Combination antimicrobial therapy for bacterial infections. Guidelines for the clinician.

Therapy with antimicrobial combinations has been used as long as antimicrobials have been available. Combinations of antibiotics are often used to take advantage of different mechanisms of action and/or toxicity profiles. Well established indications for combination antimicrobial therapy include: (a) empirical treatment of life-threatening infections; (b) treatment of polymicrobial infections; (c) prevention of the emergence of bacterial resistance; and (d) for synergism. Disadvantages of combination therapy include: (a) increased expense; (b) increased risk of adverse effects; (c) antagonism; and (d) superinfection. Combination antimicrobial therapy should be considered for the treatment of serious Gram-negative infections caused by Enterobacter cloacae, Pseudomonas aeruginosa and Serratia marcescens, and certain Gram-positive infections caused by Enterococcus spp. and Staphylococcus spp. Selection of agents should be dependent upon local susceptibility patterns, clinical experience, site of infection, potential toxicities and cost.

Influence of antibiotic and E5 monoclonal immunoglobulin M interactions on endotoxin release from Escherichia coli and Pseudomonas aeruginosa.

Recent controversy surrounding the activity of monoclonal antibodies against endotoxin highlights the necessity of identifying all factors associated with increased mortality, one of which is endotoxin concentrations. Antibiotics may induce different patterns of endotoxin release. We compared the release of free endotoxin (in endotoxin units per milliliter) over 6 h and changes in numbers of CFU of exponentially growing Escherichia coli and Pseudomonas aeruginosa (10(6) to 10(7) CFU/ml) cultured in chemically defined endotoxin-free broth combined with pooled human serum and/or 10 micrograms of E5 immunoglobulin M monoclonal antibody per ml. MICs and MBCs were tested in each medium at the same inoculum. The inoculum was exposed to antibiotics at a single fixed multiple of the MIC for each medium (range, two to eight times the MIC). E5 antibody had no effect on MICs, MBCs, bactericidal activity, or endotoxin release. In the presence of 50% serum, amikacin, ceftazidime, imipenem, and ofloxacin each killed equivalent amounts of E. coli over 6 h; however, ceftazidime induced the highest release of endotoxin. Amikacin and ofloxacin produced the most favorable ratio of endotoxin release to amount of bacterial killing. In the presence of 50% serum, ceftazidime and imipenem reduced the P. aeruginosa inoculum to the greatest extent over 6 h. Although its bactericidal activity was diminished, ofloxacin caused the lowest release of free endotoxin. Imipenem and ofloxacin showed similar low ratios of endotoxin release to bacterial killing. In summary, antibiotic class, presence of serum, and type of organism influenced bactericidal activity and endotoxin release.

Vestibulo-ocular response of human subjects seated in a pivoting support system during 3 Gz centrifuge stimulation.

The vestibulo-ocular reflex (VOR) and spatial orientation perceptions were recorded in 15 subjects during 3 Gz centrifuge runs. These data were obtained to study two issues: (1) to gain insight into reports of asymmetrical disorientation and disturbance during acceleration and deceleration of centrifuge runs like those used to train pilots on the procedures to counteract G-induced loss of consciousness (G-LOC); (2) to study the effects of sustained vertical linear acceleration on the vestibular system. The centrifuge angular velocity profile consisted of a 19 s angular acceleration to 3 Gz that was sustained for 5 min during a period of constant angular velocity, and a 19 s deceleration to 1 Gz. The runs were repeated three times with the subject facing the motion and three times with the subject's back to the motion. The VOR and spatial orientation perceptions from the eight subjects who completed all six runs were analyzed. The total VOR response during acceleration and deceleration was composed of interacting angular (AVOR) and linear components (LVOR). Asymmetries in pitch orientation perception between centrifuge acceleration and decleration were not matched by asymmetries in the total VOR slow phase velocity. During the constant velocity high-G phase of the run, sustained up-beating LVOR (Lz nystagmus) was present in 14 of the 15 subjects. Significant individual differences in Lz nystagmus were found, but the maximum Lz response in our 15 subjects was probably of insufficient magnitude to degrade visual scan of cockpit instruments. Mean magnitudes ranged from 0 to 10 deg/s at 90 s from onset of centrifuge run.

