Levofloxacin failure in a patient with pneumococcal pneumonia.

OBJECTIVE: To report a case of levofloxacin failure in a patient with a penicillin-sensitive Streptococcus pneumoniae pneumonia. CASE SUMMARY: A previously healthy, immunocompetent, 53-year-old white man presented with penicillin-sensitive S. pneumoniae pneumonia. The patient was empirically placed on levofloxacin monotherapy, which was continued due to a local penicillin shortage. When the patient failed to improve, further susceptibility testing was ordered. The organism was found to have a penicillin minimum inhibitory concentration (MIC) of 0.023 microgram/mL and a levofloxacin MIC of 6 micrograms/mL. Effective antimicrobial therapy was delayed, as clinicians did not anticipate fluoroquinolone resistance. DISCUSSION: Newer fluoroquinolones such as levofloxacin have good activity against most S. pneumoniae isolates and are used for the treatment of pneumonia. Although resistance to these agents is rare, it has been reported. Current guidelines from the National Committee for Clinical Laboratory Standards do not recommend initial fluoroquinolone susceptibility testing. CONCLUSIONS: As fluoroquinolone resistance may not be identified by susceptibility patterns to other antibiotics, early fluoroquinolone susceptibility testing and increased awareness of resistance may aid clinicians in their treatment of pneumococcal disease.

Development of a best-practice model at a university hospital to increase efficiency in the management of patients with community-acquired pneumonia.

An economic evaluation of drug acquisition, nursing care, pharmacy time, laboratory costs, supplies, and ancillary care was conducted as a first step toward developing a pneumonia management plan at the University of Kentucky Medical Center (UKMC). UKMC costs were compared with costs at other hospitals treating pneumonia patients on Medicare. Overall costs for pneumonia at the 25% of hospitals nationwide with the lowest costs for Medicare patients with this condition were determined and compared with costs at UKMC. Against nationwide benchmarks, efficiencies at UKMC for treating simple pneumonia ranged from 45% for pharmacy expenses to 81% for nursing costs. Efficiencies for complicated pneumonia ranged from 47% for laboratory costs to 67% for nursing costs. The most cost-efficient antimicrobial treatment options were promoted and integrated into a pneumonia management plan based on Infectious Diseases Society of America treatment guidelines. A comparison of pneumonia treatment costs at UKMC with those at the 25% of hospitals nationwide with the lowest treatment costs for Medicare patients with pneumonia revealed that UKMC pharmacy costs could be optimized. Strategies for standardizing the care of patients with community-acquired pneumonia (CAP) are being implemented.

Emerging bacterial pathogens: a consensus of the scientific data and the risk for development of multiple organ dysfunction syndrome.

Antibiotic resistance in the hospital setting is continuing to increase, particularly in intensive care units (ICUs) and other areas of the hospital such as oncology units, where the use of empiric broad-spectrum antibiotics is common. The problem of antibiotic resistance is also compounded in the immunocompromised patient. Multi-drug resistance is common among both Gram-positive and -negative bacteria, and becoming more prevalent among fungi (yeast). Two major antibiotic-resistant pathogens include extended-spectrum beta-lactamase producing Klebsiella pneumoniae (ESBL-KP) and vancomycin-resistant enterococci (VRE). When infections occur with ESBL-KP, a carbapenem antibiotic is usually the drug of choice. When infection occurs with VRE, specific therapy is bacteriostatic, and the clinician may have to rely on empirically selected antibiotics or combinations of antibiotics to achieve a positive outcome. Two newly-approved agents, linezolid and quinupristin/dalfopristin can be used to treat infections caused by resistant gram-positive cocci, but the latter is approved for use against VR-E. faecium. Risk factors for the development of ESBL-KP include the use of extended-spectrum cephalosporins such as ceftazidime. Risk factors for the development of VRE include inappropriate use of vancomycin, extended-spectrum cephalosporins, and antianaerobic drug therapy such as clindamycin. Several institutions have documented a reduction in one or both of these resistant pathogens following a decrease in the use of extended-spectrum cephalosporins combined with the increased use of extended-spectrum penicillins/beta-lactamase inhibitor combinations, such as piperacillin/tazobactam, for the empiric therapy of infections. For VRE, a reduction in the inappropriate use of vancomycin is also an important interventional strategy along with improved infection control practice.

