Early vancomycin,amikacin and gentamicin concentrations in pulmonary artery and pulmonary tissue are not affected by VA ECMO (venoarterial extracorporeal membrane oxygenation) in a pig model of prolonged cardiac arrest

BackgroundECMO (extracorporeal membrane oxygenation) is increasingly used in severe hemodynamic compromise and cardiac arrest (CA). Pulmonary infections are frequent in these patients. Venoarterial (VA) ECMO decreases pulmonary blood flow and antibiotic availability in lungs during VA ECMO treated CA is not known. We aimed to assess early vancomycin, amikacin and gentamicin concentrations in the pulmonary artery as well as tracheal aspirate and to determine penetration ratios of these antibiotics to lung tissue in a pig model of VA ECMO treated CA.MethodsTwelve female pigs, body weight 51.5 ± 3.5 kg, were subjected to prolonged CA managed by different modes of VA ECMO. Anesthetized animals underwent 15 min of ventricular fibrillation (VF) followed by continued VF with ECMO flow of 100 mL/kg/min. Immediately after institution of ECMO, a 30 min vancomycin infusion (10 mg/kg) was started and amikacin and gentamicin boluses (7.5 and 3 mg/kg, respectively) were administered. ECMO circuit, aortic, pulmonary arterial, and tracheal aspirate concentrations of antibiotics were measured at 30 and 60 min after administration; penetration ratios were calculated.ResultsAll 30 min antibiotic concentrations and 60 min concentration for gentamicin in the pulmonary artery were no different than the aorta. However, the 60 min pulmonary artery vancomycin and amikacin values were significantly higher than aortic, 19.8 (14.3–21.6) vs. 17.6 (14.2–19.0) mg/L, p = 0.009, and 15.6 mg/L (11.0–18.6) vs. 11.2 (10.4–17.2) mg/L, p = 0.036, respectively. One hour penetration ratios were 18.5% for vancomycin, 34.9% for gentamicin and 38.8% for amikacin.ConclusionIn a pig model of VA ECMO treated prolonged CA, despite diminished pulmonary flow, VA ECMO does not decrease early vancomycin, gentamicin, and amikacin concentrations in pulmonary artery. Within 1 h post administration, antibiotics can be detected in tracheal aspirate in adequate concentrations.     

Intra-tracheal delivery strategy of gentamicin with partial liquid ventilation

Patients with pulmonary infection often present with ventilation and perfusion abnormalities, which can impair intravenous antibiotic therapy. Intra-tracheal (i.t.) administration has met with obstacles, such as inadequate delivery to affected lung regions and the disruption of gas exchange. We hypothesized that i.t. administration of a gentamicin (G)/perfluorochemical (PFC) suspension (G/PFC) would effectively deliver and distribute gentamicin to the lung, while maintaining gas exchange and non-toxic serum levels. In addition, we sought to compare serum G and lung levels and distribution of G when G/PFC is administered at the initiation of partial liquid ventilation (PLV) vs. during PLV. To test this hypothesis, 17 newborn lambs were ventilated by PLV with perflubron (LiquiVent) for 4 h using three different G (5 mg kg-1) administration techniques: i.t. slow-fill (SF) (n = 6; G/PFC over 15 min at start of PLV), i.t. top-fill (TF) (n = 6; G/PFC 10-65 min after start of PLV), intravenous (i.v.) (n = 5, aqueous injection at start of PLV). Serum levels of gentamicin were obtained 1, 15, 30 and 60 min after administration, and hourly there after for the remainder of the protocol (4 h). Arterial blood gas and pulmonary function measurements were obtained throughout the protocol. At the conclusion of the protocol, representative samples from each lung lobe, the brain and kidney were homogenized and assayed for gentamicin. All results are presented as the mean +/- SEM; P < 0.05. Over time, serum gentamicin levels were greatest (P < 0.05) in i.v. (11.0 +/- 2.3 micrograms ml-1), followed by TF (2.3 +/- 0.1 micrograms ml-1) and SF (0.8 +/- 0.1 microgram ml-1). The percentage of the administered dose remaining in the lungs after 4 h was greater (P < 0.05) following i.t. delivery (SF 23.8 +/- 4.3%, TF 13.7 +/- 2.5%) as compared to i.v. (3.7 +/- 0.5%). These findings suggest that for a given dose of G, both SF and TF delivery methods of G/PFC can enhance pulmonary, relative to systemic, antibiotic coverage.     