Anesthesia and head trauma.

Anesthetic care for patients with traumatic brain injury involves an integration of cerebral resuscitation, resuscitation of other vital organs, the provision of "anesthesia," and the prevention of harmful physiologic responses to surgery. Adverse responses to surgery such as hypertension, tachycardia, coughing, and straining can increase intracranial pressure (ICP). Airway manipulations can aggravate spinal cord injury as well as increase ICP. Anesthetic agents can exacerbate hemodynamic instability, increase cerebral blood volume and ICP, and produce respiratory depression. Cerebral resuscitation during surgery resembles that in the preoperative and postoperative periods. ICP measurement and jugular venous saturation monitoring may help define end-points for cerebral resuscitation. Various anesthetic techniques and agents have distinct advantages and disadvantages. The choice of agents and techniques is determined by the nature and severity of the patient's injuries and by pre-existing medical problems. The investigation of drugs that might protect against cerebral ischemia has included anesthetic agents but none appear to be uniformly effective. Intraoperative hypothermia is also being investigated as a cerebral protectant.

Pharmacodynamics of levofloxacin, ofloxacin, and ciprofloxacin, alone and in combination with rifampin, against methicillin-susceptible and -resistant Staphylococcus aureus in an in vitro infection model.

The pharmacodynamic properties of levofloxacin (an optically active isomer of ofloxacin), ofloxacin, and ciprofloxacin, alone and in combination with rifampin, were evaluated over 24 to 48 h against clinical isolates of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA 1199 and MRSA 494, respectively) in an in vitro infection model. The incidence of the emergence of resistance among the test strains was also determined. The fluoroquinolones were administered to simulate dosage regimens of 200 mg, 400 mg given intravenously (i.v.) every 12 h (q12h), and 400 and 800 mg given i.v. q24h. Rifampin was dosed at 600 mg i.v. q24h. Although the MICs and MBCs of the quinolones were similar (< or = 0.49 microgram/ml), levofloxacin was the most potent agent in time-kill studies on the basis of the time required to achieve a 99.9% reduction in the number of log10 CFU per milliliter (e.g., with the regimen of levofloxacin [400 mg q24h, 6.5 h] versus ofloxacin [12.5 h], P < 0.024, and levofloxacin versus ciprofloxacin [6.5 versus 9.0 h], P < 0.0017) against MSSA 1199. The killing activity of levofloxacin was similar to that of ofloxacin against MRSA 494 (time to achieve a 99.9% reduction in the number of log10 CFU per milliliter, 11.1 versus 13.8 h, respectively). Levofloxacin and ofloxacin dosed once daily demonstrated greater bactericidal activity than when they were dosed twice daily against MSSA 1199. Resistance to levofloxacin or ofloxacin was not observed with any dosage regimen. Furthermore, resistance to ofloxacin was not detected when the half-life was reduced from 6 to 3 h. Regrowth and stable resistance (65-fold increase in the MIC for MSSA 1199; 16-fold increase in the MIC for MRSA 494) were noted within 24 h of exposure to ciprofloxacin at 200 mg q12h. Combination therapy with rifampin prevented the emergence of resistance to ciprofloxacin. Neither DNA gyrase alteration nor an energy-dependent efflux process mediated by the norA gene appeared to be responsible for the resistance observed. Our data suggest that with levofloxacin there is a more rapid onset of bactericidal activity than with ofloxacin or ciprofloxacin against MSSA 1199 and that the activity of levofloxacin is similar to that of ofloxacin but better than that of ciprofloxacin against MRSA 494. Resistance was noted only after exposure to the low dose of ciprofloxacin. Resistance to ofloxacin did not develop even when the pharmacokinetics of the drug were set to equal those of ciprofloxacin, suggesting that ofloxacin differs from ciprofloxacin irrespective of time of exposure. The resistance to ciprofloxacin that developed in our vitro model may be mediated by the cfx-ofx locus, which has been shown to be associated with low-level fluoroquinolone resistance. Overall, levofloxacin demonstrated potent bactericidal activity against S. aureus, without the emergence of resistance in our infection model. Quinolones dosed once daily were more effective than equivalent dosages administered twice daily. The addition of rifampin was not synergistic but prevented the emergence of ciprofloxacin resistance.

