Thomas J. Cumbo

Clinical and economic evaluation of oral ciprofloxacin after an abbreviated course of intravenous antibiotics

PURPOSE Oral ciprofloxacin has the requisite pharmacokinetic and antibacterial properties to rival the potency of intravenous antibiotics. This study was designed to determine whether oral ciprofloxacin could abbreviate the course of intravenous antibiotics in the treatment of serious infections. PATIENTS AND METHODS Hospitalized adult patients were eligible for enrollment if they had a serious infection that was expected to require 8 or more days of intravenous antibiotic treatment. After conventional intravenous antibiotics were administered for 3 days, informed consent was obtained and patients were randomly assigned to either continue parenteral antibiotics (n = 53) or switch to oral ciprofloxacin 750 mg taken twice daily (n = 52). Ninety-nine of the 105 patients were evaluable for the assessment of efficacy. Clinical and bacteriologic efficacy, adverse events, and costs of the two treatments were compared. RESULTS The two treatment groups were comparable for demographic characteristics, types of infections, bacteria isolated, initial intravenous antibiotic regimens, and duration of antibiotic treatment. The most common infections were of the skin and skin structure; bacteremia and infections of the lower respiratory tract, urinary tract, and bone and joint were also represented. The most commonly isolated pathogens were Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The most frequently prescribed intravenous antibiotics before randomization included aminoglycosides, cephalosporins, vancomycin, and nafcillin; 52 evaluable patients were treated with combination therapy while 47 received monotherapy. The clinical and bacteriologic outcomes and adverse reaction frequency with oral ciprofloxacin were comparable to those of the continued intravenous antibiotic regimens. Ciprofloxacin was associated with an average cost savings of

Cefmenoxime Efficacy, Safety, and Pharmacokinetics in Critical Care Patients with Nosocomial Pneumonia

293 per patient. CONCLUSION When used after 3 days of intravenous antibiotics, oral ciprofloxacin was as safe and effective as full courses of intravenous antibiotics and provided substantial cost savings.

Genesis of Methicillin-Resistant Staphylococcus aureus (MRSA), How Treatment of MRSA Infections Has Selected for Vancomycin-Resistant Enterococcus faecium, and the Importance of Antibiotic Management and Infection Control

Nephrotoxicity frequently complicates the use of aminoglycosides in severely compromised acute care patients. Therefore, an open clinical trial was initiated to determine if cefmenoxime alone is useful in serious nosocomial pneumonias. Thirty consecutive patients were entered in the trial, and 28 patients with an average age of 66 years were evaluable. Most were malnourished at entry, with serum albumin averaging 2.8 g/dl and prognostic nutritional index values over 70 percent (normal less than 40 percent). One-half the patients had severe chronic obstructive pulmonary disease and 68 percent required ventilators. Fifty-seven percent had concomitant cardiac disease, and 79 percent had previously been treated with antibiotics. Pneumonia was proven to be present by new infiltrate on chest x-ray, new fever, elevated white blood cell count, and gram-negative rods on gram stain and in cultures of tracheal aspirates or sputum. Patients were given cefmenoxime 1 to 2 g every six hours an average of 12 days. Cefmenoxime peak (one hour) and trough concentrations were measured by high pressure liquid chromatography and averaged 58 and 7 micrograms ml, respectively. Pharmacokinetic data in 18 patients were determined from serum profiles. Gram-positive organisms, Escherichia coli, Klebsiella, and Hemophilus influenzae were usually eradicated. Persistence was noted for some Enterobacter, Pseudomonas, Serratia, and Acinetobacter. Persistence in patients with good clinical response was considered colonization rather than superinfection. Overall, a satisfactory clinical response rate was noted in 78.6 percent of evaluable patients, whereas four patients responded satisfactorily with recurrence and two treatments had an unsatisfactory response. No serious adverse effects were observed. Cefmenoxime is a promising agent in the treatment of susceptible pneumonias in critical care patients.