Overview of resistant gram-positive pathogens in the surgical patient.

Staphylococci and enterococci are the most common pathogens in surgical-site and bloodstream infections. The emergence of drug resistance among these gram-positive bacteria thus poses a substantial threat to patients with surgical infections. Resistance to methicillin/oxacillin is frequently observed in Staphylococcus aureus isolates and is often accompanied by multidrug resistance. Vancomycin is usually the treatment of choice for infections caused by methicillin-resistant S. aureus (MRSA), so the recent appearance of S. aureus isolated with intermediate sensitivity to vancomycin is cause for concern. Vancomycin resistance has already appeared in most species of enterococci. Infections caused by vancomycin-resistant enterococci (VRE) are associated with increased mortality compared to infections caused by vancomycin-sensitive isolates. Measures for preventing vancomycin resistance include reducing the use of vancomycin and other agents that appear to be associated with VRE, including third-generation cephalosporins and anti-anaerobic drugs. Third-generation cephalosporins have also been implicated in the increased prevalence of MRSA infections. Prudent use of existing antibiotics is an essential strategy for combating the rising tide of drug-resistant gram-positive pathogens.

Azithromycin versus erythromycin for community-acquired pneumonia: a cost-minimization analysis.

The costs of i.v. erythromycin versus azithromycin (in terms of medication use and treatment of adverse effects) when these drugs were used with other antimicrobials to treat community-acquired pneumonia (CAP) were compared. The medical records of patients receiving i.v. azithromycin or erythromycin as part of combination antimicrobial therapy for the treatment of CAP at a 473-bed level 1 trauma center in Kentucky were retrospectively reviewed. Data were collected for patients treated from December 1, 1997, through March 31, 1998. Patient data collected included occurrence of phlebitis or pain at the injection site, number of line changes due to phlebitis, and culture results. Cost data collected included drug acquisition cost, pharmacy cost of drug preparation, nursing time to administer the agent, cost of drug supplies, and cost of managing complications. Three time-and-motion studies were conducted to determine technician preparation time and pharmacist verification time. The medical records of 62 patients were identified and reviewed; 50 patients were enrolled in the study (25 in the azithromycin group and 25 in the erythromycin group). The average total days of therapy was 5.1 for the azithromycin group and 5.6 for the erythromycin group. The average total cost, including the cost of complications ($4.36 per patient in the erythromycin group), was $66.46 in the azithromycin group and $96.56 in the erythromycin group. The difference in costs between the two groups was not significant. There was no significant cost difference between azithromycin- and erythromycin-containing combination antimicrobial therapy in the treatment of CAP.

Polymyxin B sulfate and colistin: old antibiotics for emerging multiresistant gram-negative bacteria.