High-frequency oscillation versus conventional ventilation following surfactant administration and partial liquid ventilation

Surfactant followed by partial liquid ventilation (PLV) with perfluorocarbon (PFC; LiquiVent®) improves oxygenation, lung compliance, and lung pathology in lung-injured animals receiving conventional ventilation (CV). In this study, we hypothesize that high-frequency oscillation (HFO) and CV will provide equivalent oxygenation in lung-injured animals following surfactant repletion and PLV, once lung volume is optimized. After saline-lavage lung injury during CV, newborn piglets were randomized to either HFO (n = 10) or CV (n = 9). HFO animals were stabilized over 15 min without optimization of lung volume; CV animals continued treatment with time-cycled, pressure-limited, volume-targeted ventilation. All animals then received 100 mg/kg of surfactant (Survanta®). Thirty minutes later, all received intratracheal PFC to approximate functional residual capacity. Thirty minutes after PLV began, mean airway pressure (MAP) in both groups was increased to improve oxygenation. MAP was directly adjusted during HFO; PEEP and PIP were adjusted during IMV, maintaining a pressure sufficient to deliver 15 mL/kg tidal volume. Animals were treated for 4 h. The CV group showed improved oxygenation following surfactant administration (OI: 26.79 ± 1.98 vs. 8.59 ± 6.29, P < 0.0004), with little further improvement following PFC administration or adjustments in MAP. Oxygenation in HFO-treated animals did not improve following surfactant, but did improve following PFC (OI: 27.78 ± 6.84 vs. 15.86 ± 5.53, P < 0.005) and adjustments in MAP (OI: 15.86 ± 5.53 vs. 8.96 ± 2.18, P < 0.03). After MAP adjustments, there were no significant intergroup differences in oxygenation. Animals in the CV group required lower MAP than animals in the HFO group to maintain similar oxygenation. We conclude that surfactant repletion followed by PLV improves oxygenation during both CV and HFO. The initial response to administration of surfactant and PFC was different for the conventional and high-frequency oscillation groups, likely reflecting the ventilation strategy used; animals in the CV group responded most to surfactant, whereas animals in the HFO group responded most after PFC instillation. The ultimately similar oxygenation of the two groups once lung volume had been optimized suggests that HFO may be used effectively during administration of, and treatment with, surfactant and perfluorocarbon. Pediatr Pulmonol. 1998;26:21–29. © 1998 Wiley-Liss, Inc.     

Preserved spontaneous breathing improves cardiac output during partial liquid ventilation.

The aim of this study was to examine whether preserved spontaneous breathing (SB) supported by proportional-assist ventilation (PAV) would improve cardiac output (CO) during partial liquid ventilation (PLV) in rabbits with and without lung disease if compared with time-cycled, volume-controlled ventilation (CV) combined with muscle paralysis (MP). PLV was initiated in 17 healthy rabbits and 17 surfactant-depleted rabbits using 12 to 15 ml/kg of perfluorodecaline. Both ventilatory modes, SB+PAV and CV+MP, were applied in random sequence using a crossover design. CO was measured by thermodilution. CO was significantly higher during SB+PAV than during CV+MP: 136 +/- 21 ml/kg x min (mean +/- SD) versus 120 +/- 30 ml/kg x min (p = 0.004) in healthy rabbits, and 147 +/- 19 ml/kg x min versus 111 +/- 13 ml/kg x min (p < 0.0001) in surfactant-depleted rabbits, resulting in an improved oxygen delivery. This difference was mainly caused by a larger stroke volume during SB+PAV, whereas there was little change in heart rate. In surfactant-depleted rabbits, SB+PAV resulted in improved arterial blood pressure and arterial and mixed venous pH and in a higher PaO2 at the same level of PEEP and mean airway pressure. We conclude that during PLV, CO is higher during SB+PAV than during CV+MP, resulting in an improved oxygen delivery. In surfactant-depleted rabbits, improved CO, oxygen delivery, and arterial blood pressure resulted in higher pH, possibly reflecting improved tissue perfusion and oxygenation.     

