LC-MS/MS method for simultaneous quantification of ten antibiotics in human plasma for routine therapeutic drug monitoring.

Background: Optimizing antimicrobial therapy to attain drug exposure that limits the emergence of resistance, effectively treats the infection, and reduces the risk of side effects is of a particular importance in critically ill patients, in whom normal functions are augmented or/and are infected with pathogens less sensitive to treatment. Achievement of these goals can be enhanced by therapeutic drug monitoring (TDM) for many antibiotics. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method is presented here for simultaneous quantification of ten antimicrobials: cefazolin (CZO), cefepime (CEP), cefotaxime (CTA), ceftazidime (CTZ), ciprofloxacin (CIP), flucloxacillin (FLU), linezolid (LIN), meropenem (MER), piperacillin (PIP) and tazobactam (TAZ) in human plasma. Methods: Plasma samples were precipitated with acetonitrile and injected into the LC-MS/MS. Chromatographic separation was on a Waters Acquity BEH C18 column. Compounds were eluted with water and acetonitrile containing 0.1 % formic acid, using a gradient (0.5-65 % B), in 3.8 min. The flow rate was 0.4 mL/min, and the run time was 5.8 min. Results: The calibration curves were linear across the tested concentration ranges (0.5-250, CZO, CEP, CTA, CTZ and FLU; 0.2-100, MER and TAZ; 0.1-50, CIP and LIN and 1-500 mg/L, PIP). The intra and inter-day imprecision was < 11 %. Accuracy ranged from 95 to 114 %. CTZ and MER showed ionization suppression while CIP showed ionization enhancement, which was normalized with the use of the internal standard. Conclusion: An LC-MS/MS method for simultaneous quantification of ten antimicrobials in human plasma was developed for routine TDM.

Severe soft-tissue injury following intravenous infusion of phenytoin. Patient and drug administration risk factors.

From April 8, 1982, through June 1984, 11 patients in a single hospital experienced 17 episodes of limb edema and discoloration after the intravenous (IV) administration of phenytoin sodium (Dilantin). One patient required a below-the-elbow amputation; all other patients recovered. No single drug lot was implicated. A case-control study was performed using three controls for each case; controls received IV infusions of phenytoin and were hospitalized close in time to the case patients. Compared with controls, patients with reactions were more often female and elderly and had underlying cardiovascular disease. Affected patients also received phenytoin through an IV catheter smaller than 20 gauge (50% vs 6%), at a rate greater than 25 mg/min (63% vs 19%), and in two or more IV infusions of phenytoin given "IV push" at the same site (81% vs 24%). High-risk patients require careful monitoring and stricter guidelines for the IV administration of phenytoin.

Infectious complications among patients receiving home intravenous therapy with peripheral, central, or peripherally placed central venous catheters.

Rates of bacteremia among hospitalized patients with central venous catheters range up to 21%. Few data exist for home intravenous therapy (IVT). We studied 300 patients from two hospital-based home IVT services in 29 months. Diagnoses included 92 cases of osteomyelitis, 33 of pneumonia, 35 of malnutrition, 26 of chronic pain, and 114 of other diseases. Peripheral IVT was given to 97 patients. Mean age was 39.4 years (range, 0.3-98). Hickman, Infuse-A-Port, Broviac, Arrow triple lumen, Hohn, and peripherally inserted central catheters (PICC) were used for a mean of 44 days. Six bacteremias (one death) (2%, 4.6/10,000 catheter days), two subclavian thromboses, 13 catheter site infections, and one additional death occurred. PICC experience included 76 patients, mean age 46 years (range, 4-76), primarily with infections, chronic pain, or dehydration. Mean duration of therapy was 24 days (0-67) and was completed in 51 patients; others completed therapy with standard peripheral catheters a mean of 6 days later. Complications included 17 obstructions by clot, 11 cases of phlebitis, six catheter fractures, five punctures, two accidental removals, and one infiltration. Liquid silicone repaired holes; urokinase opened clots. Successful completion of therapy was more common in the second year, 88% versus 57%. Despite more complications, patients, home IVT nurses, and physicians preferred PICCs. We conclude that home IVT is safe via many means of access, with fewer infections than with hospital care. Such infections may be termed "nosohusial."

Outbreak of pyrogenic reactions at a dialysis center. Association with infusion of heparinized saline solution.

