Alex P. Betrosian

Efficacy and safety of high-dose ampicillin/ sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia

OBJECTIVE To compare the safety and efficacy of ampicillin/sulbactam (Amp/Sulb) and colistin (COL) in the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP). METHODS A prospective cohort study in adult critically ill patients with VAP. Patients were randomly assigned to receive Amp/Sulb (9 g every 8h) or COL (3 MIU every 8h) intravenously. Dosage was adjusted according to creatinine clearance. RESULTS A total of 28 patients were enrolled (15 COL, 13 Amp/Sulb). Resolution of symptoms and signs occurred in 60% (9/15) of the COL group and 61.5% (9/13) of the Amp/Sulb group, improvement in 13.3% (2/15) vs. 15.3% (1/13) and failure in 26.6% (4/15) vs. 23% (3/13), respectively. The difference was not statistically significant. Bacteriologic success was achieved in 66.6% (10/15) vs. 61.5% (8/13) in the COL and Amp/Sulb groups, respectively (p<0.2). Mortality rates (14 days and 28 days) were 15.3% and 30% for the Amp/Sulb and 20% and 33% for the COL group, respectively. Adverse events were 39.6% (including 33% nephrotoxicity) for the COL group and 30.7% (15.3% nephrotoxicity) for the Amp/Sulb group (p=NS). CONCLUSION Colistin and high-dose ampicillin/sulbactam were comparably safe and effective treatments for critically ill patients with MDR A. baumannii VAP.

Protein C in the treatment of coagulopathy in meningococcal disease

OBJECTIVE To evaluate the clinical and laboratory effects of the substitution of protein C (PC) as an adjunct to conventional therapy in the treatment of purpura fulminans associated with meningococcal sepsis. DESIGN case series. SETTING Medical and medical-surgical intensive care units of two university hospitals. PATIENTS Three patients with purpura fulminans and multiple organ failure caused by Neisseria meningitidis. INTERVENTION Intravenous administration of PC concentrate (100 IU/kg every 6 to 8 hrs). MEASUREMENTS AND MAIN RESULTS The administration of PC resulted in normal or above normal levels of the plasma PC activity in all patients. The laboratory and clinical parameters reflecting the severity of coagulopathy improved during the treatment, as did peripheral ischemia and the clinical manifestations of multiple organ failure. No adverse events were noted. One patient died of cerebral edema. CONCLUSION The administration of PC had a beneficial effect on coagulopathy and peripheral gangrene formation associated with meningococcal disease and showed no adverse effects.

High-dose ampicillin-sulbactam as an alternative treatment of late-onset VAP from multidrug-resistant Acinetobacter baumannii

The increased incidence of multidrug-resistant (MDR) Acinetobacter baumannii ventilator-associated pneumonia in critically ill patients poses a severe therapeutic problem. The aim of this study was to evaluate the efficacy and safety of 2 high-dose treatment regimens of ampicillin-sulbactam (A/S) for MDR Acinetobacter baumannii VAP. We undertook a randomized, prospective trial of critically ill patents with (MDR) Acinetobacter baumannii VAP. Patients were randomly assigned to 1 of 2 treatment regimens of A/S (at a rate 2:1 every 8 h): 1) group A, 18/9 g daily dose (n = 14); and 2) group B, 24/12 g daily dose (n = 13). The duration of therapy was 8±2 d for both groups. A total of 27 patients were enrolled in the study. Clinical improvement was seen in 66.7% of the study population in 9/14 (64.3%) of group A patients and 9/13 (69.2%) of group B patients, respectively. Bacteriological success was achieved in 77.8% of the study population (12/14, 85.7% of group A) and in 9/13 (69.2%) of group B patients. The 14-d mortality rate was 25.9% and the all cause 30-d mortality was 48.1%. Both mortality rates did not differ significantly between the 2 groups. No major adverse reactions were recorded. We concluded that clinical and bacteriological results of the study support the use of high-dose regimen of ampicillin-sulbactam for MDR Acinetobacter baumannii VAP.

Bacterial sepsis-induced rhabdomyolysis

Objective: To describe the syndrome of rhabdomyolysis during bacterial sepsis with regard to incidence, blood bacteriology and complications and to examine the association between hyperosmolal state and rhabdomyolysis, evaluating the relationship between plasma osmolality (Posm) and serum creatine phosphokinase (CPK) levels. Design: Prospective study including all patients admitted to the intensive care unit (ICU) for sepsis with positive blood culture and rhabdomyolysis over a 3-year period. Setting: Seven-bed medical/surgical ICU of a teaching hospital. Patients: 35 patients (group 1) with bacterial sepsis-induced rhabdomyolysis (15 males, 20 females; mean age 71 ± 13 years) and 122 (group 2) bacteraemic septic patients without rhabdomyolysis (49 males, 73 females; mean age 68 ± 15) were studied. Patients with rhabdomyolysis were divided into gram( + ) and gram(–) subgroups according to the blood culture growth. Results: From 491 patients recorded, 35 fulfilled the inclusion criteria for bacterial sepsis-induced rhabdomyolysis (7.1 %). Gram-positive bacteria predominated in group 1 (69 %), while gram-negative predominated (60 %) in group 2. There was a correlation between CPK and Posm levels in the rhabdomyolysis Group (r = 0.52, R2 = 0.27, p = 0.003). There was a stronger correlation between these two variables (r = 0.67, R2 = 0.45, p = 0.001) in the gram( + ) subgroup. Acute renal failure (68.5 %) and electrolyte disorders such as hyperkalaemia (34 %) and hypocalcaemia (48.5 %) were the major complications in the rhabdomyolysis group. Sixteen (45.7 %) patients in group 1 and 49 (40 %) in group 2 died during their stay in the ICU from sepsis and multiple organ failure. Rhabdomyolysis was not considered a contributing factor to their death, as none of our patients died during or immediately after the syndrome. Conclusion: Bacterial sepsis-induced rhabdomyolysis results from certain types of microorganisms, mainly gram-positive and to a lesser extent gram-negative. Hyperosmolality is a predisposing mechanism for rhabdomyolysis during bacteraemic sepsis from any type of bacterial microorganism.