Studies on the mechanism of the diabetogenic activity of streptozotocin and on the ability of compounds to block the diabetogenic activity of streptozotocin (author's transl)]

The present study was undertaken to clarify the mechanism of the diabetogenic activity of streptozotocin. Experiments were conducted to determine the resistance of animals to the diabetogenic action of streptozotocin; to follow the time course of irreversible beta-cell damage, and to determine the influence on streptozotocin action of certain compounds. Streptozotocin, a broad spectrum antibiotic, with antitumoral properties, was shown to be diabetogenic in rats and mice, but not in cats, rabbits, or guinea pigs. Intravenous or intraperitoneal administration of 65 mg/kg body weight of streptozotocin to male Wistar rats evoked a tri-phasic blood sugar response. It induced an initial hyperglycemic peak with no apparent change in plasma insulin concentrations, followed by profound hypoglycemia caused by liberation of large amounts of insulin from the pancreas. Forty-eight hours after injection, the animals were completely diabetic. Light- and electron-microscopic exadminations during the first forty-eight hours after the injection of streptozotocin showed pyknosis, degranulation and marked degeneration of the beta-cells. 1egenerative and necrotic changes were also seen in a few alpha-cells. These streptozotocin-induced diabetic rats revealed polydipsia, polyuria, polyphagia and glucosuria, and decreased body weight. Blood sugar, plasma FFA and insulin concentrations were examined after oral administration of glucose (OGTT: 3g/kg). Blood sugar and plasma FFA were significantly elevated but plasma insulin concentrations were markedly decreased, so insulin treatments were most effective in these animals. It has been reported that nicotinamide prevents the diabetogenic activity of streptozotocin and the deformity action of 6-aminonicotinamide and 3-acetylpridine. Pre-treatment with picolinamide, methyl-nicotinamide, and nicotinohydroxamic acid also blocked its diabetogenic action, but nicotinic acid, mannoheptulose and glucose were ineffective. N-nitrosodimethylamin and ethyl-N-nitrosomethylcarbamate were devoid of diabetogenicity. It seems that streptozotocin interfers with NAD formation in the beta-cell. Functioning pancreatic islets cell tumors were observed on the rats both at 407 days after streptozotocin administration and at 473 days after streptozotocin administration with nicotinamide (500 mg/kg, i.p.).     

An optimal dose of perfluorocarbon for respiratory mechanics in partial liquid ventilation for dependent lung-dominant acute lung injury

BACKGROUND: Despite increasing knowledge about partial liquid ventilation (PLV), the optimal dose of perfluorocarbon (PFC) is not yet established. Because there exist normal regions in the lung with ARDS and because PLV in the normal lung results in worsened gas exchange, we postulated that the optimal dose of PFC for PLV may be less than the functional residual capacity (FRC) dose in the lung with limited disease. DESIGN AND SETTING: Animal study at the Asan Institute for Life Sciences, Seoul, Korea. SUBJECTS: Twelve rabbits in which dependent lung-dominant lung injury was created by a modified saline solution lavage. INTERVENTIONS: PLV performed at six different doses of perfluorodecalin in sequence (3, 6, 9, 12, 15, and 18 mL/kg every 15 min). MEASUREMENTS AND RESULTS: Our modified saline solution lavage induced atelectasis and hemorrhage confined to the dependent lung with severe hypoxia (PaO(2)/fraction of inspired oxygen = 37 +/- 6 mm Hg). Peak airway pressure (Ppeak) and inspiratory pause pressure (Ppause) with PLV were lower at doses of 3 to 15 mL/kg (all p < 0.05), but not different at a dose of 18 mL/kg, when compared with gas ventilation. Ppeak increased at doses of 12, 15, and 18 mL/kg, when each was compared with the preceding PFC dose. At increasing PFC doses, the change in the elastic component of airway pressure (Ppause after minus Ppause before) was negative until the dose of 9 mL/kg, but was positive at doses of 12 mL/kg and above. The change in the resistive component ([Ppeak minus Ppause] after minus [Ppeak minus Ppause] before) was negative until the dose of 6 mL/kg, but was positive at the dose > or = 9 mL/kg. CONCLUSION: Respiratory mechanics during PLV for dependent lung-dominant lung injury were optimal at a PFC dose less than the FRC.     