Twenty-three pyrogenic reactions occurred in 16 patients undergoing hemodialysis at a private dialysis center in the south central United States between November 23 and December 2, 1978. No deaths were attributed to reactions; however, 10 patients were hospitalized for observation after experiencing a reaction. Cultures of all blood specimens obtained from the patients gave negative results. Chills (75 percent), nausea and/or vomiting (30 percent), and fever (90 percent) were the most common signs and symptoms, with mean times of onset after starting dialysis of 1.1, 1.6, and 3.6 hours, respectively. An epidemiologic and laboratory investigation documented that reactions occurred only in patients who had anticoagulation with a dilute solution of heparin. Analyses of heparinized saline solution used during the outbreak revealed a bacterial count of 7.4 X 10(5)/ml and a bacterial endotoxin level of 1,300 ng/ml. Acinetobacter calcoaceticus var. Iwoffi was isolated from the solution. Diluted heparin solution was prepared at the dialysis center by adding commercially supplied sodium heparin to 0.9 percent sodium chloride infusion fluid. Bacteria and endotoxin were not detected in vials of stock heparin and bags of unopened 0.9 percent sodium chloride infusion fluid. We concluded that contamination of the solution occurred at the dialysis center. After changes in the preparation and use of heparin were instituted on December 4, 1978, no pyrogenic reactions occurred in more than 400 subsequent dialyses.

Does cold air affect exercise capacity and dyspnea in stable chronic obstructive pulmonary disease?

Cold air may worsen asthmatic bronchoconstriction but can lessen breathlessness in normal individuals. Patients with COPD sometimes report improvement in their dyspnea in cold weather. We examined the effect of breathing cold air on exercise tolerance and the perception of breathlessness in 19 patients with stable COPD (age [+/- SD], 63 +/- 6 years; FEV1, 0.99 +/- 0.28 L) in a randomized open study. Patients exercised on a cycle ergometer breathing either room or cold air (-13 degrees C), breathlessness being assessed by Borg scaling. Peak exercise performance improved when breathing cold air (mean +/- SE), 46 +/- 6 W compared with 37 +/- 7 W (p < 0.05) while end-exercise breathlessness fell from 4.6 +/- 0.4 compared with 4.1 +/- 0.5 (p < 0.05) when breathing cold air. End-exercise ETCO2 was higher breathing cold air (6.1 +/- 0.3 kPa compared with 5.5 +/- 0.3 kPa) (p < 0.005). There was no difference in breathlessness at equivalent levels of ventilation. Cold air reduces breathlessness in COPD, probably by inducing relative hypoventilation.

Comparison of three different methods used to achieve local anesthesia for fiberoptic bronchoscopy.

A patient's tolerance of fiberoptic bronchoscopy depends on the effectiveness of local anesthesia. This study compares the three different methods of local anesthesia in common use After sedation, patients (n = 53) received either 4 ml of 2.5 percent cocaine by intratracheal injection (TI) (n = 18), by bronchoscopic injection (BI) (n = 19), or had 4 ml of 4 percent lidocaine delivered by nebulizer 20 min before the procedure (NEB) (n = 16). Patients and bronchoscopists scored the procedure using visual analog (VAS) and severity scales. Objective measurements of cough counts and episodes of stridor were recorded by phonopneumography. Patients' VAS scores showed a clear preference for the transtracheal method compared with either bronchoscopically injected cocaine (p less than 0.001) or nebulized lidocaine (p less than 0.001). Patients also reported that the TI method produced less cough during intubation of the larynx and inspection of the airways (BI and NEB, p less than 0.01). The TI method was also preferred by the bronchoscopists (BI and NEB, p less than 0.001); they reported less cough and easier tracheal intubation. The mean cough count was significantly lower for the TI group, 49 (43) compared with 95 (52) for BI (p less than 0.01), and 81 (43) for the NEB group (p less than 0.05). Patients' and bronchoscopists' VAS showed significant correlation with cough (r = 0.63-69, p less than 0.01). Stridor occurred in only two patients after TI, compared with 15 in the other two groups. Extra local anesthesia was required by 16 patients after BI, by all the NEB group, but by only one patient after TI. Subjective and objective measurement shows that 4 ml of 2.5 percent cocaine injected into the trachea produced excellent local anesthesia for fiberoptic bronchoscopy, there were no extra complications, and it was the method preferred by both patients and bronchoscopists.

Disk diffusion antimicrobial susceptibility testing for clinical and epidemiologic purposes.

Antimicrobial susceptibility testing is one of the most important and useful tests performed by the clinical microbiology laboratory. The value of disk susceptibility testing in epidemiology is enhanced by its simplicity of performance, reproducibility of results, and ability to indicate whether a single strain is likely to be the cause of many infections. By using a specific set of antimicrobials for either gram-positive or gram-negative bacterial susceptibility testing and by following recommended testing procedures, laboratories can reliably identify similarities and differences in strains. We propose a list of antimicrobial agents chosen specifically for their value in disk susceptibility testing for clinical and epidemiologic purposes and describe the recommended methods of testing.

Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality and the need for debridements.

Twenty-nine patients with necrotizing fasciitis were treated from 1980 to 1988. This study evaluates how the addition of hyperbaric oxygen (HBO) therapy to surgical treatment has affected mortality and the number of debridements required to achieve wound control in these patients. Two groups of patients were viewed: group 1 (n = 12) received surgical debridement and antibiotics only; group 2 (n = 17) received HBO (90 minutes at 2.5 atm, average 7.4 treatments) in addition to surgery and antibiotics. Both groups were similar in age, race, sex, wound bacteriology, and antimicrobial therapy. Body surface area affected was similar, however, perineal involvement was more common in group 2 (53%) than in group 1 (12%). The admitting conditions of patients in group 1 (non-HBO) were diabetic, 33%; white blood cell count more than 12,000, 50%; and shock, 8%. The admitting conditions of patients in group 2 (HBO) were diabetic, 47%; white blood cell count more than 12,000, 59%; and shock, 29%. Although group 2 patients receiving HBO were more seriously ill on admission, mortality was significantly lower (23%) compared to group 1 (66%) (p less than 0.02). In addition, only 1.2 debridements per group 2 patient were required to achieve wound control versus 3.3 debridements per group 1 patient (p less than 0.03). The addition of HBO therapy to the surgical and antimicrobial treatment of necrotizing fasciitis significantly reduced mortality and wound morbidity (number of debridements) in this study, especially among nonclostridial infections. We conclude that HBO should be used routinely in the treatment of necrotizing fasciitis.

Diaphragmatic plication for unilateral diaphragmatic paralysis: a 10-year experience.

Unilateral paralysis of the diaphragm due to nonmalignant disease is an uncommon disorder previously thought to have benign implications. Some patients, however, experience dyspnea and orthopnea with impairment of pulmonary function. Unilateral diaphragmatic plication was performed on 17 patients (16 men and 1 woman with a mean age of 53.7 years [range, 28 to 74 years]) during the last 10 years. Preoperatively each patient was shown to have paradoxical movement of the paralyzed diaphragm on sniffing and to have a reduction in forced vital capacity and lung volumes. These reductions were greater when the patient was in the supine position. All patients had moderate hypoxemia (mean arterial oxygen tension, 73.1 +/- 10.9 mm Hg). Plication was performed by imbricating the diaphragm in layers through a thoracotomy incision. After plication, all patients showed both subjective and objective improvement. Six patients were reassessed 5 or more years after plication (range, 5 to 7 years), and the improvement was maintained. Diaphragmatic plication is a safe and effective procedure for adult patients with dyspnea due to unilateral diaphragmatic paralysis; furthermore, the initial improvement is maintained.

Acute severe asthma treated by mechanical ventilation: a comparison of the changing characteristics over a 17 yr period.

Recorded cases of asthma have increased in recent years. It is unclear, however, whether this apparent increase in prevalence is accompanied by an increase in severity of the disorder. One potential measure of asthma severity is the requirement for mechanical ventilation. This paper examines those patients ventilated for severe asthma in a district general hospital over a 17 yr period. Since the methods used to assess asthma attacks and the criteria for instituting mechanical ventilation in this hospital did not alter between 1973 and 1992 (Jones criteria), it was possible to compare directly characteristics of all ventilated patients during the study period. The comparison showed that there was a significant increase between the two study periods in the number of patients who required mechanical ventilation. Moreover, in the more recent period both the subjective speed of onset of the asthma attack and the objective time between admission and ventilation were significantly shorter. However, despite this increase in asthma severity the mortality and morbidity in the more recent study period were lower. Overall the results of this study support the view that, in the population served by our district general hospital, asthma has increased in severity. This increased severity is indicated by an increase in the number of patients requiring mechanical ventilation and in the rapidity with which attacks evolved. However, for patients in whom ventilation was required, improved care has lowered both morbidity and mortality.

Experimental evaluation of the antibiotic carrying capacity of a muscle flap into a fibrotic cavity.

A study was undertaken to determine the antibiotic carrying capacity of a transferred muscle flap into a fibrotic cavity using a tissue cage model in rabbits. Blood and chamber fluid antibiotic levels were determined after intramuscular hindlimb gentamicin injection up to 56 days following muscle transfer. This study suggests that muscle flaps increase the concentration of antibiotics that can be achieved within a fibrotic cavity. The measurable peak level decreases with time, probably due to increased scarring around the muscle. This model should enable the study of many different classes of antibiotics with different protein binding and other administration schedules using multiple timed doses or a combination of agents.