Gentamicin disposition and tissue accumulation on multiple dosing

We extensively studied the epidemiology and time course of endemic methicillin-resistant Staphylococcus aureus (MRSA) in the Millard Fillmore Hospital, a 600-bed teaching hospital in Buffalo. The changeover from methicillin-susceptible S. aureus to MRSA begins on the first hospital day, when patients are given cefazolin as presurgical prophylaxis. Under selective antibiotic pressure, colonizing flora change within 24 to 48 hours. For patients remaining hospitalized, subsequent courses of third-generation cephalosporins further select and amplify the colonizing MRSA population. Therefore, managing antibiotic selective pressure might be essential. Other strategies include attention to dosing, so that serum concentrations of drug exceed the minimum inhibitory concentration, and antibiotic cycling. Although there are some promising new antibiotics on the horizon, it is necessary to deal with many resistance patterns by using the combined strategies of infection control and antibiotic management.

Changes in antimicrobial agent usage resulting from interactions among clinical pharmacy, the infectious disease division, and the microbiology laboratory

Gentamicin pharmacokinetics was examined in a group of 47 patients with stable renal function treated an average of 10 days for severe infection. Serum concentrations rose continually during treatment, and declined in two phases after the drug was stopped, with a mean half-life of 112hr (range 27–693 hr) in the second phase. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of drug in the tissue compartment at all times during and after treatment. Predicted tissue amounts of gentamicin rose continually on multiple dosing in all patients. In six patients who died, postmortem tissues were obtained to quantitate recovery. In all cases, the predicted amount of gentamicin in tissues was in close agreement with the amount recovered at autopsy. Tissue distribution and accumulation constitute a major reason for variability in gentamicin pharmacokinetics and explain both the rising peak and trough serum concentrations and the prolonged detection of gentamicin in serum and urine after the drug is stopped.

Mathematical Examination of Dual Individualization Principles (II): The Rate of Bacterial Eradication at the Same Area under the Inhibitory Curve is More Rapid for Ciprofloxacin Than for Cefmenoxime

Rapid reporting of culture and susceptibility data is the first of several important steps in the successful management of infected patients. As has been said many times, rapidly reported data are of little value unless the patient directly benefits. Benefit requires better overall communication and an action plan linked to timely use of these results. In 1989 the Millard Fillmore Hospital Antibiotic Review Committee developed and implemented a prototype approach to hospital wide antimicrobial management. The formulary was revised and the drug use evaluation process modified to enhance effectiveness and to lower the cost of therapy and inventory. Clinical pharmacy antimicrobial agent management specialists were then recruited to individualize patient treatments to the isolated pathogens in conjunction with the Division of Infectious Diseases. To provide the clinical pharmacy specialists with rapid and clinically useful information, a real-time computer link was created between the pharmacy (antibiotic orders) and the microbiology laboratory (culture results). Customized software was implemented to screen all patients automatically for mismatches between pathogens and drugs, or to screen for doses inappropriate to minimum inhibitory concentration or renal function. Special attention was paid to identification of opportunities to target a more appropriate narrow-spectrum regimen after culture results became available. Changes in antimicrobial regimen or dosage were made by contacting the prescribing physician. Over 90% of the recommended changes were made, and virtually all changed regimens had satisfactory clinical outcome. Real dollar expenditures for antimicrobial agents declined by >

Accumulation Pharmacokinetics of Tobramycin

200,000 per year. Prior to the institution of this computerized clinical management strategy, antimicrobial purchases were rising yearly at the rate of 12%-15%. The combined efforts of clinical pharmacy, microbiology, and infectious disease personnel successfully optimized antimicrobial therapy on a hospital wide basis. Antimicrobial agent optimization improved patient outcome, and the cost savings more than covered the costs of the program personnel and software.

Prolonged use of a diaphragm and toxic shock syndrome

OBJECTIVE: To compare two antibiotics at equal ranges of area under the inhibitory curve (AUIC) exposure to determine if the rate of bacterial eradication differed between these antibiotics. DESIGN: Retrospective comparison of two previously collected studies of similar patients with nosocomial pneumonia. SETTING: Hospitalized patients, most intubated in critical care units with nosocomial pneumonia. PARTICIPANTS: Patients treated with either iv ciprofloxacin (n=74) or the iv third-generation cephalosporin cefmenoxime (n=43) were compared for their length of treatment required to eradicate bacterial pathogens from their respective infection sites, using serial cultures from the site of infection. All patients were also assessed for clinical outcomes. Serum samples were obtained to evaluate individual patient antibiotic pharmacokinetics, which were used to model pharmacodynamics of response. The HPLC assay used for each antibiotic had interday coefficients of variation <10 percent. Serum concentration versus time profiles were fit using the computer program ADAPT II to determine pharmacokinetic parameters for each patient. The primary drug exposure measure that related to response was the AUIC, calculated as steady-state AUC0–24/minimum inhibitory concentration. RESULTS: AUIC values in the patients ranged from 6.0 to more than 7000, yet the AUIC value was highly predictive of time to bacterial eradication (p<0.OO 1). Although more than 75 percent of patients eventually achieved eradication of pathogens from tracheal aspirate cultures, ciprofloxacin and cefmenoxime differed significantly in the time required to sterilize these cultures. At appropriate AUIC values (>250) for ciprofloxacin, the median time to eradication was two days, while cefmenoxime (also at AUIC values >250) required six days to achieve the same result. CONCLUSIONS: We conclude that the more rapid in vitro bacterial killing, which is characteristic of ciprofloxacin at optimal AUIC values, can manifest in vivo as more rapid clearance of bacteria from the respiratory tract of patients, even when both agents are controlled for initial antibacterial exposure (i.e., same AUIC).