BACKGROUND: Polymyxin B sulfate and colistin, also known as colistimethate, have not been used for many years because less toxic antimicrobials are available. Gram-negative bacteria that are resistant to the aminoglycosides, beta-lactams, and fluoroquinolones are becoming more common. These bacteria are often susceptible to the polymyxins. OBJECTIVE: To present a review of the chemistry, antibacterial spectrum, dosing, pharmacokinetics, toxicity, and indications for polymyxin B sulfate and colistin. DATA SOURCE: A MEDLINE search (1966-1998) of the English-language literature was performed to identify primary literature on the polymyxins. Older citations ( 1949-1965) were identified through the bibliographies of these articles. STUDY SELECTION: All available reports of in vitro antibacterial activity, animal and clinical trials, and case reports were reviewed. DATA SYNTHESIS: The polymyxins are amphipathic molecules that interact with lipopolysaccharide in the bacterial outer membrane. They have potent antiendotoxic properties and antibacterial activity against Pseudomonas aeruginosa and many of the Enterobacteriaceae. Polymyxin B and colistin are usually given at a dose of 1.5-2.5 and 5 mg/kg/d, respectively, in two divided doses. Dosing must be altered in renal failure since the kidney is the primary route of elimination. Distribution into pleural fluid, joints, and cerebrospinal fluid is poor. Toxic effects involve the kidney and central nervous system. The polymyxins are recommended for serious systemic infections caused by gram-negative bacteria that are resistant to other agents. CONCLUSIONS: Polymyxin B sulfate and colistin have a role in the therapy of multidrug-resistant gram-negative bacterial infections.

Antimicrobial resistance in gram-positive bacteria: the myth of the MIC. Minimum inhibitory concentration.

Although much progress has occurred in the fight to treat infection, resistant bacteria increasingly are becoming problematic. The minimum inhibitory concentration is easily determined, yet its definition, clinical application, and relevance are confusing. In addition, errors can occur during in vitro susceptibility testing. The mechanism of resistance for different organisms is discussed as are the pitfalls of susceptibility testing and the prescription of antimicrobial agents.

Vancomycin use in a university medical center: effect of a vancomycin continuation form.

OBJECTIVE: To examine the impact of a new policy to ensure appropriate use of vancomycin in a 461-bed tertiary-care hospital. DESIGN: We instituted a policy that allowed physicians to prescribe vancomycin but that required them to complete a vancomycin continuation form and document that use conformed to Hospital Infection Control Practices Advisory Committee (HICPAC) guidelines if they wished to continue the drug beyond 72 hours. Vancomycin was stopped automatically at 72 hours if use was not consistent with guidelines, if an infectious diseases consultant did not approve the drug, or if the form was not completed. A pharmacist and infectious diseases specialist monitored use of vancomycin prospectively and interacted with prescribers when indicated. Educational efforts were limited to printing the HICPAC guidelines on the form and providing information about the policy in a newsletter. Patterns of prescribing and the economic impact of the form were evaluated over a 6-month period. RESULTS: Only 29% to 48% of vancomycin orders initially met HICPAC guidelines, but 77% to 96% of use was appropriate after 72 hours when the form was used. Inappropriate surgical prophylaxis, empirical therapy of intensive-care unit and transplant patients, and therapy for inadequately documented coagulase-negative staphylococcal infections remained problems. Vancomycin use fell from a mean of 136 (+/-52) g/1,000 patient days in the 12 months before the form to 78 (+/-22) g/1,000 patient days in the 9 months after institution of the form (P<.05). Net vancomycin acquisition costs and costs of ordering vancomycin serum levels fell by $357 and $19 per 1,000 patient days, respectively (P<.05). This represented annualized saving of approximately $47,000 in drug and monitoring costs. No adverse patient outcomes were seen as a result of the program. CONCLUSIONS: A vancomycin continuation form can decrease inappropriate vancomycin use and may save money. Additional educational efforts may be required to increase compliance with HICPAC guidelines during initial prescribing.

Pharmacokinetics and pharmacodynamics of intravenous and oral azithromycin: enhanced tissue activity and minimal drug interactions.

