When More Is Still Not Enough: A Case of Ceftazidime-Avibactam Resistance in a Burn Patient.

Burn patients have numerous risk factors for multidrug-resistant organisms (MDROs) and altered pharmacokinetics, which both independently increase the risk of treatment failure. Data on appropriate antimicrobial dosing are limited in this population and therapeutic drug monitoring (TDM) for beta-lactams is impractical at most facilities. Technology is available that can detect genetic markers of resistance, but they are not all encompassing, and often require specialized facilities that can detect less common genetic markers. Newer antimicrobials can help combat MDROs, but additional resistance patterns may evolve during treatment. Considering drug shortages and antimicrobial formularies, clinicians must remain vigilant when treating infections. This case report describes the development of resistance to ceftazidime-avibactam in a burn patient. The patient was a 54-year-old burn victim with a 58% total body surface area (TBSA) thermal burn who underwent multiple courses of antibiotics for various Pseudomonal infections. The initial Pseudomonal wound infection was sensitive to cefepime, aminoglycosides, and meropenem. A subsequent resistant pseudomonal pneumonia was treated with ceftazidime-avibactam 2.5 g every 6 hours due to the elevated MIC to cefepime (16 mcg/mL) and meropenem (>8 mcg/mL). Although the patient improved over 7 days, the patient again spiked fevers and had increased white blood counts (WBC). Repeat blood cultures demonstrated a multidrug-resistant (MDR) Pseudomonas with a minimum inhibitory concentration (MIC) to ceftazidime-avibactam of 16 mcg/mL, which is above the Clinical and Laboratory Standards Institute (CLSI) breakpoint of 8 mcg/mL. At first, resistance was thought to have occurred due to inadequate dosing, but genetic work demonstrated multiple genes encoding beta-lactamases.

A Cautionary Tale of Etanercept Use in Patients With Toxic Epidermal Necrolysis.

Toxic epidermal necrolysis (TEN) is a severe cutaneous reaction that can be life-threatening. In the United States, there are no established guidelines for the treatment of TEN. Supportive care including fluids and supportive therapies are the current recommendations. Research surrounding TEN involves mostly case studies or small, uncontrolled studies. Recent literature describes the use of tumor necrosis factor blockers in the treatment of TEN with positive results. These case reports describe decreased time to reepithelization, hospital length of stay, and minimal side effects. Conversely, we present three fatalities after the administration of etanercept.

Impact of Genitourinary Injuries on Patients Requiring an Emergency Laparotomy for Trauma.

Introduction In patients having emergency abdominal surgery for trauma, the presence of urologic injury tends to increase mortality and morbidity. Methods This retrospective study evaluated patients requiring emergency surgery for abdominal trauma at a Level 1 Trauma Center over 30 years (1980-2010). Special attention was given to patients with concomitant genitourinary (GU) injuries. Results Of 1105 patients requiring an emergency laparotomy for trauma, 242 (22%) had urologic injuries including kidney 178 (16%), ureter 47 (4%), and bladder 46 (4%). Of the 242 patients, 50 (20%) died early (<48 hours) and 13 (5%) died later, primarily due to infection. A concept of "seven deadly signs" of hypoperfusion was developed. In patients with GU injuries, the presence of any deadly sign of hypoperfusion increased the mortality rate from 4% (6/152) to 63% (56/90), p<0.001. Of the 53 patients having a nephrectomy, 36 (68%) had one or more deadly signs and 27 (75%) died. Of 17 without deadly signs, only 2 (12%) died (p=0.001). Of 167 GU patients receiving blood, 59 (35%) developed infection vs 3/75(4%) in those receiving no blood (p<0.001). Conclusions The presence of deadly signs of severe injury and hypoperfusion on admission was the major factor determining mortality. With a severely injured kidney plus any deadly signs of hypoperfusion, special efforts should be made to avoid a nephrectomy.

Hydromorphone vs fentanyl for epidural analgesia and anesthesia.

BACKGROUND: Epidural analgesia/anesthesia is used during surgery because it dramatically relieves pain and attenuates the stress response. Because limited data exist regarding the relative merits of hydromorphone (HM) and fentanyl (FENT), the objective was to determine which was more safe and effective. METHODS: Prospective case-matched, observational study evaluated elective surgery patients: 30 HM and 60 FENT. Variables were measured perioperatively. RESULTS: Of the 90 patients, mean age was 52 years; simplified acute physiology score was 26 ± 10; and American Society of Anesthesiologists score was 2.4 HM vs 2.7 FENT, P = .03. HM patients were more apt to be excessively sedated (16% HM vs 1% FENT, P = .007) and have poor mental unresponsiveness (6% HM vs 0% FENT, P = .04). The incidence of hypotension was not different, 76% HM vs 80% FENT, not significant. CONCLUSIONS: In a closely case-matched population, FENT caused less excessive sedation and unresponsiveness. FENT patients had better intraoperative urine output and tended to have less repeated episodes of hypotension.