Semi-fluorinated alkanes as carriers for drug targeting in acute respiratory failure

Partial liquid ventilation (PLV) with perfluorocarbons may cause pulmonary recruitment in acute lung injury (ALI). Semi-fluorinated alkanes (SFAs) provide biochemical properties similar to perfluorocarbons. Additionally, SFAs are characterized by increased lipophilicity. Therefore, SFA-PLV may be considered for deposition of certain therapeutic drugs into atelectatic lung areas. In this experimental study SFA-PLV was evaluated to demonstrate feasibility, pulmonary recruitment, and efficacy of drug deposition. Feasibility of SFA-PLV was determined in pigs with and without experimental ALI. Animals were randomized to PLV with SFAs up to a cumulative amount of 30 mL x kg?1 or to conventional mechanical ventilation. Pulmonary recruitment effects were determined by analyzing ventilation-perfusion distributions. Efficacy of intrapulmonary drug deposition was evaluated in further experiments by measuring drug serum concentrations in the course of PLV with SFA-dissolved α-tocopherol and ibuprofen. Increasing SFA doses caused progressive reduction of intrapulmonary shunt in animals with ALI, indicating pulmonary recruitment. PLV with SFA-dissolved α-tocopherol had no effect on serum levels of α-tocopherol, whereas PLV with SFA-dissolved ibuprofen caused a rapid increase of serum levels of ibuprofen. The authors conclude that SFA-PLV is feasible and causes pulmonary recruitment in ALI. Effectiveness of drug deposition in the lung obviously depends on the partitioning drugs out of the SFA phase into blood.     

Antibiotic levels in empyemic pleural fluid

OBJECTIVE: To determine the degree to which bioactive penicillin, metronidazole, ceftriaxone, clindamycin, vancomycin, and gentamicin penetrate into empyemic pleural fluid using our new rabbit model of empyema. METHODS: An empyema was created via the intrapleural injection of 10(8)()Pasteurella multocida bacteria into the pleural space of New Zealand white rabbits. After an empyema was verified by thoracentesis and pleural fluid analysis, penicillin, 24,000 U/kg; metronidazole, 37 mg/kg; ceftriaxone, 30 mg/kg; clindamycin, 9 mg/kg; vancomycin, 15 mg/kg; or gentamicin, 1 mg/kg, were administered IV. Antibiotic levels in samples of pleural fluid and serum, collected serially for up to 480 min, were then determined using a bioassay. RESULTS: The degree to which the different antibiotics penetrated into the infected pleural space was highly variable. Penicillin penetrated most easily, followed by metronidazole, ceftriaxone, clindamycin, vancomycin, and gentamicin. Of the antibiotics tested, penicillin and metronidazole equilibrated the most rapidly with the infected pleural fluid. Penicillin levels remained elevated in pleural fluid even after serum levels had decreased. CONCLUSIONS: Using this rabbit model of empyema, there was marked variation in the penetration of antibiotics into the empyemic fluid. Although there are species differences between rabbit and human pleura, the variance in degree of penetration of antibiotics into the pleural space should be considered when antibiotics are selected for the treatment of patients with empyema.     

Lung function and structure after Escherichia coli endotoxin in rabbits: effect of dose and rate of administration

