Cefotaxime vs nafcillin and tobramycin for the treatment of serious infection. Comparative cost-effectiveness.

To evaluate the cost-effectiveness of cefotaxime sodium at a dosage of 12 g/day vs nafcillin sodium and tobramycin sulfate for the treatment of serious infection, the hospital and physician charges of patients enrolled in a prospective, randomized, clinical trial were analyzed. For 187 patients receiving therapy empirically, mean hospital charges for the interval in which the trial antibiotics were used were $3,550 +/- $1,740 for cefotaxime and $3,160 +/- $1,990 for nafcillin and tobramycin. After adjusting for cost-generating factors, charges for cefotaxime were greater than for nafcillin and tobramycin, but the difference was not significant. For 107 patients with clinically or bacteriologically documented infection, mean charges were $3,980 +/- $1,800 for cefotaxime and $4,170 +/- $1,780 for nafcillin and tobramycin. Adjusted charges did not differ. Incremental charges for cefotaxime per additional response were $1,630 in all patients and -$820 in patients with clinically or bacteriologically documented infections.

Two doses of PMPA protect newborn macaques against oral simian immunodeficiency virus infection.

BACKGROUND: Simple and affordable intervention strategies are needed to reduce the rate of HIV transmission from mother to infant in developing countries. Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is considered to be a useful model of human pediatric HIV infection. OBJECTIVE: To investigate whether short-term 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) administration can protect newborn rhesus macaques against perinatal SIV infection. DESIGN AND METHODS: Eight newborn macaques were inoculated orally with highly virulent SIVmac within the first 3 days of life. Four of these animals were untreated controls. The other four animals were given one dose of PMPA (30 mg/kg subcutaneously) 4 h before oral SIV inoculation, and were then given a second and final dose of PMPA 24 h later. RESULTS: All four untreated control animals were persistently SIV-positive within 2 weeks after virus inoculation. In contrast, no virus could be detected in the four animals that received two doses of PMPA; these animals were seronegative and healthy at 10 months. CONCLUSIONS: Two doses of PMPA prevented SIV infection of newborn macaques. Our data suggest that short-term administration of PMPA to HIV-infected pregnant women at the onset of labor and to their newborns after delivery may reduce the rate of intrapartum HIV transmission.

Herpes simplex-1 virus thymidine kinase gene is unable to completely eliminate live, nonimmunogenic tumor cell vaccines.

Recent experiments with genetically engineered tumors have generated renewed interest in active cellular immunotherapy as a cancer treatment modality. In order to consider the use of live tumor cells for immunotherapy in human cancer patients, it will be important to ensure that these cells do not themselves produce morbidity in the event the immune system fails to eliminate them. Toward this end, we have examined a strategy for eliminating genetically manipulated nonimmunogenic tumors in vivo. When B16F10 melanoma cells were transfected with the Herpes simplex virus 1 thymidine kinase (HSV-TK) gene, cells were rendered susceptible to killing by the nucleoside analogs acyclovir (ACV) and ganciclovir (GCV). B16-HSV-TK+ tumors established in C57BL6 mice were successfully "suicided" in vivo when GCV was administered by continuous infusion. However, late recurrences were observed even after 1 month of continuous GCV treatment. In vivo growth kinetics suggested that the recurrences resulted from a tiny number (< 20) of cells that had survived the GCV treatment. Interestingly, recurrent tumors were as sensitive to GCV as the parental B16-HSV-TK+ line. While these results demonstrate potential feasibility of the suicide gene strategy for active immunotherapy with live tumor cells, they also illustrate that approaches dependent on the intracellular generation of cell cycle-dependent toxins may fail to eliminate small numbers of cells that temporarily exit cell cycle or that are pharmacologically sequestered.

Continuous sampling as a pharmacokinetic tool.

