Steady-state moxalactam kinetics: comparisons with other cephalosporins.

Moxalactam is a new beta-lactam antimicrobial with an extended spectrum. Serum concentrations were determined in 14 patients at steady state using bioassay and high-pressure liquid chromatography methods. Mean peak and trough serum concentrations were 195 and 29.5 micrograms/ml for the 20-gm dose and 214 and 28.8 micrograms/ml for the 3-gm dose. Peak and trough levels exceeded the minimum inhibitory concentration of the infecting bacteria in 100% and 67% of the patients. The 3-gm dose is recommended for infections caused by Pseudomonas aeruginosa and other organisms with higher minimum inhibitory concentrations. Half-lifes ranged from 1.7 to 5.7 hr and reflected the varying renal functions of the patients. A relationship (r = 0.878, p less than 0.001) between creatinine clearance and elimination rate constant was established by bivariant linear regression analysis.

Pneumonia due to the Pittsburgh pneumonia agent: new clinical perspective with a review of the literature.

We review the current knowledge concerning this newly recognized pathogen, Pittsburgh pneumonia agent (PPA), and present a new, comprehensive perspective of PPA based on our extensive clinical experience: 1) PPA pneumonia is more common and affects a broader range of patients than previously appreciated. 2) In the general population, the disease is not distinguishable from acute pneumonia due to other causes. Because specialized diagnostic tests are required for detection, it is likely that many cases in other hospitals go unrecognized. 3) Diagnosis is important, as erythromycin appears to improve outcome, whereas beta-lactam antibiotics and aminoglycosides, frequently used as empiric therapy for nosocomial bacterial pneumonias, do not. 4) The presence of both PPA and L. pneumophila in the same environmental sites, and the discovery of seven cases of simultaneous infection by both organisms suggest that both organisms are likely to share a common reservoir within the hospital and a common mode of transmission. 5) PPA infection occurs in a more debilitated population than does Legionnaires' disease. This may represent differences in intensity of exposure to the two organisms or may reflect inherent differences in virulence.

Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients.

PURPOSE AND PATIENTS AND METHODS: We performed a prospective clinical study of 200 consecutive patients with Pseudomonas aeruginosa bacteremias to analyze in vitro susceptibility and synergistic testing of antibiotics the patients received and clinical parameters to assess their relationship to survival. RESULTS: No significant correlation between in vitro susceptibility testing (minimal inhibitory concentrations/minimal bactericidal concentrations) and outcome could be demonstrated. Similarly, improved outcome could not be demonstrated for patients receiving antibiotic combinations that were synergistic in vitro (either time-kill or checker-board) versus those combinations that were not. There was also no correlation between results obtained by time-kill curve and checkerboard synergistic testing, i.e., combinations found to be synergistic by one method were not necessarily synergistic by the other method. Clinical parameters associated with improved survival were a urinary portal of entry and absence of neutropenia. Conversely, survival was significantly decreased when the portal was the respiratory tract. The mortality rate between patients receiving combination therapy (27%) and monotherapy (47%) was significant (p less than 0.02); this significant relationship held true for most subgroups including malignancy, nosocomial infection, and infection site. CONCLUSION: Increasing effort should be placed on ensuring timely administration of combination therapy to patients with P. aeruginosa bacteremia since the use of combination therapy was even more important in determining outcome than was underlying disease.

Intraocular distribution of intravitreally administered amphotericin B in normal and vitrectomized eyes.

A study was performed to determine how amphotericin B is distributed in the eye after direct intravitreal injection. Radiolabeled amphotericin B was administered by direct injection into the vitreous space of unmodified phakic control or vitrectomized aphakic eyes in the rabbit model. The eyes were removed at different post-injection times, frozen and dissected into anatomical subparts of cornea, aqueous, iris, lens, vitreous and sclera-choroid-retina. The parts were assayed for total radioactivity (expressed as remaining amphotericin B). No accumulation of drug was observed in the cornea, lens, iris or aqueous region. The majority of drug was found in the vitreous cavity. The rate of disappearance of radiolabeled drug or radiolabeled drug degradation products from the vitreous space was similar to the rate of disappearance from the eye. However, progressive accumulation of radioactivity was observed in the sclera-choroid-retina tissue in the unmodified phakic eyes. This was not observed in vitrectomized aphakic eyes. The accumulated radioactivity could have represented drug degradation products or active drug. These results shed light on the distribution of amphotericin B in the eye after direct intravitreal injection, a procedure often employed clinically for fungal endophthalmitis.

An ophthalmic surgeon's view of orbital imaging techniques.

Selection of an orbital imaging technique requires a thorough understanding of pertinent anatomy applied to relevant clinical history and detailed ophthalmic examination. The clinical finding should direct the clinician to the imaging study that provides maximum information and narrows diagnostic considerations for the individual patient. Clinical examples are provided to illustrate the rationale in ordering magnetic resonance images, computed tomography, ocular ultrasound, and color Doppler arteriography of orbital processes.