We evaluated the effect of increasing doses of Escherichia coli endotoxin and its rate of administration on systemic blood pressure, alveolar-arterial oxygen gradient (A- aDO2 1.0), dynamic compliance (Cdyn), circulating platelets and leukocytes, and postmortem bloodless wet to dry ratios in anesthetized rabbits. Infusion of endotoxin resulted in systemic hypotension, diminished Cdyn, thrombocytopenia, and leukopenia, but did not influence venous admixture. These parameters were not affected by the rapidity of administration, but changes in Cdyn and circulating platelets were dose-dependent. High (15 mg/kg), but not low (0.5 mg/kg), doses of endotoxin resulted in an early but transient increase in lung water, but bloodless wet to dry weight ratios were not increased at 4-6 h following endotoxin even when high doses were injected. Ultrastructural studies done in six rabbits showed an early but transient platelet sequestration in pulmonary capillaries, progressive increase in intracapillary leukocytes, interstitial edema, and focal, although minimal, endothelial injury at 4 h after injection. Thus, infusion of E coli endotoxin in rabbits does not result in increased lung water and intrapulmonary shunting acutely; this tolerance to endotoxin is not related to the dose or rates of administration studied.     

Endotoxin increases the nephrotoxic potential of gentamicin and vancomycin plus gentamicin

To assess the possible role of endotoxin as an amplification factor for experimental nephrotoxicity due to gentamicin plus vancomycin, rats were given continuous intravenous (iv) endotoxin or saline followed by twice-daily intraperitoneal (ip) saline, vancomycin (20 mg/kg ip), gentamicin (15 mg/kg subcutaneously), or both gentamicin and vancomycin. After 5 or 8 days of treatment, functional and histologic parameters of renal function were evaluated: cortical drug levels, tritiated thymidine incorporation into cellular DNA, creatinine clearance, and appearance by light and electron microscopy. In animals not given endotoxin, only rats that received gentamicin plus vancomycin developed measurable abnormalities. Endotoxin did not cause nephrotoxicity in vancomycin-treated rats. However, in endotoxin-infused rats treated with gentamicin or gentamicin plus vancomycin for 8 days, the increase in blood urea nitrogen, decrease in creatinine clearance, and rise in renal cortical DNA synthesis were more severe than those in non-endotoxin-infused rats (P less than .01). In these studies, endotoxin amplified the nephrotoxic potential of gentamicin alone and gentamicin plus vancomycin.     

Effect of Acute Ethanol Administration on Toloxatone Pharmacokinetics in Rabbits

The pharmacokinetics of toloxatone and ethanol were determined in plasma and cerebrospinal fluid of conscious rabbits. According to a cross-over design, rabbits (n = 5) randomly received on three separate occasions either toloxatone (5 mg/kg), ethanol (1 g/kg), or toloxatone and ethanol (5 mg/kg and 1 g/kg, respectively) by intravenous injection. Toloxatone and ethanol concentrations were measured by HPLC with UV detection and GC with flame ionization detection, respectively. Ethanol concentration profiles in plasma were characterized by a rapid decline occurring within the first 30 min after administration followed by a linear (zero-order) phase that persisted for the length of the experiment. The maximum ethanol elimination rate was 0.31+/-0.20 g/h x kg. Toloxatone concentrations in plasma and cerebrospinal fluid were characterized by a multiexponential decay with effective half-lives of 0.39+/-0.06 and 0.56+/-0.07 hr, respectively. Toloxatone passage through the blood brain barrier was rapid and important. Our results also demonstrate that acute ethanol administration had no effect on toloxatone pharmacokinetics and that toloxatone administration had no effect on ethanol pharmacokinetics.     

Effect of single versus multiple dosing on perfluorochemical distribution and elimination during partial liquid ventilation.

The objective of this study was to quantitate perfluorochemical (PFC) elimination kinetics during partial liquid ventilation (PLV) following an initial fill with or without hourly dosing. Young New Zealand rabbits were studied in two groups: Gr I (n = 6), PLV with a single dose of PFC liquid (perflubron: LiquiVent, Alliance Pharmaceutical Corp.); and Gr II (n = 5), PLV with PFC liquid and multiple hourly dosing . All rabbits were studied for 4 h, following initial instillation of a volume of PFC liquid equal to the measured gas functional residual capacity. Animals were ventilated at a constant breathing frequency (30 br/min), tidal volume (9.3+/-0.3 SE mL/kg), positive end expiratory pressure (4 cm H2O), and inspiratory time (0.30 s). PFC saturation of mixed expired gas (PFC-Sat) was assessed with a thermal conductivity analyzer, and PFC elimination was calculated from PFC-Sat, minute ventilation, and temperature of the expired gas. In GR II, PFC was supplemented hourly at a volume determined by PFC elimination calculations. The results demonstrated a decrease in PFC-sat and PFC loss with time, independent of group (P< 0.05). In addition, with hourly supplementation (GR II), PFC-Sat and PFC elimination over time was significantly (P < 0.05) greater than in animals (GR I) which did not receive additional doses. These data demonstrate that the PFC elimination rate is not constant and is related to the amount of PFC in the respiratory system. This may have occurred due to distributional differences of ventilation and PFC liquid between the single and multiple dosing groups. These findings also suggest that evaluation of PFC concentrations in expired gas may be a clinically useful index of intrapulmonary PFC distribution during PLV, and that maintained elevation of expired gas PFC saturation may guide optimal PFC dosing intervals and distribution to maximize protection against barotrauma.     