The level of hypotension during hemorrhagic shock is a major determinant of the post-resuscitation systemic inflammatory response: an experimental study

BackgroundTo evaluate whether the level of hypotension during hemorrhagic shock may influence the oxidative and inflammatory responses developed during post-ischemic resuscitation.MethodsFifteen rabbits were equally allocated into three groups: sham-operated (group sham); bled within 30 minutes to mean arterial pressure (MAP) of 40 mmHg (group shock-40); bled within 30 minutes to MAP of 30 mmHg (group shock-30). Shock was maintained for 60 min. Resuscitation was performed by reinfusing shed blood with two volumes of Ringers lactate and blood was sampled for estimation of serum levels aminotransferases, creatinine, TNF-α, IL-1β, IL-6, malondialdehyde (MDA) and total antioxidant status (TAS) and for the determination of oxidative burst of polymorhonuclears (PMNs) and mononuclear cells (MCs).ResultsSerum AST of group shock-30 was higher than that of group shock-40 at 60 and 120 minutes after start of resuscitation; serum creatinine of group shock-30 was higher than group shock-40 at 120 minutes. Measured cytokines, MDA and cellular oxidative burst of groups, shock-40 and shock-30 were higher than group sham within the first 60 minutes after start of resuscitation. Serum concentrations of IL-1β, IL-6 and TNF-α of group shock-30 were higher than group shock-40 at 120 minutes (p < 0.05). No differences were found between two groups regarding serum MDA and TAS and oxidative burst on PMNs and MCs but both groups were different to group sham.ConclusionThe level of hypotension is a major determinant of the severity of hepatic and renal dysfunction and of the inflammatory response arising during post-ischemic hemorrhagic shock resuscitation. These findings deserve further evaluation in the clinical setting.

Administration of human protein C improves survival in an experimental model of sepsis

Objective:Study the effect of human protein C (PC) concentrate administration on organ damage and survival in septic rats. Design:Animal study. Setting:University laboratory. Subjects:Male Wistar rats. Interventions:Cecal ligation and puncture (CLP) was performed in 210 rats. Rats were randomly assigned to receive either human protein C (PC) IV 1, 7, and 13 hrs after CLP (CLP+PC) or placebo (CLP). Septic animals were again randomized in a survival group (CLP: n = 50 and CLP+PC: n = 40) that was monitored for 60 hrs and time groups (CLP: n = 60 and CLP+PC: n = 60) that were killed at 6, 12, 24, 36, 48, and 60 hrs after CLP. Brain, heart, lung, liver, kidney, gastric, and colon tissue were removed and postfixed in paraffin sections. Measurements and Main Results:PC infusion increased PC serum levels in early sepsis (median 7.25) compared with late sepsis (median 2, p = .001). Activated protein C/a1-antitrypsin complex levels in the CLP+PC group were significantly increased in late sepsis (60 hrs after CLP) compared with early sepsis (6, 12, and 24 hrs after CLP, p = .009, p = .004, and p = .008, respectively) and to late septic CLP and normal rats (p = .005 and p = .007, respectively). Their IL-6 and tumor necrosis factor a plasma levels were decreased (by 27% and 25%, respectively) at 6 hrs compared with placebo (p = .008 and p = .016). Their serum PC levels were also decreased in CLP+PC survivors compared with nonsurvivors of the same group (median = 1.5 vs. median = 7, p = .001). Apoptosis was reduced in brain (10% vs. 77.8%, p < .001), stomach (66.7% vs. 100%, p < .002) and intestine (33.3% vs. 85.2%, p < .001) compared with placebo. Finally, the survival of septic rats treated with human PC was significantly increased compared with placebo (75% vs. 54%, p = .033). Conclusions:Human Protein C administration increased survival in septic rats, decreased plasma inflammatory cytokines levels and tissue injury in vital organs.