Genital herpes simplex infections in patients with the acquired immunodeficiency syndrome.

On August 14, 1987, the Centers for Disease Control revised the surveillance case definition for the acquired immunodeficiency syndrome (AIDS) to include several indicator diseases. The addition of herpes simplex virus (HSV) infections to the definition reemphasized the increasing frequency of severe HSV infections in patients also infected with the human immunodeficiency virus (HIV). These infections in patients with AIDS are associated with considerable morbidity similar to reports of HSV in other immunocompromised populations. Their spectrum can include persistent or recurrent genital disease, severe visceral involvement, and disseminated infection. Patients with AIDS also are at increased risk of drug toxicities when receiving treatment for HSV infections in addition to antiretroviral therapy. Acyclovir, a selective and specific inhibitor of HSV replication, has been the mainstay of safe and effective treatment for HSV for more than a decade. However, reports of acyclovir-resistant strains of HSV in patients with AIDS have been steadily increasing since 1989. Although foscarnet has been successful in treating acyclovir-resistant strains, foscarnet-resistant strains have also been isolated. The search to find novel approaches for the treatment and suppression of HSV in patients with AIDS has become an added challenge in the management of this devastating disease.

Bactericidal activities of teicoplanin, vancomycin, and gentamicin alone and in combination against Staphylococcus aureus in an in vitro pharmacodynamic model of endocarditis.

We adapted an in vitro pharmacodynamic model of infection to incorporate simulated endocardial vegetations. The bactericidal activities of teicoplanin, vancomycin, gentamicin, and various combinations of these drugs were studied against a strain of methicillin-susceptible Staphylococcus aureus obtained from a patient being treated for endocarditis at Detroit Receiving Hospital. Bacteria were grown overnight, concentrated, and added to a mixture of cryoprecipitate (80%) and thrombin (10%) to achieve approximately 5 x 10(9) CFU/g. Fibrin clots (8 to 10) were suspended into the model, removed at 24, 48, and 72 h in duplicate, weighed, and homogenized in 1.25% trypsin. Control experiments were conducted to characterize the growth kinetics. The following antibiotics were administered to simulate the pharmacokinetics of the drugs in humans: teicoplanin at 3 and 15 mg/kg of body weight, vancomycin at 15 mg/kg, and gentamicin at 1 mg/kg. Fibrin clot samples used to detect resistance were plated on antibiotic-containing tryptic soy agar plates. For the teicoplanin and vancomycin regimens, protein binding to cryoprecipitate, thrombin, and fibrin clot was determined to be 32, 43, and 50% and 26, 28, and 29%, respectively. In comparison with no treatment, vancomycin or teicoplanin at 15 mg/kg or either of these regimens combined with gentamicin significantly reduced bacterial counts (P < 0.0001). Monotherapy with teicoplanin at 3 mg/kg or gentamicin resulted in no killing activity. Combination treatment with teicoplanin at 3 mg/kg and gentamicin resulted in the killing of approximately 2 log10 CFU/g by 72 h and the development of resistance to gentamicin. The results obtained with the in vitro model of endocarditis are similar to the results reported by several investigators with the rabbit model of infective endocarditis. This unique infection model is useful for designing initial drug dosage regimens and may be predictive of drug efficacy against infective endocarditis.

Venous embolization after deflation of lower extremity tourniquets.

Massive pulmonary embolism has been reported to occur with the use of lower extremity tourniquets. We used transesophageal echocardiography to determine the incidence of venous embolism during lower extremity orthopedic surgery performed with a pneumatic tourniquet. The hemodynamic and respiratory consequences of all embolic events were assessed. Venous emboli were detected after tourniquet deflation in 8 of 30 procedures. The incidence of embolism was unrelated to the type of surgical procedure performed or the duration of tourniquet inflation. There were no significant differences in preoperative characteristics or postdeflation hemodynamic and respiratory responses between patients with and without emboli. Venous embolization is a relatively common event after tourniquet deflation. The clinical significance of these events remains to be determined.