Impact of inappropriate initial antibiotics in critically ill surgical patients with bacteremia.

BACKGROUND: Bloodstream infections in critically ill patients are associated with mortality as high as 60% and a prolonged hospital stay. We evaluated the impact of inappropriate antibiotic therapy (IAAT) in a critically ill surgical cohort with bacteremia. METHODS: This retrospective study evaluated adults with intensive care unit admission greater than 72 hours and bacteremia. Two groups were evaluated: appropriate antibiotic therapy (AAT) vs IAAT. RESULTS: In 72 episodes of bacteremia, 57 (79%) AAT and 15 (21%) IAAT, mean age was 54 ± 17 years and APACHE II of 17 ± 8. Time to appropriate antibiotics was longer for IAAT (3 ± 5 IAAT vs 1 ± 1 AAT days, P = .003). IAAT was seen primarily with Acinetobacter spp (33% IAAT vs 9% AAT, P = .01) and Enterococcus faecium (26% IAAT vs 7% AAT, P = .03). If 2 or more bacteremic episodes occurred, Acinetobacter spp. was more likely, 32% vs 2%, P = .001. CONCLUSIONS: AAT selection is imperative in critically patients with bacteremia to reduce the significant impact of inappropriate selection. Repeated episodes of bacteremia should receive special attention.

Impact of minimizing diagnostic blood loss in the critically ill.

BACKGROUND: The use of a small-volume phlebotomy tube (SVPT) versus conventional-volume phlebotomy tube (CVPT) has led to a decrease in daily blood loss. Blood loss due to phlebotomy can lead ultimately to decreased rates of anemia and blood transfusions, which can be important in the critically ill patient. METHODS: We compared SVPT vs CVPT retrospectively in critically ill adult patients age ≥18 years admitted to a surgical intensive care unit for ≥48 hours. CVPT were evaluated from January 2011 to May 2011 and SVPT from June 2012 to October 2012. RESULTS: Amount of blood drawn for laboratory tests and transfusions were evaluated in 248 patients (116 SVPT vs 132 CVPT). When compared with CVPT, total blood volume removed (mean ± SD) with SVPT was less overall, 174 ± 182 mL vs 299 ± 355 mL, P = .001. Daily blood draws also were less, 22.5 ± 17.3 mL vs 31.7 ± 15.5 mL, P < .001. The units of packed red blood cells given were not significant, 4.4 ± 3.6 units vs 6.0 ± 8.2 units, P = .16. CONCLUSION: The use of SVPT blood sampling led to a decreased amount of blood drawn. Strategies that use SVPT in a larger cohort also may decrease the number of transfusions in selected patients. Every effort should be made to use SVPT.

Hyperbaric oxygen therapy for systemic gas embolism after hydrogen peroxide ingestion.

BACKGROUND: Hydrogen peroxide is a commonly available product and its ingestion has been demonstrated to produce in vivo gas bubbles, which can embolize to devastating effect. OBJECTIVE: We report two cases of hydrogen peroxide ingestion with resultant gas embolization, one to the portal system and one cerebral embolus, which were successfully treated with hyperbaric oxygen therapy (HBO), and review the literature. CASE REPORT: Two individuals presented to our center after unintentional ingestion of concentrated hydrogen peroxide solutions. Symptoms were consistent with portal gas emboli (Patient A) and cerebral gas emboli (Patient B), which were demonstrated on imaging. They were successfully treated with HBO and recovered without event. CONCLUSIONS: As demonstrated by both our experience as well as the current literature, HBO has been used to successfully treat gas emboli associated with hydrogen peroxide ingestion. We recommend consideration of HBO in any cases of significant hydrogen peroxide ingestion with a clinical picture compatible with gas emboli.

Estimating the parameters of audible clinical percussion signals by fitting exponentially damped harmonics.