Ampicillin-sulbactam: an update on the use of parenteral and oral forms in bacterial infections

Ampicillin-sulbactam has a wide range of antibacterial activity that includes Gram-positive and Gram-negative aerobic and anaerobic bacteria. However, the drug is not active against Pseudomonas aeruginosa and pathogens producing extended-spectrum β-lactamases. The combination could be considered particularly active against Acinetobacter baumannii infections due to the intrinsic activity of sulbactam. The drug is indicated as empirical therapy for a broad range of community acquired infections supervened in adults or children and is effective in either parenteral (ampicillin-sulbactam) or oral (as a mutual prodrug sultamicillin) form. In clinical trials, sultamicillin has proved clinically and bacteriologically effective in adults and children against a variety of frequently encountered infections, including mild upper and lower respiratory tract infections, urinary tract infections, diabetic foot and skin and soft tissue infections. Furthermore, adverse effects rarely occur with the diarrhoea to represent the most commonly reported. The parenteral ampicillin-sulbactam is indicated for community infections of mild-to-moderate severity acquired infections such as intra-abdominal or gynecological. Moreover, it seems to represent the alternative of choice for the treatment of A. baumannii infections for carbapenem-resistant strains in the nosocomial setting. Thus, ampicillin-sulbactam remains a valuable agent in the physicians armamentarium in the management of adult and pediatric infections.

Heparin-Induced Thrombocytopenia with Pulmonary Embolism and Disseminated Intravascular Coagulation Associated with Low-Molecular-Weight Heparin

Heparin-induced thrombocytopenia (HIT) is a severe adverse effect of heparin therapy. Although most cases occur in patients receiving unfractionated heparin, HIT can arise in venous thrombosis prophylaxis with a low-molecular-weight heparin (LMWH). We report an uncommon case of HIT in a postoperative orthopedic patient associated with LMWH (nadroparin), complicated by deep venous thrombosis, pulmonary embolism, and disseminated intravascular coagulation, treated successfully with recombinant hirudin and immunoglobulin therapy.

Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report

IntroductionAzoles, and specifically itraconazole, are often prescribed for the treatment of fungal diseases or empirically for persistent sepsis in patients who are neutropenic or in intensive care. Occasional cardiovascular adverse events have been associated with itraconazole use, and are usually attributed to the interaction of itraconazole with cisapride, terfenadine or digoxin. Its interaction with amiodarone has not been previously described.Case presentationA 65-year-old Caucasian man was admitted to the Intensive Care Unit at our facility for an extensive ischemic stroke associated with atrial fibrillation. Due to rapid ventricular response he was started on intravenous amiodarone and few days later itraconazole was also prescribed for presumed candidemia. After receiving the first dose our patient became profoundly hypotensive but responded rapidly to fluids and adrenaline. Then, two months later, itraconazole was again prescribed for confirmed fungemia. After receiving the first dose via a central venous catheter our patient became hypotensive and subsequently arrested. He was resuscitated successfully, and as no other cause was identified the arrest was attributed to septic shock and his antifungal treatment was changed to caspofungin. When sensitivity test results became available, antifungal treatment was down-staged to itraconazole and immediately after drug administration our patient suffered another arrest and was once again resuscitated successfully. This time the arrest was related to itraconazole, which was discontinued, and from then on our patient remained stable until his discharge to our neurology ward.ConclusionsItraconazole and amiodarone coadministration can lead to serious cardiovascular adverse events in patients who are critically ill. Intensivists, pharmacists and medical physicians should be aware of the interaction of these two commonly used drugs.

Hypoxemic resuscitation from hemorrhagic shock prevents lung injury and attenuates oxidative response and IL-8 overexpression

We investigated whether hypoxemic resuscitation from hemorrhagic shock prevents lung injury and explored the mechanisms involved. We subjected rabbits to hemorrhagic shock for 60 min by exsanguination to a mean arterial pressure of 40 mm Hg. By modifying the fraction of the inspired oxygen, we performed resuscitation under normoxemia (group NormoxRes, P(a)O(2)=95-105 mm Hg) or hypoxemia (group HypoxRes, P(a)O(2)=35-40 mm Hg). Animals not subjected to shock constituted the sham group (P(a)O(2)=95-105 mm Hg). We performed bronchoalveolar lavage (BAL) fluid, lung wet-to-dry weight ratio, and morphological studies. U937 monocyte-like cells were incubated with BAL fluid from each group. Cell peroxides, malondialdehyde, proteins, and cytokines in the BAL fluid were lower in sham than in shocked animals and in HypoxRes than in NormoxRes animals. The inverse was true for ascorbic acid and reduced glutathione. Lung edema, lung neutrophil infiltration, myeloperoxidase, and interleukin (IL)-8 gene expression were reduced in lungs of HypoxRes compared with NormoxRes animals. A colocalized higher expression of IL-8 and nitrotyrosine was found in lungs of NormoxRes animals compared to HypoxRes animals. The BAL fluid of NormoxRes animals compared with HypoxRes animals exerted a greater stimulation of U937 monocyte-like cells for proinflammatory cytokine release, particularly for IL-8. In the presence of p38-MAPK and Syk inhibitors and monosodium urate crystals, IL-8 release was reduced. We conclude that hypoxemic resuscitation from hemorrhagic shock ameliorates lung injury and reduces oxygen radical generation and lung IL-8 expression.