Continuous sampling (CS) of blood through a nonthrombogenic catheter is presented as a tool for determining various pharmacokinetic parameters after a single injection of a drug. In addition to defining many of the usual parameters used in pharmacokinetic analyses, CS provides an accurate and direct determination of the total area under the plasma concentration curve. The theoretic background underlying the CS method is derived, and a practical formulation for its use in a clinical setting is described. The aminoglycoside antibiotic, amikacin, was chosen to exemplify the use of this technique. The drug was administered to 6 children, and CS was used to define plasma and single organ (kidney) clearance, volume of distribution, half-life during the final elimination phase, the shape of the plasma concentration curve, and the exponential factorization of this curve for multicompartmental analysis. The CS method has several theoretical and practical advantages over the usual technique of intermittent blood sampling; such as accuracy in the determination of the plasma concentration-time curve integral, relative model independence, requirement for few samples, and ease in obtaining samples.

Netilmicin and gentamicin multidose kinetics in normal subjects.

Multidose netilmicin and gentamicin kinetics were studied in 20 healthy subjects who received 1.7 mg/kg gentamicin (n = 10) or netilmicin (n = 10) as a 20-min infusion every 8 hr for 10 days (28 doses) during a randomized, double-blind comparative trial designed to study adverse effects and kinetics of netilmicin and gentamicin. Multidose kinetics were of the same order for gentamicin and netilmicin with the exception of the terminal plasma t 1/2 (94 and 156 hr) and the volume of distribution at steady state (450 and 1072 ml/kg). Mean peak plasma concentrations of netilmicin were slightly lower than gentamicin. Percentage of the dose eliminated in urine did not differ for the two aminoglycosides. Aminoglycoside was detectable in plasma and continued to be eliminated in urine for at least 6 days after the final dose. The plasma concentration-time profiles for both netilmicin and gentamicin were well fitted with the sum of three exponential terms; urinary excretion rates-time plots showed biexponential decay. None of the subjects had any auditory, vestibular, or renal toxicity. Although the data confirm a deep tissue compartment, they suggest that the kinetic processes involved may be more complex than previously supposed.

Effects of prednisone, aspirin, and acetaminophen on an in vivo biologic response to interferon in humans.

In healthy volunteers receiving a single intramuscular dose of 18 X 10(6) U interferon alone or after 24 hours of an 8-day course of prednisone (40 mg/day), aspirin (650 mg every 4 hours), or acetaminophen (650 mg every 4 hours), the magnitude of the biologic response to interferon was quantified by measuring the time course of the induction of 2'-5'-oligoadenylate synthetase and resistance to vesicular stomatitis virus infection in human peripheral blood mononuclear cells. Prednisone decreased the AUC of 2'-5'-oligoadenylate synthetase activity (p less than 0.05), whereas administration of aspirin or acetaminophen did not affect this biologic response. No measurable effect was seen during administration of prednisone, aspirin, or acetaminophen on the duration or intensity of vesicular stomatitis virus yield reduction. The side effects seen with interferon administration at the dose tested were not altered in a clinically meaningful manner by prednisone, aspirin, or acetaminophen.

Acyclovir kinetics in end-stage renal disease.

Acyclovir (ACV) is almost entirely eliminated by the kidneys and has a terminal plasma half-life (t1/2) of 2 to 3 hr in subjects with normal renal function. To determine the drug's kinetics and tolerance in patients with severe renal failure, six anuric subjects on long-term hemodialysis were studied. Each received a 1-hr infusion of 2.5 mg/kg IV ACV. The kinetics are well described by a two-compartment open model. ACV terminal plasma t 1/2 and the total body clearance were 19.5 +/- 5.9 hr (mean +/- SD) and 28.6 +/- 9.5 ml/min/1.73 m2. Peak (end of infusion) and 8- and 24-hr plasma ACV concentrations were 37.5 +/- 23.3, 10.3 +/- 2.9, and 6.4 +/- 2.4 microM. Approximately 48 hr after the start of the infusion the subjects were hemodialyzed for 6 hr. The pre- and posthemodialysis ACV plasma levels were 2.74 +/- 1.38 and 1.11 +/- 0.60 microM. The terminal ACV t1/2 during hemodialysis was 5.7 +/- 0.85 hr. During hemodialysis paired arterial and venous samples showed that ACV was readily dialyzed, with a mean coefficient of extraction of 0.45 +/- 0.12. The dialysis clearance of acyclovir was 81.8 +/- 12.6 ml/min. None of the patients had any ACV-related adverse effects. Since ACV elimination is markedly reduced in end-stage renal failure and because ACV is readily hemodialyzible, dosage modification are needed to avoid cumulation and to replace dialyzed drug.