OBJECTIVE: To review the pharmacokinetics and pharmacodynamics of oral and intravenous azithromycin compared with other macrolide antibiotics, and to evaluate these differences and their relation to clinical effectiveness. DATA SOURCE: A MEDLINE search (1966-May 1998) was performed to identify applicable English-language clinical, animal, and microbiologic studies pertaining to pharmacokinetic and pharmacodynamic parameters. STUDY SELECTION: Relevant studies concerning microbiology, pharmacokinetics, tissue concentrations, pharmacodynamics, and the clinical effects of these parameters were selected. DATA SYNTHESIS: The structural modification that distinguishes the azalide antibiotics from the macrolide antibiotics is responsible for the pharmacokinetic and pharmacodynamic behavior of azithromycin, resulting in the high and sustained tissue and intracellular concentrations seen with this agent. Drug delivery to the site of infection by phagocytes and fibroblasts is the hallmark of azithromycin's tissue-directed pharmacodynamics, allowing for convenient once-daily, 5-day regimens for most infections that respond to oral therapy and 7-10 days for more serious infections requiring initial intravenous therapy. Metabolism is via hepatic pathways other than cytochrome P450, thus minimizing the risk of drug interactions. CONCLUSIONS: Compared with other macrolide antibiotics, the unique pharmacokinetic and pharmacodynamic features of azithromycin offer the potential for improved efficacy and safety from drug interactions. These attributes, combined with its once-daily dosing schedule, make azithromycin suitable for the treatment of many types of bacterial infection.

Amphotericin B lipid complex.

OBJECTIVE: To evaluate the published data on the effectiveness and safety of amphotericin B lipid complex (ABLC) for the treatment of invasive mycosis and to evaluate data describing the pharmacologic properties and pharmacokinetic behavior of ABLC in both animals and humans. DATA SOURCE: A MEDLINE search was conducted to identify literature published from 1965 to January 1997 for amphotericin B deoxycholate (DCAB) and ABLC. In addition, preliminary data published as abstracts and presented at national conferences on infectious disease and hematology within the last 6 years were also included in this review. STUDY SELECTION: Both human and animal studies were reviewed. Animal and in vitro studies were selected to evaluate the pharmacologic and toxicologic properties of ABLC. For the evaluation of the efficacy, safety, and pharmacokinetic behavior of ABLC, large, well-controlled studies were reviewed. In addition, data from open-label and emergency use protocols were also included in the review. DATA EXTRACTION: The study and analytical methods, results, and conclusions of the selected studies were evaluated. Pharmacokinetic data for both ABLC and DCAB that were derived from human subjects were also evaluated. DATA SYNTHESIS: DCAB has been the cornerstone for the treatment of invasive mycosis, even though it has a narrow therapeutic index. Infusion-related toxicities (e.g., fever, chills, rigors) are likely due to DCAB stimulation of cytokine and prostaglandin synthesis. Conversely, nephrotoxicity, the primary non-infusion-related toxicity, likely results from the nonselective cytotoxic interaction between DCAB and cholesterol-containing mammalian cells. ABLC represents a new approach to improving the therapeutic index of DCAB. Mammalian cytotoxicity is attenuated by complexing amphotericin B to a mixture of phospholipids. This alters the affinity of amphotericin B and decreases its selective transfer from the complex to cholesterol-containing mammalian cells. Fungi also possess lipase, which improves the selective transfer from the complex to ergosterol-containing cell membranes. In humans, the lipid formulation increases the volume of distribution of amphotericin B. Thus, compared with DCAB, larger doses of ABLC can be administered for a longer duration with less nephrotoxicity. However, the prevalence of infusion-related toxicities associated with ABLC is similar to that of DCAB. Whether the alteration in distribution improves efficacy by improving tissue concentrations of amphotericin B has not been determined. The cost of this agent will limit its use. CONCLUSIONS: ABLC has been shown to be at least as effective as DCAB, and it has been well tolerated in the clinical studies to date. Despite large dosages and extended courses of administration, there is little nephrotoxicity associated with its use. However, the cost of this agent will limit its use to the treatment of refractory mycosis or to cases where DCAB is contraindicated due to significant renal insufficiency.

Intra-arterial urokinase versus surgery for acute peripheral arterial occlusion.