Effect of human serum on killing activity of vancomycin and teicoplanin against Staphylococcus aureus.

STUDY OBJECTIVE: To investigate the effects of pooled human serum (PHS) on the killing activity of vancomycin and teicoplanin against two isolates of Staphylococcus aureus from patients treated for endocarditis. DESIGN: An in vitro assessment of antibiotic susceptibility and killing rates. SETTING: An urban university teaching hospital. PATIENTS: Pooled human serum from patients treated for endocarditis. INTERVENTIONS: Two clinical isolates of Staphylococcus aureus were obtained from patients treated for endocarditis. Media consisted of cation-supplemented Mueller-Hinton broth alone and in 1:1 dilutions with PHS, 2-hour heat-inactivated PHS (HI-PHS), ultrafiltrate (UF), and 2-hour heat-inactivated ultrafiltrate (HI-UF). Heat inactivation of PHS and UF was accomplished by treatment at 56 degrees C for 2 hours. MEASUREMENTS AND MAIN RESULTS: Killing curves with vancomycin and teicoplanin were performed using drug concentrations of 45 micrograms/ml and a starting inoculum of approximately 1 x 10(6) colony-forming units (cfu)/ml. Bactericidal rates (-log cfu/ml/hr) were calculated from the slope of the killing curves over 0-12 hours (mean 3-8 replicates). CONCLUSIONS: The killing activity of vancomycin in PHS and HI-PHS against both isolates was significantly greater than all other media tested (p < 0.0001). Ultrafiltrate tended to reverse this enhancement effect. Addition of PHS or UF did not enhance teicoplanin's killing activity against either isolate. Further investigations in our laboratory will determine if the factor is antibiotic class or organism specific.

Pharmacodynamic effects of extended dosing intervals of imipenem alone and in combination with amikacin against Pseudomonas aeruginosa in an in vitro model.

The pharmacodynamic effects of extended imipenem dosing intervals were studied against two strains of Pseudomonas aeruginosa (ATCC 27853 and an imipenem-resistant mutant, 27853R) in an in vitro model of infection. Imipenem was administered as monotherapy (simulated 1-g bolus every 8 or every 12 h) and in combination with amikacin (7.5-mg/kg bolus every 12 h or a 15-mg/kg bolus once). Monotherapy with imipenem administered every 8 h was equally bactericidal at 24 h compared with regimens combined with amikacin for ATCC 27853. Imipenem administered every 12 h against the sensitive strain and both imipenem monotherapy regimens against the resistant strain demonstrated regrowth at 24 h. Although both amikacin regimens administered as monotherapy resulted in rapid bacterial killing activity with respect to time to a 99.9% reduction in log10 CFU/milliliter, regrowth at 24 h was observed at levels reaching or exceeding the initial inoculum. All combination regimens resulted in no detectable growth by 24 h regardless of dosing interval for either drug or initial susceptibility to imipenem. Results from this study indicate the potential for several novel dosing regimens against P. aeruginosa. Monotherapy with imipenem, 1 g every 8 h, was effective against a sensitive strain of P. aeruginosa. Combination therapy with imipenem and once-daily or twice-daily amikacin resulted in increased killing activity against imipenem-resistant P. aeruginosa. Once-daily or twice-daily amikacin in combination therapy, regardless of P. aeruginosa susceptibility, allowed for extension of imipenem dosing intervals.

In vitro postantibiotic effect following repeated exposure to imipenem, temafloxacin, and tobramycin.

The postantibiotic effect (PAE) following three consecutive 2-h exposures to imipenem, temafloxacin, and tobramycin was determined in Pseudomonas aeruginosa. A PAE and a bactericidal effect were consistently observed for imipenem following each cycle of drug exposure and regrowth. In contrast, the PAE increased with repeated exposure with temafloxacin (1.8 to > 5 h), but disappeared with tobramycin by the third exposure (0.9 to 0 h). These data show that the in vitro PAE may change within a strain following multiple cycles of drug exposure and bacterial regrowth.