Used for centuries in the clinical practice, audible percussion is a method of eliciting sounds by tapping various areas of the human body either by finger tips or by a percussion hammer. Despite its advantages, pulmonary diagnostics by percussion is still highly subjective, depends on the physician's skills, and requires quiet surroundings. Automation of this well-established technique could help amplify its existing merits while removing the above drawbacks. In this work, clinical percussion signals from normal volunteers are decomposed into a sum of exponentially damped sinusoids (EDS) whose parameters are determined using the Matrix Pencil Method. Some EDS represent transient oscillation modes of the thorax/abdomen excited by the percussion event, while others are associated with the noise. It is demonstrated that relatively few EDS are usually enough to accurately reconstruct the original signal. It is shown that combining the frequency and damping parameters of these most significant EDS allows for efficient classification of percussion signals into the two main types historically known as "resonant" and "tympanic." This classification ability can provide a basis for the automated objective diagnostics of various pulmonary pathologies including pneumothorax. The algorithm can be implemented on an embedded platform for the battlefield and other emergency applications.

Effects of vitamin D deficiency in critically ill surgical patients.

BACKGROUND: The incidence of vitamin D deficiency in critically ill patients is reported to be up to 50%, with a 3-fold increase in predicted mortality, but limited data exist concerning vitamin D deficiency in critically ill surgical patients. METHODS: Sixty-six adult surgical intensive care unit patients who had 25-hydroxyvitamin D serum levels evaluated from January 2010 to February 2011 were prospectively identified. Patients were divided into groups according to vitamin D level (<20 vs ≥20 ng/mL). RESULTS: Of the 66 patients evaluated, 49 (74%) had vitamin D levels < 20 ng/mL, and 17 (26%) had vitamin D levels ≥ 20 ng/mL. Patients with vitamin D levels < 20 versus ≥ 20 ng/mL had longer lengths of hospital stay. Lengths of intensive care unit stay were clinically longer, although not significant. Infection rates tended to be higher (P = .09), and a higher incidence of sepsis was seen in the patients with vitamin D levels < 20 ng/mL. CONCLUSIONS: Vitamin D levels < 20 ng/mL have a significant impact on length of stay, organ dysfunction, and infection rates. More data are needed on the value of supplementation to improve these outcomes.

Impact of evaluating antibiotic concentrations in abdominal abscesses percutaneously drained.

BACKGROUND: Appropriate antibiotic therapy and prompt drainage are essential for optimal results with abdominal abscesses. METHODS: In this prospective study, 47 abdominal abscesses from 42 patients over 2 years who had percutaneous drainage were evaluated. Antibiotic concentrations were evaluated from the abscess fluid and correlated with clinical and microbiologic cure. RESULTS: Only 23% of patients had appropriate antibiotic selection with optimal concentrations for the bacteria recovered. Piperacillin/tazobactam, cefepime, and metronidazole provided adequate concentrations in all except the largest abscesses, whereas fluconazole required higher doses in all abscesses. Vancomycin and ciprofloxacin levels were inadequate in most abscesses. With gram-negative aerobes, the use of appropriate antibiotics resulted in a relatively higher incidence of presumed eradication (100% [4 of 4] vs 75% [9 of 12], P = .26). With ≥ 3 organisms identified, clinical failure was significant (58% vs 13%, P = .01). CONCLUSIONS: For optimal treatment, abdominal abscesses require prompt drainage and properly selected antibiotics at adequate doses. Essential information can be obtained from abscess cultures and their antibiotic concentrations.

Twelve hundred abscesses operatively drained: an antibiotic conundrum?

BACKGROUND: The incidence of soft tissue infections from antimicrobial-resistant pathogens is increasing. This study evaluated the epidemiology of operatively drained soft tissue abscesses. METHODS: This retrospective study evaluated 1,200 consecutive patients from 2002 to 2008 who underwent incision and drainage (I&D) in the main operating room. Patients were excluded for perirectal or hidradenitis infections. RESULTS: Of 1,200 consecutive cases with an I&D, 1,005 patients had intraoperative cultures. The 1,817 positive isolates included gram-positive aerobes (1,180 [65%]), gram-negative aerobes (207 [11%]), anaerobes (416 [23%]), and fungi (14 [1%]). The most prevalent organism was Staphylococcus aureus, 30% (536), with 80% (431) being methicillin-resistant S aureus (MRSA). MRSA was the predominant organism in all except the breast abscesses. Anaerobes were identified primarily in the breast in diabetics, and in trunk and extremity abscesses in intravenous drug users. The most frequently prescribed empiric antibiotic was ampicillin/sulbactam (66%). The initial empiric antibiotic did not cover MRSA (82%; P < .001), resistant gram-negative aerobes (24%), and anaerobes (26%). CONCLUSION: Gram-positive aerobes plus anaerobes represented approximately 80% of the pathogens in our series, with the anaerobic rates being underestimated. Empiric antibiotics should cover MRSA and anaerobes in patients with superficial abscesses drained operatively.

