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Levofloxacin, levo-isomer of the D,L-racemate ofloxacin, is a new fluoroquinolone antibiotic approved for use in the United States in December 1996. It has an extended spectrum of activity compared with older-generation fluoroquinolones (ciprofloxacin, ofloxacin), with improved activity against gram-positive bacteria and excellent activity against gram-negative bacteria and atypical organisms. Although its activity against anaerobic organisms is improved over that of earlier fluoroquinolones, levofloxacin should not be considered a first-line anaerobic agent. It is available in an injectable form, as well as an oral formulation with virtually 100% oral bioavailability. The plasma elimination half-life ranges from 6-8 hours in individuals with normal renal function. Approximately 80% of drug is eliminated unchanged in urine through glomerular filtration and tubular secretion. The pharmacokinetics are not appreciably affected by age, gender, or race when differences in renal function and body mass and composition are taken into account. Levofloxacin had impressive efficacy in clinical studies of community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, acute sinusitis, skin and skin structure infections, and complicated urinary tract infections and pyelonephritis. It is well tolerated; its adverse event profile is similar to that of other fluoroquinolones, with gastrointestinal and central nervous system effects reported most commonly. Drug interactions are uncommon with levofloxacin; however, coadministration with antacids or with other agents containing divalent or trivalent cations reduces levofloxacin absorption. The agent should prove to be more effective than older fluoroquinolones, especially for infections caused by pneumococci highly resistant to penicillin.

To evaluate the pulmonary tissue distribution of levofloxacin, the new once-daily fluoroquinolone, after a single 500-mg oral dose.Open-label study.One pulmonary clinic and two university-affiliated teaching hospitals.Eighteen adults undergoing lung biopsy or lobectomy.Levofloxacin plasma and lung tissue concentrations were determined by high-performance liquid chromatography with fluorescence detection. Lung tissue levofloxacin concentrations were corrected for blood contamination by measuring hemoglobin.After a single 500-mg oral dose, concentrations of levofloxacin in lung tissue consistently exceeded those in plasma at every time point over the 24-hour sampling period, with tissue:plasma penetration ratios of 2.02 (2-3 hrs), 5.02 (4-6 hrs), 5.13 (11-17 hrs), and 4.13 (22-25 hrs). The mean penetration ratio over the 24-hour sampling period was 3.95 (range 1.06-9.98). Lung tissue concentrations of levofloxacin also exceeded minimum inhibitory concentration values for most community-acquired respiratory tract pathogens over the 24 hours.This study supports clinical evaluation of levofloxacin as once-daily oral therapy for community-acquired lower respiratory tract infections.

A previously healthy 33-year-old woman received neuromuscular blocking agents during treatment of severe adult respiratory distress syndrome secondary to pneumococcal pneumonia and septic shock. Atracurium infusion rates were progressively increased, preceded by repeated loading doses up to a maximum of 3.57 mg/kg/hour, but produced inadequate neuromuscular blockade as assessed by clinical and ventilatory parameters as well as train-of-four (TOF) monitoring. Atracurium was discontinued and vecuronium infusions of 2.3 mg/kg/hour finally produced adequate paralysis for 7 days. Increasing vecuronium requirements then prompted discontinuation of neuromuscular blockade. Atracurium was reinstituted 2 days later because of worsening pulmonary function. Infusion rates of 3.04 mg/kg/hour were again required, together with high-dose midazolam and fentanyl, to achieve adequate oxygenation with acceptable airway pressures; however, TOF monitoring showed an unacceptable level of paralysis. Cross-resistance among chemically dissimilar neuromuscular blocking agents poses a difficult patient management problem and supports a pharmacodynamic basis of resistance to these agents.

Meropenem is the second carbapenem antibiotic available in the United States. It has a broad spectrum of activity that includes moderate activity against gram-positive bacteria and excellent gram-negative aerobic and anaerobic activity. Meropenem has enhanced gram-negative activity relative to imipenem-cilastatin and often retains activity against strains resistant to third-generation cephalosporins and imipenem-cilastatin. The drug penetrates well into most body fluids and tissues, including cerebrospinal fluid. It is also stable against renal dehydropeptidase hydrolysis and does not require coadministration of a dehydropeptidase inhibitor. Meropenem showed excellent efficacy in clinical studies involving seriously ill patients with intraabdominal, central nervous system, lower respiratory tract, skin and soft tissue, urinary tract, and febrile neutropenic infections. It appears well tolerated and, relative to imipenem-cilastatin, may have reduced potential for causing seizures and other central nervous system toxicities. Although it has many favorable qualities and some potential advantages relative to other broad-spectrum agents, additional trials and clinical experience are necessary to define its optimal place in clinical practice.