Changing the infection control paradigm from off-line to real time: the experience at Millard Fillmore Health System.

Tobramycin pharmacokinetics is usually described by a one-compartment model, but this model fails to account for both the incomplete urinary recovery and prolonged post-treatment persistence noted with this drug. We examined the multiple-dose behavior of tobramycin in 35 treated patients with stable renal function, using peak and trough serum concentrations, urine recovery, and postmortem tissue analysis. Serum concentrations rose slowly throughout treatment and declined in two phases after the drug was stopped. The first-phase half-life correlated well with renal function, but the second averaged 146 h and was poorly related to creatinine clearance. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of drug in the tissue compartment at all times during and after treatment. Predicted tissue amounts rose continually throughout treatment in all study patients. In 5 patients, the total amount of tobramycin in the body after the final dose was recovered in the urine, but urine had to be collected for 10 to 20 days to achieve complete recovery of the drug. In four patients, the predicted tissue amount was recovered from postmortem tissues. Regardless of the dose, tobramycin accumulated in the tissues of all patients receiving this antibiotic. The two-compartment pharmacokinetic model explains both the rising peak and trough concentrations during treatment and the detection of the drug in serum and urine long after the last dose.

Mathematical Examination of Dual Individualization Principles (III): Development of a Scoring System for Pneumonia Staging and Quantitation of Response to Antibiotics: Results in Cefmenoxime-Treated Patients

A case report is presented that involves the extended use of a contraceptive diaphragm and illustrates the problems in promptly establishing a clinical diagnosis of staphylococcal toxin syndrome. A 27-year old woman, 2 months postpartum, was admitted to the hospital after 24 hours of fever, shaking, chills, sweats, nausea and vomiting, and diminished urine output. She had been unable to remove a new coil spring diaphragm, used for the 1st time since parturition, for 3-1/2 days before admission. On the day of admission the diaphragm was removed with some difficulty. A purulent, foul-smelling vaginal discharge at the time the diaphragm was extracted was noted. She was lactating and had had no menses since conception. Her past medical history was unremarkable except for mitral valve prolapse. Evaluation at the time of admission was remarkable for a pulse rate of 120 beats/minute and orthostatic lightheadness. The blood pressure was 110/70 mm Hg when the patient was supine and fell less than 15 mm Hg systolic when she was seated. The white blood cell count was 17,000 with 63% segmented and 33% juvenile polymorphonuclear leukocytes. The sedimentation rate was 45 mm/hour. Multiple cultures of vagina, throat, urine, and blood were obtained. Vigorous intravenous fluid and electrolyte therapy was administered, and the patient was initially begun on ampicillin and tobramycin. Shortly after the appearance of the rash, staphylococcal toxic shock syndrome (TSS) was suspected, and the ampicillin was changed to oxacillin. The rash and strawberry tongue faded within 24 hours, and she became normotensive and afebrile by the 2nd hospital day. She was changed to oral dicloxacillin as the only antibiotic on the 4th hospital day, after the culture results were confirmed. At the time of discharge on the 6th hospital day, desquamation of the skin on the palms and soles had started and continued for another 7-10 days. A 10 day course of dicloxacillin was completed. Follow-up vaginal, cervical, and pharyngeal cultures 3 and 5 months later contained no S. aureus. The patient had resumed menstruation but was not using tampons or a diaphragm. Increased vigilance for the potential dangers of using vaginal occulusive devices when the lower genital tract is colonized by S. aureus is necessary.