Development of immortalized rat conjunctival epithelial cell lines: an in vitro model to examine transepithelial antigen delivery.

The objective of these studies was to develop conjunctival epithelial cell lines for investigation of antigen translocation across a mucosal barrier. Conjunctival epithelial cells from Fischer 344 rats were immortalized with pSV3(neo) resulting in two cell lines--CJ4.1A and CJ4.3C. Each formed confluent cell layers with epithelial morphology when grown on permeable membrane filters. They expressed the SV40 T antigen, the conjunctiva-specific cytokeratin 4, the goblet cell-specific cytokeratin 7 and were negative for the corneal epithelial cell-specific cytokeratin 12. The cell lines have been in culture for over 60 passages, and the population doubling times were 22+/-7h for CJ4.1A and 23+/-9h for CJ4.3C. When grown on Transwell membranes, each cell line achieved a transepithelial electrical resistance of 600-800 Omega cm2 by 3-4 days and maintained a high resistance for several days. Both cell lines expressed zona occludens-1 at confluence. At 24h following addition of 250 microg of FITC-labeled ovalbumin to the apical chambers, 15+/-6 microg could be detected in the basal chamber of CJ4.1A and 6+/-1 microg in the basal medium of CJ4.3C. In contrast, 82+/-6 microg was detected in the lower chambers of cell-free Transwells. Similarly, Transwells containing confluent CJ4.1A or CJ4.3C cells impeded passage of 0.1 microm diameter polystyrene microspheres (5+/-1% and 4+/-1%, respectively, of the apical input), compared to 26+/-6% of the input microspheres recovered from the basal chambers of cell-free Transwells. Pretreatment with 4mM EGTA for 10 min caused an increase in OVA-FITC translocation across CJ4.3C cells. Incubation in the presence of 4mM EGTA significantly increased OVA-FITC translocation across both cell lines, relative to untreated cell layers. Morphological and functional characterization indicates that these cells provide a useful experimental tool to assess strategies for enhancing transepithelial antigen uptake.

The pivotal role of tumor necrosis factor-alpha in signaling apoptosis in intestinal epithelial cells under shock conditions.

BACKGROUND: Apoptosis is essential for the regulation of cell number and function of intestinal epithelial cells but may contribute to intestinal barrier failure after shock and other low-flow conditions to the gut. METHODS: Caco2 intestinal cell monolayers were challenged with recombinant tumor necrosis factor (TNF). In a second group of experiments, Caco2 cells were exposed to bacteria and/or hypoxia followed by reoxygenation. Apoptosis was detected using annexin-V propidium-iodide staining. Cell culture supernatants were also obtained in the second group of experiments and TNF levels quantitated. Monolayer integrity was assessed by measurement of paracellular permeability and transepithelial electrical resistance. RESULTS: Apical but not basal recombinant TNF increased Caco2 apoptosis. Exposure to either bacteria alone or hypoxia/reoxygenation alone did not increase apoptosis; however, the combined insults significantly increased apoptosis. The increased apoptosis occurred in a delayed fashion in both groups. TNF was released in a polar fashion, and the greatest levels were noted after exposure to both bacteria and hypoxia-reoxygenation. There was also an increase in paracellular permeability in this group; however, no change in transepithelial electrical resistance was noted. The effects on apoptosis and permeability were abrogated by anti-TNF antibodies. CONCLUSION: Intestinal epithelial cell apoptosis contributes to barrier failure after shock conditions and is related to augmented TNF release.

Immunoglobulin A protease is a virulence factor for gram-negative pneumonia.

BACKGROUND: Secretory immunoglobulin A (SIgA) is the principal immunologic defense of respiratory and other mucosal surfaces in the body. SIgA is relatively stable in mucosal secretions. However, cleavage of SIgA by bacterial proteases might render it immunologically inactive and thus contribute to the development of pneumonia as well as other infections. Bacterial species and infection sites might be important in the expression of bacterial protease activity and serve as the impetus to this study. METHODS: Bacterial isolates from respiratory and nonrespiratory sites were incubated with SIgA in vitro. SIgA degradation was determined by size exclusion ultrafiltration and gel electrophoresis. RESULTS: IgA protease activity was evident in gram-negative but not gram-positive respiratory isolates. Gram-negative isolates from nonrespiratory sources did not exhibit IgA protease activity. CONCLUSIONS: Expression of IgA protease activity might be important in the development and subsequent outcome of gram-negative pneumonia in the patient in the surgical intensive care unit.