The outcomes of intra-arterial urokinase versus surgery for acute peripheral arterial occlusion (PAO) were compared. Patients at a university hospital who had received intraarterial urokinase for PAO were identified by computer and pair-matched on the basis of comorbidities, age, sex, and site of occlusion to computer-selected patients who had undergone surgery. Only patients with category I or II ischemia were considered. The study period for the urokinase group was February 1995 through January 1996, and the period for the surgery group was June 1993 through January 1996. Twenty-eight patients in each group met the selection criteria. Patients who had received urokinase had a significantly shorter median length of stay (8.5 days) than patients in the surgery group (13 days) and significantly fewer infectious complications (2 versus 10). No differences in amputation rates, total hospital costs, or mortality rates were detected. Patients who received intra-arterial urokinase for PAO had a shorter length of stay in the hospital and fewer infectious complications than those who underwent surgery.

Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: a phase II safety and efficacy trial.

The purpose of this study was to determine the effect of insulin-like growth factor-I (IGF-I) on the catabolic state and clinical outcome of head-injured patients. Thirty-three patients between the ages of 18 and 59 years with isolated traumatic head injury and Glasgow Coma Scale (GCS) scores of 4 to 10 were randomized to one of two groups. All patients received standard neurosurgical intensive care plus aggressive nutritional support; the patients in the treatment group also received intravenous therapy with continuous IGF-I (0.01 mg/kg/hour). During the 14-day dosing period, the control patients lost weight, whereas treated patients gained weight despite a significantly higher measured energy expenditure and lower caloric intake (p = 0.02). Daily glucose concentrations and nitrogen outputs were greater in control patients (p = 0.03) throughout the study period. During Week 1, only treated patients achieved positive nitrogen balance. Fifteen of 17 treated and 13 of 16 control patients survived the 1st week. No deaths occurred in patients whose serum IGF-I concentrations were higher than 350 ng/ml. Dichotomized Glasgow Outcome Scale scores for patients with baseline GCS scores of 5 to 7 improved from poor to good for eight of 12 treated patients but for only three of 11 control patients (p = 0.06). Eight of 11 treated patients with serum IGF-I concentrations that were at least 350 ng/ml achieved moderate-to-good outcome scores at 6 months, compared to only one of five patients with lower concentrations (p < 0.05). These findings indicate that pharmacological concentrations of IGF-I may improve clinical outcome and nitrogen utilization in patients with moderate-to-severe head injury.

Intravenous insulin-like growth factor-I (IGF-I) in moderate-to-severe head injury: a Phase II safety and efficacy trial.

The purpose of this study was to determine the effect of insulin-like growth factor-I (IGF-I) on the catabolic state and clinical outcome of head-injured patients. Thirty-three patients between the ages of 18 and 59 years with isolated traumatic head injury and Glasgow Coma Scale (GCS) scores of 4 to 10 were randomized to one of two groups. All patients received standard neurosurgical intensive care plus aggressive nutritional support; the patients in the treatment group also received intravenous therapy with continuous IGF-I (0.01 mg/kg/hour). During the 14-day dosing period, the control patients lost weight, whereas treated patients gained weight despite a significantly higher measured energy expenditure and lower caloric intake (p = 0.02). Daily glucose concentrations and nitrogen outputs were greater in control patients (p = 0.03) throughout the study period. During Week 1, only treated patients achieved positive nitrogen balance. Fifteen of 17 treated and 13 of 16 control patients survived the 1st week. No deaths occurred in patients whose serum IGF-I concentrations were higher than 350 ng/ml. Dichotomized Glasgow Outcome Scale scores for patients with baseline GCS scores of 5 to 7 improved from poor to good for eight of 12 treated patients but for only three of 11 control patients (p = 0.06). Eight of 11 treated patients with serum IGF-I concentrations that were at least 350 ng/ml achieved moderate-to-good outcome scores at 6 months, compared to only one of five patients with lower concentrations (p < 0.05). These findings indicate that pharmacological concentrations of IGF-I may improve clinical outcome and nitrogen utilization in patients with moderate-to-severe head injury.