Pseudomonas aeruginosa is one of the leading gram-negative organisms associated with nosocomial infections. The increasing frequency of multi-drug-resistant Pseudomonas aeruginosa (MDRPA) strains is concerning as efficacious antimicrobial options are severely limited. By searching MEDLINE from January 1966-February 2005 and relevant journals for abstracts, we reviewed the frequency, risk factors, and patient outcomes of MDRPA nosocomial infections in critically ill patients, determined the available antimicrobial therapies, and then provided recommendations for clinicians. The definition of MDRPA was established as isolates intermediate or resistant to at least three drugs in the following classes: beta-lactams, carbapenems, aminoglycosides, and fluoroquinolones. Reported rates of MDRPA varied from 0.6-32% according to geographic location and type of surveillance study. Risk factors for MDRPA infection included prolonged hospitalization, exposure to antimicrobial therapy, and immunocompromised states such as human immunodeficiency virus infection. Emergence of MDRPA isolates during therapy was reported in 27-72% of patients with initially susceptible P. aeruginosa isolates. Patients with severe MDRPA infections should be treated with combination therapy, consisting of an antipseudomonal beta-lactam with an aminoglycoside or fluoroquinolone rather than aminoglycoside and fluoroquinolone combinations, to provide adequate therapy and improve patient outcomes. Synergy has been observed when resistant antipseudomonal drugs were combined in vitro against MDRPA with successful clinical application reported in two centers. Colistin with adjunctive therapy, such as a beta-lactam or rifampin, may be a useful agent in MDRPA when antimicrobial options are limited, but patients should be monitored closely for toxicities associated with this agent. Standardization of terminology for MDRPA isolates is needed for consistency and comparability of surveillance and institutional reports. Clinical studies are needed to identify risk factors for MDRPA development and to determine the economic impact of these infections, as well as to determine the most efficacious antimicrobial regimens and duration of therapy to maximize outcomes in the treatment of MDRPA infections.

Nosocomial infections caused by Pseudomonas aeruginosa in critically ill patients are often difficult to treat due to resistance to multiple antimicrobials. The purpose of this study was to evaluate antimicrobial resistance among P. aeruginosa isolates from intensive care unit patients in the United States from 1993 to 2002 by using the Intensive Care Unit Surveillance Study database. Over the 10-year period, susceptibility of 13,999 nonduplicate isolates of P. aeruginosa was analyzed. From 1993 to 2002, nationwide increases in antimicrobial resistance were greatest for ciprofloxacin, imipenem, tobramycin, and aztreonam. Rates of multidrug resistance (resistance to >3 of the following drugs: ceftazidime, ciprofloxacin, tobramycin, and imipenem) increased from 4% in 1993 to 14% in 2002. The lowest dual resistance rates were observed between aminoglycosides or fluoroquinolones with piperacillin-tazobactam while the highest were for those that included ␤-lactams and ciprofloxacin. Ongoing surveillance studies are crucial in monitoring antimicrobial susceptibility patterns and selecting empirical treatment regimens.Pseudomonas aeruginosa is one of the most common gramnegative pathogens associated with nosocomial infections (11). Unfortunately, resistance to available antipseudomonal agents is on the rise, jeopardizing selection of appropriate treatment and subsequently increasing morbidity and mortality in patients infected with this pathogen (1, 9). In fact, inadequate empirical therapy has been associated with mortality exceeding 30% (6), and delays in the initiation of appropriate therapy contribute to increased length of hospital stay and persistence of infection (8).The selection of appropriate antimicrobial therapy requires active surveillance of emerging resistance trends and continuing education among the health care providers and institution(s) involved. The objectives of this study were to analyze data from the Intensive Care Unit Surveillance Study (ISS) to assess the rates of resistance and multidrug resistance among P. aeruginosa isolates in intensive care units (ICUs) in the United States from 1993 to 2002 and to use these data to evaluate current recommendations for empirical antibiotic regimens.(These data were presented as a poster presentation at the 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy on 17 September 2003.) MATERIALS AND METHODSThe ISS is a national postmarketing surveillance program sponsored by Merck and Company Inc. (Rahway, N.J.) since 1989. Participating institutions submitted susceptibility data for approximately 100 to 200 consecutive gram-negative aerobic isolates from ICU patients annually. All organisms were identified to the species level and susceptibility testing was conducted at each institution using a standardized custom microdilution MIC panel (Microscan MKD MIC; Dade International MicroScan, Sacramento, Calif.) (10). The P. aeruginosa quality control strain ATCC 27853 was used weekly in each laboratory.In this study, independent of the res...

Septic shock that requires therapy with adrenergic agents is associated with high rates of mortality. Inappropriately normal or low serum concentrations of vasopressin contribute to the development of hypotension during sepsis. We critically evaluated the role of administering exogenous vasopressin to patients with septic shock. A computerized search of MEDLINE from January 1966--December 2003 and a manual search of relevant journals for abstracts were conducted. Eleven retrospective, six prospective cohort, and four prospective randomized studies were identified. Most studies evaluated short-term infusions of vasopressin at 0.08 U/minute or less as add-on therapy in patients requiring adrenergic agents. The results show that starting vasopressin in patients with septic shock increases systemic vascular resistance and arterial blood pressure, thus reducing the dosage requirements of adrenergic agents. These effects are rapid and sustained. Substantial enhancement of urine production, likely due to increased glomerular filtration rate, was shown in several studies. A few studies demonstrated clinically significant reduced cardiac output or cardiac index after vasopressin was begun, necessitating cautious use in patients with cardiac dysfunction. Vasopressin was associated with ischemia of the mesenteric mucosa, skin, and myocardium; elevated hepatic transaminase and bilirubin concentrations; hyponatremia; and thrombocytopenia. Limiting the dosage to 0.03 U/minut or less may minimize the development of these adverse effects. Vasopressin 0.03 U/minute or less should be considered if response to one or two adrenergic agents is inadequate or as a method to reduce the dosage of adrenergic agents. At present, vasopressin therapy should not be started as first-line therapy. Additional studies are needed to determine the optimum dosage, duration, and place in therapy of vasopressin relative to adrenergic agents. A multicenter, comparative study of vasopressin 0.03 U/minute as add-on therapy is under way and should provide mortality data.

Vasopressin infusion was effective in increasing MAP and reducing heart rate while decreasing the dopamine dosage in patients with septic shock. Comparative studies with catecholamine vasopressors are needed to define the optimal role of vasopressin in septic shock therapy. In the meantime, vasopressin infusion at

When compared with OCT, HRS patients treated with AVP had significantly higher recovery rates, improved survival and were more likely to receive a liver transplant.

The presence of one regulatory gene mutation or simple expression of a single outer membrane protein was not linked to multidrug resistance. However, OprM overexpression and multiple efflux regulatory gene mutations or efflux protein expression were associated with MDR P. aeruginosa isolates.

Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means ؎ standard deviations; age, 41 ؎ 17 years; weight, 81 ؎ 12 kg; creatinine clearance, 114 ؎ 40 ml/min) received intravenous levofloxacin at 750 mg (n ‫؍‬ 10 patients) or 500 mg (n ‫؍‬ one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 ؎ 3.2 liters/h, 7.8 ؎ 1.6 h, and 93 ؎ 31 mg · h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of <0.5 g/ml and MICs of <1 g/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 g/ml or any organism with a MIC of >2 g/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 g/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens.

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