The synergistic effects of hypoxia/reoxygenation or tissue acidosis and bacteria on intestinal epithelial cell apoptosis.

BACKGROUND: Clinical data indicate that gut perfusion deficits must be rectified within 24 hours after traumatic injury to decrease organ failure and death. Ischemia/reperfusion injury to the gut causes enterocyte apoptosis (Apo), which may contribute to intestinal barrier failure. The temporal response of enterocyte Apo to acidosis and hypoxia/reoxygenation (H/R) in vitro is unknown. The purpose of this study was to examine the effect of various time points of acidosis or H/R on enterocyte apoptosis and monolayer integrity in an in vitro model. METHODS: Caco-2 cell monolayers were made acidic (Dulbecco's modified Eagle's medium, pH 6.9) by hydrochloric acid or exposed to 95% nitrogen/5% carbon dioxide (hypoxia) and then 21% oxygen (reoxygenation). Escherichia coli C-25 were added to the apical media in subsets. Apo and necrosis were quantified by flow cytometry. Permeability was determined by fluorescein isothiocyanate-dextran. Transepithelial electrical resistance (TEER) indexed monolayer. RESULTS: Extracellular acidosis and C-25 significantly increased apoptosis of Caco-2 cells at 18 hours (extracellular acidosis [EC] + C-25, 14.5 +/- 3.0; control, 3.8 +/- 0.8; p < 0.001 by analysis of variance). Similarly, the H/R + C-25 group showed a significant increase in apoptosis at 12 hours (H/R + C-25 vs. control, 22.86 +/- 2.12 vs. 3.74 +/- 0.7; p < 0.001 by analysis of variance). The permeability difference was not significant for EC + C-25 versus control at 18 hours (0.68 +/- 0.25 vs. 0.43 +/- 0.0.0.36, respectively; p > 0.05). The H/R + C-25 group had a profound increase in permeability over control at 12 hours (10.8 +/- 0.5 vs. 2.1 +/- 0.3, respectively; p < 0.001). The TEER was significantly lowered for EC versus control at 18 hours (458 +/- 1.5 vs. 468 +/- 8.2) and at 0, 6, and 18 hours for EC + C-25 (409 +/- 28.1, 443 +/- 16.8, and 438 +/- 8.9 vs. 455 +/- 6.5, 467 +/- 6.5, and 469 +/- 8.2, respectively). There was no significant change in the H/R and H/R + C-25 groups. CONCLUSION: Synergism of H/R or tissue acidosis and bacteria caused increased Apo, TEER, and permeability in vitro.

The effects of varying oxygen conditions and immunoglobulin A on barrier defense to bacterial invasion.

Tissue oxygenation is a critical factor in host defense against bacteria. Gut mucosal tissue oxygenation (partial pressure of O2) is normally low putting the gut at risk of invasion by luminal microbes. Secretory immunoglobulin (Ig) A (sIgA) is the principal immune defense at mucosal surfaces. The protective effect of IgA under low oxygen conditions is unknown. We studied the interaction of varying O2 environments and sIgA on protection against bacterial invasion in our in vitro model. Cell monolayers of Madin-Darby canine kidney (MDCK) cells transfected with the cDNA for polymeric immunoglobulin receptor were established in a two-chamber cell culture system. A commensal strain of Escherichia coli (10(8) colony-forming units) was added to the apical medium and cell cultures were placed in either a 5, 21, or 95 per cent O2 environment at 37 degrees C. Polyclonal sIgA (100 microg/mL) was added to the apical chamber in subsets. Basal medium was sampled at intervals and bacterial translocation quantitated. The cell monolayers of MDCK transfected cells then had 100 microg/mL IgA added to the basal compartment at 4 degrees C for 2 hours followed by various oxygen environments for 90 minutes. Afterwards apical medium was removed at one, 3, and 12 (overnight) hours. The bacterial translocation data showed a significance increase in translocation with hypoxia. Both increased oxygen and IgA abrogated these effects significantly. The transcytosis of IgA was increased during hypoxic conditions. Normal and hyperoxic conditions did not produce any significant difference in IgA transcytosis. We conclude that O2 and sIgA are protective against bacterial invasion at epithelial surfaces. Effects to either boost O2 delivery to the gut or enhance mucosal IgA production and delivery may be protective in the critically ill surgical patient.