Antibiotic concentrations in serum and wound fluid after local gentamicin or intravenous dicloxacillin prophylaxis in cardiac surgery

One important aim of antibiotic prophylaxis in cardiac surgery is preventing mediastinitis and thus it would appear to be relevant to study the antibiotic concentrations in pericardial/mediastinal fluid. Local administration of gentamicin in the wound before sternal closure is a novel way of antibiotic prophylaxis and could be effective against bacteria resistant to intravenous antibiotics. This study measured dicloxacillin concentrations in 101 patients in serum and wound fluid following intravenous administration of dicloxacillin. Similarly, concentrations of gentamicin in serum and wound fluid were determined in 30 patients after administration of 260 mg gentamicin in the wound at sternal closure. Median dicloxacillin concentrations in serum and wound fluid at sternal closure were 59.4 and 55.35 mg/l, respectively. Gentamicin levels in the wound were very high (median 304 mg/l), whereas serum concentrations were low (peak median 2.05 mg/l). Dicloxacillin, 1 g given intravenously, according to the clinical protocol, resulted in levels in serum and wound fluid at sternal closure likely to prevent Staphylococcus aureus infections. Locally administered gentamicin resulted in high local concentrations, potentially effective against agents normally considered resistant.     

Relationship of serum antibiotic concentrations to nephrotoxicity in cancer patients receiving concurrent aminoglycoside and vancomycin therapy

Methicillin-resistant coagulase-negative staphylococci have become increasingly responsible for febrile episodes in cancer patients, often necessitating the addition of vancomycin to an aminoglycoside-containing broad-spectrum antibiotic regimen. A total of 229 courses of antibiotic therapy in 229 patients were evaluated for nephrotoxicity associated with the administration of an aminoglycoside and/or vancomycin. The incidence of nephrotoxicity observed in patients administered an aminoglycoside (Group A) was 18 percent; vancomycin (Group B) 15 percent; and an aminoglycoside concurrently with vancomycin (Group C) 15 percent. The following pharmacokinetic/dosing factors were significantly associated with increased nephrotoxicity in the groups: baseline serum creatinine level, mean daily dose during the first three days of therapy (Group B), and elevated serum trough aminoglycoside or vancomycin concentrations (2 micrograms/ml or more or 10 micrograms/ml or more, respectively). No cumulative nephrotoxicity was demonstrated with the concurrent administration of vancomycin and an aminoglycoside. A higher incidence of nephrotoxicity was seen in Group C (42 percent) and Group B (27 percent) patients, in whom trough serum vancomycin concentrations were 10 micrograms/ml or more.     

Intraosseous administration of antibiotics: same-dose comparison with intravenous administration in the weanling pig