Disposition of intravenous radioactive acyclovir.

The kinetic and metabolic disposition of (8-14C)acyclovir (ACV) was investigated in five subjects with advanced malignancy. The drug was administered by 1-hr intravenous infusion at doses of 0.5 and 2.5 mg/kg. Plasma and blood radioactivity-time, and plasma concentration-time data were defined by a two-compartment open kinetic model. There was nearly equivalent distribution of radioactivity in blood and plasma. The overall mean plasma half-life and total body clearance +/- SD of ACV were 2.1 +/- 0.5 hr and 297 +/- 53 ml/min/1.73 m2. Binding of ACV to plasma proteins was 15.4 +/- 4.4%. Most of the radioactive dose excreted was recovered in the urine (71% to 99%) with less than 2% excretion in the feces and only trace amounts in the expired Co2. Analyses by reverse-phase high-performance liquid chromatography indicated that 9-(carboxymethoxymethyl)guanine was the only significant urinary metabolite of ACV, accounting for 8.5% to 14.1% of the dose. A minor metabolite (less than 0.2% of dose) had the retention time of 8-hydroxy-9-[(2-hydroxyethoxy)methyl]guanine. Unchanged urinary ACV ranged from 62% to 91% of the dose. There was no indication of ACV cleavage to guanine. Renal clearance of ACV was approximately three times the corresponding creatinine clearances.

Clinical pharmacology: foscarnet.

Foscarnet exerts its antiviral effects via reversible inhibition of viral polymerases. Pharmacodynamic data indicate that herpesvirus and human immunodeficiency virus replication is inhibited by therapeutically achievable concentrations of foscarnet; however, the concentrations of foscarnet required for such inhibition have been found to vary widely. Pharmacokinetic data indicate that foscarnet is eliminated via the renal route, undergoes negligible metabolism, and appears to be distributed widely from the circulation. However, the available data indicate that the pharmacokinetics of the drug varies among patients and within the individual patient, particularly with regard to plasma drug levels; furthermore, such factors as the intracellular kinetics of the drug have yet to be well characterized. It is thus difficult to formulate optimal dosing regimens on the basis of what is known of foscarnet pharmacodynamics and pharmacokinetics. Nevertheless, dosages that produce clear-cut therapeutic benefits without unacceptable toxicity have been identified in clinical trials of foscarnet in acquired immunodeficiency syndrome (AIDS) patients with cytomegalovirus (CMV) retinitis.

Acyclovir clinical pharmacology. An overview.

The current status of pharmacokinetic and toxicologic information on acyclovir is reviewed from a clinical pharmacologist's perspective. Acyclovir pharmacokinetics is accurately described by a two-compartment open model. The volume of distribution at steady state is about two-thirds of the body weight. The half-life of its beta phase of elimination is about three hours with normal renal function and increases to about 18 hours with anuria. Hemodialysis removes about 60 percent of the acyclovir in the body. The pharmacokinetics is independent of dose at least up to 15 mg/kg. Acyclovir is minimally (15 percent) protein-bound an only a small percentage (15 percent) of an intravenous dose is metabolized in persons with normal renal function. Acyclovir is eliminated primarily by glomerular filtration with a small addition from tubular secretion. The toxicity of acyclovir seems to be acceptably low. Local irritation with extravasation exists. Transient glomerular dysfunction is occasionally seen after bolus administration. Other side effects remain to be clearly established.

Increased risk of renal dysfunction due to interaction of liver disease and aminoglycosides.