Development of septic arthritis by hematogenous seeding in a pediatric patient with burns.

We describe a pediatric patient with burns who experienced a septic hip joint from hematogenous seeding by sustained Staphylococcus aureus bacteremia. A search for a central vascular focus of the bacteremia included the use of an indium scan, which localized purulence within the left hip joint. The physical findings, radiographic findings, and subsequent aspiration of the hip joint were diagnostic for a septic arthritis. This case alerts the physician that the pediatric hip is a potential site for infection in the presence of bacteremia. Once infected, the joint may become a secondary source of an ongoing bacteremia. The diagnostic work-up and treatment for a septic hip have been discussed. This occult site of infection is easy to overlook because a painful hip joint in the pediatric patient with burns may be confused for painful burn wounds. The prerequisites to joint infections in this population were all present: bacteremia, intercurrent illness, unique vascular anatomy, and an impaired immune response.

Overwhelming postsplenectomy sepsis in a patient with burns: a case report and a rational approach to treatment.

Overwhelming postsplenectomy sepsis is a dreaded sequel of splenectomy. The rate of overwhelming sepsis in children after splenectomy for trauma is reported to be 10 to 30 times that of the general population. Episodes of pneumonia, septicemia, and meningitis in adults after a splenectomy are 166 times more common than in the general population. The care of a patient with burns and asplenia presents many unique management challenges to the burn physician. Awareness of the development of overwhelming postsplenectomy sepsis and its most common infecting organisms is crucial. The specific immunologic deficiencies of reduced immunoglobulin production and cell-mediated immunity that exist in patients after a splenectomy may be compounded by burn injury. Specific treatment recommendations for patients with burns and asplenia are lacking. We report a fatal case of overwhelming sepsis in a patient with asplenia and with an 8% total body surface area partial-thickness burn, and we review the pathogenesis of overwhelming postsplenectomy sepsis. We focus on treatment recommendations regarding the use of prophylactic antimicrobials, intravenous immunoglobulin replacement therapy, and pneumococcal polyvalent vaccine to standardize the care of the patient with burns and asplenia and reduce infectious morbidity and deaths.

Susceptibility testing of topical antibacterials against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) isolates that were collected from 44 consecutive patients during 1 year in a community hospital were tested for susceptibility to five commonly used topical antibacterial agents. Agar-well susceptibility testing, which was based on zones of inhibition, was used to compare the effectiveness of the antibacterials against MRSA. Nitrofurazone was effective in inhibition of bacterial growth and was relatively inexpensive. Mupirocin was found to be effective but more costly for treatment of MRSA. Varying degrees of susceptibility to silver sulfadiazine, mafenide acetate, and bacitracin were noted in the cultures that were obtained at this medical center. On the basis of our findings from susceptibility tests compared with those of another center, we recommend that all hospitals undertake topical sensitivity testing of their MRSA isolates. Appropriate and effective topical antibacterial therapy can then be planned within each center.

Postoperative toxic shock syndrome.

PURPOSE: To determine risk factors for postoperative toxic shock syndrome (PTSS), a rare, rapidly progressive, and potentially fatal syndrome associated with postoperative wound infections. Components of PTSS include fever, rash, desquamation, hypotension, and multisystem organ dysfunction. METHODS: We conducted a retrospective review of all cases of PTSS occurring in 2 community hospitals from 1981 to 1993, following 390,000 surgical procedures. RESULTS: There were 12 cases of PTSS among the procedures reviewed (0.003%). Orthopedic procedures included excision of accessory navicular and patellar realignment. Wounds ranged from those with scant superficial exudates to those with gross purulence; all cultures yielded Staphylococcus aureus. All tested isolates were susceptible to methicillin or cephalothin. Mean time from surgery to onset of symptoms was 4 days. All patients had sudden onset of fever; mean maximal temperature was 40 degrees C. All patients displayed a rash, most in a truncal "sunburn" pattern. Eleven of 12 patients desquamated. All patients required vigorous fluid resuscitation. All patients survived. No correlation could be demonstrated between PTSS and patient age, sex, preoperative skin preparation or antibiotics, members of surgical team, or duration of procedure. CONCLUSIONS: Early recognition and treatment of PTSS are essential. No risk factors for PTSS have been identified. PTSS should be considered in the postoperative, acutely febrile, systemically ill patient, though surgical wounds may be deceptively benign in appearance.

How well are graduates prepared for practice when measured against the latest GMC recommendations?

This article investigates the perspectives of University of Liverpool graduate foundation doctors and their consultants on their preparedness for professional practice.