Steven C. Ebert

Correlation between in vitro and in vivo activity of antimicrobial agents against gram-negative bacilli in a murine infection model.

We studied the relationship between in vitro susceptibility tests (MICs, MBCs) and in vivo activity of tobramycin, pefloxacin, ceftazidime, and imipenem against 15 gram-negative bacilli from five different species in a murine thigh infection model. Complete dose-response curves were determined for each antimicrobial agent against each strain, and three parameters of in vivo activity were defined: maximal attainable antimicrobial effect (i.e., reduction in log10 CFU per thigh compared with untreated controls) at 24 h (Emax), total dose required to reach 50% of maximal effect (P50), and total dose required to achieve a bacteriostatic effect (static dose). Pefloxacin demonstrated the greatest Emax (P less than 0.05). Tobramycin was the most potent antimicrobial agent, as indicated by its having the lowest static dose/MIC ratio (P less than 0.002). Log10 P50s and static doses correlated significantly with log10 MICs or MBCs for the 15 strains of each antibiotic (P less than 0.01) except imipenem (P greater than 0.50). The greater potency of imipenem against the three Pseudomonas aeruginosa strains than against strains of the family Enterobacteriaceae (P less than 0.01) explained this lack of correlation. A longer duration of postantibiotic effect for imipenem against P. aeruginosa (P = 0.02) contributed to its increased potency against these strains. We conclude that in vitro susceptibility tests correlated well with in vivo activity in this animal model and that variations in potency among the four antimicrobial agents could be explained by differences in pharmacokinetics or pharmacodynamic activity.

Pharmacodynamic Properties of Antibiotics: Application to Drug Monitoring and Dosage Regimen Design

The goal of antimicrobial chemotherapy is to effectively eradicate pathogenic organisms while minimizing the likelihood of drug-related adverse effects. In this era of cost containment, consideration should also be given to performing this task with the smallest total dose of drug and the shortest duration of therapy. Determination of the appropriate dose and dosing interval of an antimicrobial requires knowledge and integration of both its pharmacokinetic and pharmacodynamic properties.

Ciprofloxacin pharmacokinetics in patients with normal and impaired renal function.

The pharmacokinetics of ciprofloxacin following single oral doses of 500 and 750 mg in 32 patients with various degrees of renal function impairment were investigated in an open, randomized crossover fashion. Ciprofloxacin was administered after overnight fasting; the washout time between the two doses was 1 week. Serum and urine samples were collected serially between 0 and 24 h and subjected to bioassay and high-performance liquid chromatography. Pharmacokinetic parameters were analyzed, assuming an open two-compartment model with first-order input and elimination. A distinct difference was observed in pharmacokinetic parameters between patients with impaired renal function (creatinine clearance, less than 50 ml/min per 1.73 m2) and those with normal renal function (creatinine clearance, greater than or equal to 50 ml/min per 1.73 m2). For the former group, the area under the curve of serum concentration versus time was doubled, the renal clearance of ciprofloxacin was cut to one-fourth, the total and nonrenal ciprofloxacin clearance was reduced by 50%, and the elimination half-life was prolonged by a factor of approximately 1.7. The correlation between renal drug clearance and creatinine clearance was highly significant (r = 0.890; P less than 0.001). On the basis of these findings, it appears that a 50% dose reduction of ciprofloxacin in patients with impaired renal function (creatinine clearance, less than 50 ml/min per 1.73 m2) may be indicated to achieve concentrations in serum similar to those observed in normal individuals. As the concentration of ciprofloxacin in urine after 24 h remained above the MIC for most urinary pathogens, this drug appears to be of potential benefit for the treatment of urinary tract infections in patients with impaired renal function.

Factors Contributing to Excessive Antimicrobial Prescribing

Several elements are known to influence the prescribing behaviors of clinicians; these elements may indirectly contribute to the current antibiotic resistance crisis. Lack of knowledge and time, as well as prescriber beliefs and attitudes, may be just as persuasive as test results when a clinician considers prescribing an antibiotic. In addition, patient expectations and demands may also sway some prescribers to write a prescription for an antibiotic that is unnecessary. Although culture and susceptibility testing methods are widely available in outpatient and institutional settings, they are often underused. As a result, broad‐spectrum antibiotics frequently are prescribed inappropriately In addition, prescribers may be unaware of local resistance patterns, and available antibiograms may not be updated appropriately or referenced by clinicians. Prescriber and patient education, as well as shifts in beliefs and attitudes, are required to help fight antibiotic resistance.

Penetration of antibiotics into the surgical wound in a canine model.

The dose and timing of antimicrobial agents given for surgical wound prophylaxis should be based on the concentration-time profile of the drug in tissue at the site of contamination. However, concentrations of antimicrobial agents in surgical wounds are difficult to determine accurately. Since a surgical wound is a unique extravascular compartment with increased vascular permeability and a high surface area/volume ratio, antibiotic concentrations in sera and surgical wounds should be similar. To test this hypothesis, the pharmacokinetics of single intravenous doses of cefazolin (40 mg/kg) and gentamicin (4 mg/kg) in sera and surgical wounds in a clinically relevant surgical model using dogs were compared. Drug concentrations were determined in interstitial fluid in muscle biopsies taken randomly from wound surfaces and serial wound fluid samples collected after the incisions were closed. Protein binding of cefazolin and gentamicin in sera and wound fluids was low (less than or equal to 29 +/- 9%) in this canine model. Cefazolin and gentamicin equilibrated rapidly (less than or equal to 30 min) between serum and the surgical wound, and concentrations in the two sites declined in parallel. Values for the area under the concentration-time curve, mean residence time, and terminal half-life in serum and the surgical site for each drug were similar. Cefazolin concentrations in serum underestimated the time during which concentrations in surgical wounds exceeded the susceptibility breakpoint MIC for important pathogens by an average of 58 min (range, 26 to 109 min; P = 0.036); for gentamicin, the underestimation averaged 30 min (range, 10 to 60 min; P = 0.036). These data support the concept that the concentration-time profiles of antimicrobial agents in serum may prove valuable clinically as guides to determining the and timing of antibiotic administration necessary for effective antimicrobial prophylaxis in surgery. Further studies are needed to determine the surgical wound pharmacokinetics of highly protein-bound antibodies.

Prevalence, consequences, and solutions.

Since the early development of antibiotics, antimicrobial resistance has continued to emerge as a formidable adversary in the fight against infectious disease. Once an issue confined to hospitals, antibiotic resistance has now invaded communities, targeting not only the immunocompromised patient, but also those who are immunocompetent. To stem this crisis, researchers have developed more powerful and more costly antibiotics, which have only complicated the resistance problem. Education of the patient and the prescriber, as well as antimicrobial stewardship programs, are necessary to avert a global antibiotic resistance catastrophe.

Case study and panel discussion.

A 38-year-old woman went to her physician with a 2-day history of erythema and warmth behind her left leg after sustaining a slight nick while shaving her leg. She had no significant medical history and no known drug allergies. Oral cephalexin was prescribed, and she began treatment that day. Two days later, she came to the emergency department with increased erythema and bullae with necrosed centers. Fluid was aspirated from the bullae and sent for culture, which grew Staphylococcus aureus resistant to penicillin, amoxicillin, erythromycin, and ciprofloxacin but susceptible to tetracycline, vancomycin, and sulfamethoxazole. Oral clindamycin was prescribed.