To determine if aminoglycoside use and liver disease interact to cause an increased risk for renal dysfunction, data from 179 hospitalized patients who had been enrolled in a prospective, randomized trial of nafcillin/tobramycin versus cefotaxime were analyzed. The cefotaxime-treated patients served as a control group not receiving an aminoglycoside. Renal dysfunction occurred in seven of 88 (8 percent) given cefotaxime and 37 of 91 (41 percent) given tobramycin (p less than 0.001), in 11 of 29 (38 percent) with liver disease and 33 of 150 (22 percent) without liver disease (p less than 0.08), and occurred in 11 of 15 (73 percent) with both liver disease and tobramycin use and in 0 of 14 (0 percent) with liver disease and cefotaxime use (p less than 0.001). By logistic regression analysis, the relative odds of renal dysfunction developing during tobramycin treatment in a patient were 6.0 (95 percent confidence interval: 3.8 to 9.5). The relative odds of renal dysfunction developing in a patient receiving tobramycin and having liver disease were 31.8 (95 percent confidence interval: 19.7 to 51.4). This analysis demonstrates an interaction between tobramycin use and liver disease for increasing the risk of renal dysfunction.

Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia.

To determine the association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia, the case reports of 37 patients from four prospective, randomized, controlled trials of gentamicin, tobramycin, and amikacin were analyzed. Twenty (54 percent) of these patients had a favorable outcome. Patients with maximal one-hour postinfusion (peak) levels of 7 micrograms/ml or greater for gentamicin and tobramycin or 28 micrograms/ml or greater for amikacin more often had successful outcomes (14 of 20, 70 percent) than those with levels less than this (six of 19, 32 percent) (p less than 0.006). Patients with overall mean peak levels of 6 micrograms/ml or greater for gentamicin and tobramycin or 24 micrograms/ml or greater for amikacin more often had successful outcomes than those with levels less than this (six of 17, 35 percent) (p less than 0.04). The initial patient temperature, serum urea nitrogen/creatinine ratio, initial polymorphonuclear leukocyte count, and age were also associated with outcome; but by multivariate analysis, achieving an adequate peak concentration was the most important discriminating factor. These results suggest the potential importance of achieving adequate aminoglycoside levels in patients with gram-negative pneumonia.

Carbenicillin-trimethoprim/sulfamethoxazole versus carbenicillin-gentamicin as empiric therapy of infection in granulocytopenic patients. A prospective, randomized, double-blind study.

The results of therapy with carbenicillin plus trimethoprim-sulfamethoxazole (C-T/S) were compared to those obtained with carbenicillin plus gentamicin (C-G) in a prospective double-blind study of empiric antibiotic therapy in granulocytopenic patients. Patients were stratified into two groups: favorable-prognosis, group 1 (carcinoma, lymphoma, multiple myeloma), or unfavorable-prognosis, group 2 (acute leukemia, bone marrow transplantation), based on anticipated duration of granulocytopenia. Over-all, empiric antibiotic trials were more often successful (P = 0.004) in group 1 (55 of 62 patients or 89 per cent) than in group 2 (42 of 64 patients, 66 per cent)mwithin group 1, there was a favorable outcome in 30 of 32 (94 per cent) C-T/S trials and in 25 of 30 (83 per cent) C-G trials (P = 0.25); within group 2, there was a favorable outcome in 23 of 30 (77 per cent) C-T/S trials and in 19 of 34 (56 per cent) C-G trials (P = 0.14), Combined results in both groups indicated a higher proportion of favorable outcome in C-T/S trials (53 of 62, 85 per cent) than in C-G trials (44 of 64, 69 per cent). Further analysis (Manetl-Naenszel test) showed the over-all difference in outcome to be significant (P = 0.049), but the general applicability of this result may be limited by the rather low incidence of gram-negative bacterial infections in this study. There was no difference between the treatment regimens in antibiotic toxicity, and serious superinfection occurred only in group 2 patients (21 per cent of trials), equally divided between treatment arms. Initial protocol dosing achieved target plasma levels of trimethoprim (3 to 8 micrograms/ml) or gentamicin (4 to 10 micrograms/ml) in 57 of 68 (84 per cent) C-T/S trials compared to 21 of 60 (35 per cent) C-G trials.

Acyclovir concentrations and tolerance during repetitive administration for 18 days.