STUDY OBJECTIVES: To assess the reliability of the intraosseous route of administration for delivery of a loading dose of broad-spectrum antibiotics in a pediatric animal model. DESIGN: Serum levels achieved within 90 minutes of equivalent intraosseous (IO) and IV bolus dosing of ceftriaxone, cefotaxime, and a combination of ampicillin and gentamicin were compared in the weanling pig. SUBJECTS: Twelve female weanling pigs were studied in the Animal Facilities Laboratory at the University of Mississippi Medical Center. INTERVENTIONS: Through a proximal tibial IO catheter, each anesthetized animal received one of the following: 50 mg/kg ceftriaxone, 50 mg/kg cefotaxime, or 300 mg/kg ampicillin followed immediately by 2.5 mg/kg gentamicin. Venous blood was obtained for antibiotic assay at 15, 30, 45, 60, and 90 minutes after IO injection. The animals were allowed to recover, and, after a one-week washout period, each received the same antibiotic and dose as before through a peripheral IV. Levels were assayed at the same intervals and IO versus IV were compared. MEASUREMENTS AND MAIN RESULTS: Comparable serum levels of all four antibiotics were achieved by the two routes. Gentamicin levels were statistically indistinguishable IO versus IV at all assay intervals. Ampicillin and cefotaxime levels achieved by the two routes were equivalent within one hour of dosing. Serum levels of ceftriaxone after IO administration paralleled those after IV dosing but remained significantly lower at all time intervals. CONCLUSIONS: In the weanling pig model, the IO route was used to deliver serum levels of broad-spectrum antibiotics comparable to those attained after IV administration. The data support the use of standard parenteral doses for IO administration. To overcome potential avid protein binding of ceftriaxone in the bone marrow, we recommend using ceftriaxone at its highest recommended IO loading dose. Consistent with many other medications that have been similarly tested, these data indicate that initial or empiric antibiotic coverage in hypodynamic and shock states in infants and young children need not await the establishment of traditional IV access.     

Gentamicin sulfate pharmacokinetics: lower levels of gentamicin in blood during fever.

The effect of fever on serum concentrations and urinary excretion of gentamicin sulfate was studied in humans and dogs. Endotoxin-induced fever in dogs resulted in a decrease of approximately 25% in levels of gentamicin in serum 30 and 60 min after intravenous injection of the antibiotic (1.5 mg/kg) when compared with corresponding afebrile values. In six volunteers with etiocholanolone-stimulated fever, serum concentrations of gentamicin was reduced by an average of 40% in all measurements made 1.2, and 3 hr after intramuscular injection (1.5 mg/kg) as compared with afebrile control values in the same subject. Fever was thought to be the principal factor associated with lower levels of gentamicin, although the half-life of gentamicin in serum and renal clearance of the antibiotic were not significantly affected. These findings emphasize the need for frequent measurements of gentamicin in serum as a guide to adjustment of gentamicin treatment in febrile subjects, and perhaps in all patients receiving the antibiotic.     

Theoretical approach to local infusion of antibiotics for infected pancreatic necrosis

Background/objectivesInfected pancreatic necrosis is a major complications of acute pancreatitis. If drainage is required, local administration of antibiotics through transmural nasocystic or percutaneous catheter may allow increasing local antibiotic concentrations. Drug diffusion becomes the main factor influencing local drug tissue penetration. The present study aims at providing the rationale for the design of new research protocols evaluating the efficacy of local antibiotics for infected pancreatic necrosis.MethodsA review of microbiological data was performed for the most common organisms causing the infection, antibiotics spectrum and minimum inhibitory concentrations (MIC). A search of the physico-chemical properties of antibiotics was performed to calculate the diffusion coefficients. An estimation of the antibiotic concentrations in pancreatic tissue was obtained using a mathematical model. Efficacy factors (EF) were calculated and the stability of the antibiotic solutions were evaluated to optimize the dosing regimen.ResultsPiperacillin, vancomycin and metronidazole achieve high concentrations in the surrounding tissue very fast. Imipenem, ceftriaxone, ciprofloxacin, gentamicin, linezolid and cloxacillin achieve intermediate concentration values. Tigecycline, showed the lowest concentration values (<2 mg/L). Calculated EF is highest for piperacillin and imipenem short after administration and near to surface diffusion area (0.5 cm), but EF of imipenem is higher at deeper areas and longer time after administration.ConclusionsConsidering obtained results, some solutions are proposed using saline as diluent and 25 °C of temperature during administration. Imipenem has the best theoretical results in empiric local treatment. Linezolid and tigecycline solutions are not recommended.     