The incidence of emergent resistance and clinical factors affecting its development were evaluated by retrospective review of 173 studies encompassing over 14,000 patients. Eight antibiotic classes and 225 individual treatment regimens were evaluated. Emergent resistance occurred among 4.0% of all organisms and 5.6% of all infections treated. It appeared to be significantly more frequent with penicillin and aminoglycoside monotherapy, with significantly lower rates associated with imipenem-cilastatin, aztreonam, and combination therapy. Clinical failure also appeared to be significantly more likely to occur after emergence of resistance among organisms treated with fluoroquinolones or aminoglycosides. Infections associated with higher resistance rates were cystic fibrosis, osteomyelitis, and lower respiratory tract infections. Resistance was most common in patients in intensive care units or receiving mechanical ventilation. It was also significantly frequent among studies performed in university or teaching hospitals. Organisms associated with high resistance rates were Pseudomonas aeruginosa, Serratia, Enterobacter, and Acinetobacter sp. Factors such as infection type, underlying diseases, type of institution, and specific pathogens warrant consideration when examining emergent resistance.

Continuous arteriovenous hemodiafiltration (CAVHD) is being used increasingly in critically ill patients with acute renal failure (ARF). We prospectively evaluated extracorporeal and total systemic clearances (ClCAVHD and Cls) of ciprofloxacin during CAVHD in four patients with severe ARF to assess the adequacy of drug dosing. Ciprofloxacin serum and ultrafiltrate concentrations were measured by high-performance liquid chromatography. The ClCAVHD accounted for approximately 5.9% (range 2.8-11.6%) of Cls of ciprofloxacin. However, large variability in serum concentrations was observed with the normally recommended dose of 400 mg/day, and doses of up to 800 mg/day were required to maintain concentrations suitable for treatment of serious infections. High daily doses of ciprofloxacin required in these patients are likely related to altered pharmacokinetics in serious illness as well as to the increased extracorporeal clearance during CAVHD. Clinical studies to define appropriate dosing recommendations for ciprofloxacin during CAVHD are necessary to guide clinicians in optimum drug use.

Bacterial infections, including those that cause infection in the healthy host as well as those that are more opportunistic, occur very commonly among persons infected with the human immunodeficiency virus (HIV). Bacterial infections are a direct result of the severe humoral and cellular immune defects found in these patients. Epidemiologic factors such as intravenous drug use and stage of HIV infection may also play important roles. Pulmonary, bloodstream, gastrointestinal, central nervous system, skin and soft tissue, and catheter-related infections are common, as are endocarditis, prostatitis, and others. Frequently reported pathogens are common organisms such as Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, and enteric gram-negative pathogens, as well as less typical ones such as Listeria monocytogenes and Nocardia sp. The frequency of infection is specific to organ system and pathogen, often being many times higher than in immunocompetent hosts. Prompt recognition and aggressive therapy are required to reduce morbidity and mortality due to these infections.

The results of a survey of the use of antibiotic-impregnated bone cement and cement beads in U.S. hospitals are reported. A random sample of hospitals was selected from all hospitals registered with the American Hospital Association. A questionnaire designed to characterize the extent of use of the products and the degree of pharmacy involvement was mailed to the pharmacy directors at 547 hospitals nationwide. The response rate was 61.7% (336 evaluable returns). Ninety hospitals (26.9%) reported using antibiotic-impregnated bone cement or cement beads. Product use was significantly greater in urban hospitals, hospitals larger than 200 beds, teaching hospitals, and hospitals with pharmaceutical services in the operating rooms. Most facilities using the products were community hospitals. Total hip arthroplasty, total knee arthroplasty, and chronic osteomyelitis were the most common indications for use. Systemic antibiotics were also administered in the great majority of hospitals reporting use of the products. The products were generally used in fewer than one procedure per month. Aminoglycosides and various cephalosporins were the antibiotics most commonly used; most have not been adequately studied for this use. Although nearly all the hospital pharmacies purchased antibiotics for these products, none mixed cement and only two premanufactured antibiotic beads. About one fourth of the hospitals surveyed reported using antibiotic-impregnated bone cement and cement beads, although the total number of patients being treated was small.

The clinical use of neuroleptics, benzodiazepines, narcotic analgesics, barbiturates, and neuromuscular blockers to manage delirium and agitation in the intensive-care setting is reviewed. Delirium is the most commonly encountered mental disturbance in critically ill patients and may be precipitated by factors such as physical illness, medications, pain, and emotional stress. If agitation cannot be controlled through nonpharmacologic means, pharmacologic intervention may be necessary. Haloperidol is the neuroleptic of choice for rapid control of delirium and agitation in the critically ill patient. It has few adverse effects in most patients, even at high doses, although it can cause extrapyramidal symptoms. Among the benzodiazepines, lorazepam should be considered a first-line agent. It may be used alone or in combination with haloperidol (or another neuroleptic). Midazolam is suitable for administration by continuous i.v. infusion in the intensive-care setting because of its water solubility, short half-life, and short duration of action. The sedative effects of narcotics may be advantageous in patients with both agitation and pain. Barbiturates are not recommended for routine use in the treatment of delirium and agitation. The use of neuromuscular blocking agents such as pancuronium bromide and metocurine iodide may be necessary when other therapies have failed. Haloperidol and the benzodiazepines, alone or in combination, are the drugs of choice for treatment of acute agitation and delirium in critically ill patients.