Chest tubes: indications, placement, management, and complications.

Use of tube thoracostomy in intensive care units for evacuation of air or fluid from the pleural space has become commonplace. In addition to recognition of pathological states necessitating chest tube insertion, intensivists are frequently involved in placement, maintenance, troubleshooting, and discontinuation of chest tubes. Numerous advances have permitted safe use of tube thoracostomy for treatment of spontaneous or iatrogenic pneumothoracies and hydrothoracies following cardiothoracic surgery or trauma, or for drainage of pus, bile, or chylous effusions. We review current indications for chest tube placement, insertion techniques, and available equipment, including drainage systems. Guidelines for maintenance and discontinuation are also discussed. As with any surgical procedure, complications may arise. Appropriate training and competence in usage may reduce the incidence of complications.

Pharmacodynamics of once-daily amikacin in various combinations with cefepime, aztreonam, and ceftazidime against Pseudomonas aeruginosa in an in vitro infection model.

The pharmacodynamics of once-daily amikacin administered as monotherapy and in combination with aztreonam, ceftazidime, and cefepime against Pseudomonas aeruginosa ATCC 27853 and clinical isolate 16690 (moderately susceptible to ceftazidime) were investigated with an in vitro model of infection over a 24-h period. Monotherapy with aztreonam, ceftazidime, and cefepime and combinations of aztreonam with cefepime or ceftazidime were also studied. MICs and MBCs were determined for viable organisms at 24 h to test for the development of resistance. Once-daily amikacin demonstrated killing activity over the initial 8 h superior to those of all other drugs administered as monotherapy against both strains tested (P < 0.01). Regrowth by 24 h was greatest for the amikacin regimen (P < 0.01) but was apparent for all monotherapy regimens against both strains. No changes in susceptibilities were observed. All combination therapies containing once-daily amikacin achieved 99.9% reductions in log10 CFU/ml by 2.0 h against both strains, with no regrowth of organisms at 24 h. Aztreonam-cefepime and -ceftazidime combinations required approximately 5 to 6 h to achieve a 99.9% reduction in log10 CFU/ml. Although there was no difference in time to the 99.9% kill between the aztreonam-cefepime and -ceftazidime regimens against either strain, the killing activity of these combinations was significantly less than those of regimens containing once-daily amikacin (P < 0.01). Minor differences in the initial susceptibilities of beta-lactams and the monobactam aztreonam against P. aeruginosa may not be important for therapeutic outcomes when used in combination with single-daily aminoglycoside therapy.

Pulmonary arteriovenous fistula: mechanical ventilation and hypoxemia.

Pulmonary arteriovenous malformation (PAVM) is an uncommon congenital anomaly. As PAVM is a direct communication between branches of the pulmonary artery and vein, major disturbances in gas exchange can result. We present a patient with an unsuspected PAVM who came to our institution for drainage of a brain abscess. Arterial blood gas analysis during and after surgery demonstrated a large alveolar-arterial gradient for oxygen in the absence of any obvious pulmonary pathology while the patient was receiving positive pressure ventilation (PPV). Oxygenation improved considerably upon resumption of spontaneous ventilation. A diagnosis of PAVM was made subsequently. We conclude that positive pressure ventilation can worsen right to left shunting in patients with PAVM.

The dynamics of spatial orientation during complex and changing linear and angular acceleration.

The dynamics of spatial orientation perception were examined in a series of experiments in which a total of 43 subjects were passively exposed to various combinations of linear and angular acceleration during centrifuge runs. Perceptual effects during deceleration were much stronger than effects during acceleration. The dynamics of spatial orientation perception differed substantially from changes in the vestibulo-ocular reflex (VOR). VOR was fairly well predicted by a current model, but our experiments revealed perceived change in attitude (roll, pitch, yaw tilt position in space) and perceived angular velocity in space that was not reflected by parallel changes in the plane or magnitude of the VOR. This series of experiments establishes several facts concerning spatial orientation perception beyond the predictive domain of any current model. New concepts are needed and several are suggested to deal with changing reactions to complex combinations of linear and angular accelerations.