven bite injuries of the hand were reviewed for incidence of infectious complications. A policy to hospitalize all patients with human bite injuries was maintained, but noncompliance was high. Patients with uninfected or superficially infected bites (131) were hospitalized and treated with parenteral penicillin, cephalosporins, or clindamycin (mean duration, 45 hours). Among the 62 patients not lost to followup three minor septic complications occurred. Of similar patients not hospitalized (134), only two thirds received antibiotic therapy but no complications were observed. These data suggest that human bite hand infections can be averted and that established superficial infections can be successfully treated with outpatient antibiotic therapy. Of the 62 patients with moderately to severely infected human bites, 77% were injured by striking an opponent; 52% suffered injury over metacarpophalangeal joints. The mean delay in seeking medical attention was 2 1/2 days, compared to 1/2 day in the less severely infected group. Of the patients with more seriously infected bites, 94% received parenteral antibiotic therapy. Of 30 patients with known outcome in the latter group 27% suffered complications (stiffness; recurrent infection; other infectious complication), confirming the high morbidity of established deep hand infections secondary to human bites.