Acyclovir, a new antiherpetic agent, was administered for 18 days to 10 recipients of bone marrow transplants as a part of a double-blind, randomized, placebo-controlled trial assessing its prophylactic efficacy and safety. Renal glomerular function diminished over the time of the study in the 10 acyclovir-treated and 10 placebo-treated patients. The decline in glomerular filtration rate (GFR) did not differ significantly between the two groups and is unlikely to be associated with acyclovir. The pharmacokinetics of acyclovir is expected to be altered by a change in GFR since glomerular filtration is probably the major process involved with the excretion of acyclovir. Such an alteration was seen as an increase over time of both peak (one hour after the end of an infusion) and trough (immediately before a dose) plasma acyclovir concentrations. Although peak and trough acyclovir concentrations rose from 8.5 to 15.8 microM and from 1.7 to 4.1 microM, respectively, these rises are fully attributable to the decreases in GFR seen in both drug- and placebo-treated groups. The placebo-controlled and blinded nature of this trial allows an assessment of the effects of acyclovir on a battery of hematologic, renal, and hepatic tests. The only adverse effects observed that statistically differed in the acyclovir-treated group compared with controls were the rises in SGOT (53.2 +/- (SEM) 19.9 versus 3.1 +/- 12.2) and SGPT (59.7 +/- 15.3 versus 12.3 +/- 13.8).

Influence of hemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure.

The pharmacokinetic disposition of acyclovir was studied in six patients with chronic renal failure (CRF) and anuria. At the end of a one-hour intravenous infusion (2.5 mg/kg), the mean peak acyclovir plasma level (+/- SD), determined by radioimmunoassay, was 37.5 +/- 24.2 microM (8.4 +/- 5.4 microgram/ml), twice the level found at this dose in patients with normal renal function (NRF). In the CRF volunteers, significant plasma levels (3.0 +/- 1.4 microM) persisted at 47 hours after drug administration (before hemodialysis) whereas in the NRF patients levels dropped to less than 1 microM by 11 hours. Hemodialysis was started 47 hours after infusion and was continued for six hours. The pre-dialysis plasma drug level was reduced by 61.5 percent at 0.25 to 1.5 hours after the end of dialysis. The mean plasma t 1/2 during dialysis of 5.4 hours, the extraction ratio of 0.44, and the dialysis clearance for plasma of 113 ml/min indicate that acyclovir is efficiently removed by hemodialysis. One-half the suggested intravenous dose for a particular indication can be given every 24 hours and a similar replacement dose should be given after each dialysis.

Metabolic fate of radioactive acyclovir in humans.

The metabolic fate and the kinetics of elimination of [8-14C]acyclovir in plasma and blood was investigated in five cancer patients. Doses of 0.5 and 2.5 mg/kg were administered by one-hour intravenous infusion. Radioactivity was distributed nearly equally in blood and plasma. The plasma and blood concentration-time data were defined by a two-compartment open pharmacokinetic model. The overall mean acyclovir plasma half-life and total body clearance +/- SD were 2.1 +/- 0.5 hours and 297 +/- 53 ml/min/1.73 m2. Binding of acyclovir to plasma proteins was 15.4 +/- 4.4 percent. The radioactive dose was excreted predominantly in the urine (71 to 99 percent) with less than 2 percent excretion in the feces and only trace amounts of radioactivity in the expired air. Reverse-phase high-performance liquid chromatography indicated that 9-carboxymethoxymethylguanine was the only significant urinary metabolite of acyclovir accounting for 8.5 to 14.1 percent of the dose. A minor metabolite (less than 0.2 percent of dose) had the retention time of 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine. Unchanged urinary acyclovir ranged from 62 to 91 percent of the dose. There was no indication of acyclovir cleavage to guanine. The renal clearances of acyclovir were three times higher than the corresponding creatinine clearances.

Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host.

Intravenous acyclovir was evaluated in the treatment of 97 immunocompromised patients with mucocutaneous herpes simplex virus infection in a randomized, double-blind, placebo-controlled trial. Acyclovir recipients had significantly shorter periods of virus shedding (p less than 0.0002) and lesion pain (p less than 0.01), and more rapid lesion scabbing (p less than 0.004) and lesion healing (p less than 0.04). The most common adverse reaction was a low incidence of peripheral vein irritation; no serious toxicity could be definitely attributed to acyclovir treatment even in these seriously ill patients. Intravenous acyclovir offers both safe and effective treatment for mucocutaneous herpes simplex virus infection in the immunocompromised host.

Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy.

PURPOSE: To compare the efficacy and safety of inpatient oral antibiotic treatment (oral) versus standard parenteral antibiotic treatment (intravenous) for right-sided staphylococcal endocarditis in injection drug users. PATIENTS AND METHODS: In a prospective, randomized, non-blinded trial, febrile injection drug users were assigned to begin oral or intravenous (IV) treatment on admission, before blood culture results were available. Oral therapy consisted of ciprofloxacin and rifampin. Parenteral therapy was oxacillin or vancomycin, plus gentamicin for the first 5 days. Antibiotic dosing was adjusted for renal dysfunction. Administration of other antibacterial drugs was not permitted during the treatment or follow-up periods. Bacteremic subjects having right-sided staphylococcal endocarditis received 28 days of inpatient therapy with the assigned antibiotics. Test-of-cure blood cultures were obtained during inpatient observation 6 and 7 days after the completion of antibiotic therapy, and again at outpatient follow-up 1 month later. Criteria for treatment failure and for drug toxicity were prospectively defined. RESULTS: Of 573 injection drug users who were hospitalized because of a febrile illness and suspected right-sided staphylococcal endocarditis, 93 subjects (16.2%) had two or more sets of blood cultures positive for staphylococci; 85 of these bacteremic subjects (14.8%) satisfied diagnostic criteria for at least possible right-sided staphylococcal endocarditis (no other source of bacteremia was apparent) and entered the trial. Forty-four (oral, 19; IV, 25) of these 85 subjects completed inpatient treatment and evaluation including test-of-cure blood cultures. There were four treatment failures (oral, 1 [5.2%]; IV, 3 [12.0%]; not significant, Fisher's exact test). Drug toxicity was significantly more common in the parenterally treated group (oral, 3%; IV, 62%; P < 0.0001), consisting largely of oxacillin-associated increases in liver enzymes. CONCLUSIONS: For selected patients with right-sided staphylococcal endocarditis, oral ciprofloxacin plus rifampin is effective and is associated with less drug toxicity than is intravenous therapy.

Fluoroquinolone toxicities. An update.

The main types of adverse effects associated with quinolones are uncommon and reversible and vary in frequency among different agents. Phototoxicity appears more frequent with lomefloxacin than with some other quinolones. Three mechanisms have been proposed to explain the neurotoxic effects, including rare proconvulsant activity, associated with quinolone therapy. Arthropathy remains a dilemma for paediatricians deciding whether to use quinolones in growing children. Importantly, the experience with temafloxacin, which has now been withdrawn from the market, emphasises the need for thorough postmarketing surveillance. Nonetheless, it should be remembered that the fluoroquinolones as a group are effective and very well tolerated antimicrobial drugs.

Safety and tolerability of fluoroquinolones.

Since their introduction in the mid-1980s, the fluoroquinolones have been administered to more than 100 million patients. Generally, adverse effects reported in association with the fluoroquinolones have been those that could have been predicted by previous experience with non-fluorinated derivatives and by animal toxicity studies. Examples of such adverse events are CNS-related toxicity, upper gastrointestinal tract reactions and phototoxicity. Some adverse experiences in animals, notably cartilage toxicity, have been of minimal clinical importance. This should lead to a re-evaluation of the possible paediatric indications for the fluoroquinolones. With temafloxacin, which was withdrawn from clinical use in June 1992, new and serious adverse events were reported at a frequency of about 1 per 3500 patients treated. This frequency of adverse events is too low to be detected even in very careful analyses of phase III registration studies. Anaphylaxis, haemolytic anaemia and renal failure were the most striking adverse events reported with temafloxacin, and, in addition, hypoglycaemia and hepatic failure were reported. These reactions may be attributable to an immunological reaction in some patients. Because of the rarity of these reactions, they can be detected only by studies encompassing thousands of patients, usually during postmarketing surveillance. Safety monitoring of each new fluoroquinolone during its early clinical use is therefore recommended.