Penetration of gentamicin into the alveolar lining fluid of critically ill patients with ventilator-associated pneumonia

STUDY OBJECTIVES: To estimate the penetration of gentamicin into lung tissue by measuring its concentrations in alveolar lining fluid (ALF) and blood in critically ill patients with ventilator-associated pneumonia (VAP). PATIENTS AND INTERVENTIONS: The study population consisted of 24 patients who were admitted to an ICU for respiratory failure and developed VAP. Patients were scheduled to undergo bronchoscopy with BAL after IV administration of a once-daily, 240-mg schedule of gentamicin for the treatment of VAP. Patients were assigned at random to one of four groups of six patients each according to the scheduled time for bronchoscopy (1, 2, 4, or 6 h, respectively). A serum sample was obtained at 0.5 h (n = 24), and both serum and ALF samples (n = 6) were collected at each of the above specified times for measurement of antibiotic concentrations. MEASUREMENTS AND RESULTS: Mean +/- SEM gentamicin concentrations in the ALF were 2.95 +/- 0.37, 4.24 +/- 0.42, 3.10 +/- 0.39, and 2.65 +/- 0.35 microg/mL at 1, 2, 4, and 6 h, respectively, after the start of antibiotic infusion. Maximum gentamicin concentrations in serum (13.39 +/- 0.91 mug/mL, n = 24) and ALF (4.24 +/- 0.42 microg/mL, n = 6) were achieved at 0.5 h and 2 h, respectively, giving a penetration ratio of 0.32. The mean ratios of ALF/serum concentrations between 1 h and 6 h ranged from 0.30 to 1.14. After completion of the distribution phase, a significant positive correlation (p = 0.02) was found between gentamicin concentrations in the serum and ALF. CONCLUSIONS: Once-daily IV administration of 240-mg gentamicin achieved average peak antibiotic concentrations of 4.24 microg/mL in the ALF 2 h after administration, and an ALF/serum penetration ratio of 32%. Higher gentamicin doses to produce higher peak blood levels than those found with the study dose are necessary to obtain active alveolar concentrations against less sensitive microorganisms in the treatment of VAP in ICU patients.     

The granulocyte colony-stimulating factor response after intrapulmonary and systemic bacterial challenges

In contrast to many cytokines such as tumor necrosis factor (TNF)-alpha, we hypothesized that, after an intrapulmonary bacterial challenge, lung-derived granulocyte colony-stimulating factor (G-CSF) would subsequently enter the systemic circulation. BALB/c mice were given Escherichia coli or saline, either intratracheally or intravenously. Four hours after intratracheal E. coli administration, bronchoalveolar lavage fluid (BALF) and plasma G-CSF concentrations increased, compared with concentrations in phosphate-buffered saline-treated controls. Lung G-CSF messenger RNA (mRNA) increased to 586+/-229 copies G-CSF mRNA/ng ribosomal RNA (rRNA) from the values in control animals (<0.5 copies/ng rRNA). In contrast, G-CSF mRNA was not increased in the extrapulmonary tissues examined (liver, spleen, and kidney) in mice challenged with intratracheal E. coli (<1 copy/ng rRNA). Intravenous E. coli increased plasma G-CSF and TNF-alpha, but neither cytokine was detected in BALF. These data show that, after an intrapulmonary infection, both lung and circulating G-CSF increase and that the lung is the likely source.     

Distribution of ethambutol in primate tissues and cells

Ethambutol (EMB) concentrations that kill Mycobacterium tuberculosis in vitro accumulated in squirrel monkey tissues and cells known to be sites of tubercular infections. After oral administration of a clinically relevant 25 mg/kg dose, the whole-body distribution and intracellular localization of EMB were studied by radioautography. Tissue concentrations of drug were assayed by radiochemical and microbiological methods. The EMB was distributed rapidly and widely to most body tissues including lung and localized within pulmonary alveolar and axillary lymph node macrophages. The EMB in lung at 2 and 5 h after drug administration was markedly higher than the corresponding plasma concentrations and exceeded concentrations that are bactericidal in vitro for tubercle bacilli. These observations may help explain the early bactericidal activity of EMB in humans. Similarities in plasma and tissue concentrations of the drug in both species suggest the usefulness of the squirrel monkey as a model for the use of EMB in humans.