Infections caused by Pseudomonas maltophilia with emphasis on bacteremia: case reports and a review of the literature.

Ten cases of Pseudomonas maltophilia bacteremia were identified over a five-year period at the University of Pittsburgh Medical Center. Our experience and a review of the literature show that P. maltophilia can cause a wide spectrum of disease. We present cases of pneumonia and infections of the biliary tract and urinary tract in which the organism was isolated simultaneously from blood. P. maltophilia endocarditis occurs in the context of iv drug abuse or as a postoperative complication of prosthetic valve surgery. Pseudobacteremia from contaminated equipment, disinfectants, and vascular catheters is the newest presentation for P. maltophilia infection. Hospitalization and prior antibiotic therapy are risk factors for serious P. maltophilia infection. Mortality due to P. maltophilia infection is low, despite the notable in vitro resistance of the organism to antibiotics. Trimethoprim-sulfamethoxazole, minocycline, doxycycline, and moxalactam are highly active in vitro against P. maltophilia. The triple combination of trimethoprim-sulfamethoxazole plus carbenicillin plus rifampin has been found to be synergistic in vitro and can be considered for serious infections.

Ticarcillin-tobramycin-rifampin: in vitro synergy of the triplet combination against Pseudomonas aeruginosa.

MICs of ticarcillin, tobramycin, and rifampin alone and in combination were determined by a three-dimensional checkerboard method for 33 isolates of Pseudomonas aeruginosa. Twenty-nine of 33 isolates were affected synergistically (FIC index less than 1.0) by the combination of ticarcillin-tobramycin, including 13 of the 16 isolates resistant to ticarcillin and/or tobramycin alone. However, despite fulfilling the criteria for synergy, the MIC of the ticarcillin and/or tobramycin when in combination still exceeded attainable serum concentrations for 12 of the 13 resistant isolates. When rifampin was added to ticarcillin-tobramycin, a synergistic interaction was observed for all 33 isolates. Furthermore, of the 16 isolates resistant to ticarcillin and/or tobramycin, eight were inhibited by attainable concentrations of all three antibiotics in combination. If these results can be confirmed in the clinical situation, application of the three-drug combination of ticarcillin-tobramycin-rifampin might improve survival in selected patients with serious P. aeruginosa infections.

Comparative susceptibilities of Pseudomonas aeruginosa to 1-oxacephalosporin (LY 127935) and eight other antipseudomonal antimicrobial agents (old and new).

In vitro susceptibilities of 53 clinical isolates of Pseudomonas aeruginosa to nine antipseudomonal antibiotics were determined. From 96 to 100% of the isolates were susceptible to piperacillin, ticarcillin, and 1-oxacephalosporin (LY 127935). Of the aminoglycosides, 89, 82, 79, and 29% were susceptible to amikacin, tobramycin, gentamicin, and netilmicin, respectively. A total of 96% and 78% of the isolates were susceptible to 1-oxacephalosporin (LY127935) and cefotaxime, respectively, at concentrations of 62.5 micrograms/l. Supplementation of testing media by calcium and magnesium not only markedly increased the minimal inhibitory concentrations of the aminoglycosides, but also raised those of cefotaxime and the penicillins; no significant effect was noted with 1-oxace-phalosporin. Synergy was not demonstrated consistently in vitro with 1-oxace-phalosporin combined with either carbenicillin, ticarcillin, gentamicin, or tobramycin.

Legionella pneumophila contamination of a hospital humidifier. Demonstration of aerosol transmission and subsequent subclinical infection in exposed guinea pigs.

Water from a humidifier located in the hospital was found to be contaminated with Legionella pneumophila, serogroup 1. The source of water for the humidifier was the hospital potable water system. Exposure of culture mediums to the humidifier aerosols yielded L. pneumophila, serogroup 1. Exposure of guinea pigs to humidifier aerosols produced a subclinical infection as demonstrated by seroconversion to L. pneumophila. Seroconversion rate of guinea pigs to L. pneumophila was higher when greater quantities of L. pneumophila were present in the water; a corresponding increase in recovery of the organism from culture mediums exposed to aerosols was also seen. This report shows that mechanically created aerosols of Legionella-contaminated potable water might be the vehicle of transmission of Legionnaires' disease, especially in the hospital setting.

Addition of rifampin to ticarcillin-tobramycin combination for the treatment of Pseudomonas aeruginosa infections: assessment in a neutropenic mouse model.

The efficacy of ticarcillin (100 mg/kg), tobramycin (1 mg/kg), and rifampin (43 and 7.2 mg/kg) individually and in combination was assessed in neutropenic mice infected with an LD90 of one of four Pseudomonas aeruginosa isolates. The study end point was survival at 120 hours after infection. Treatment with the triple combination, ticarcillin plus tobramycin plus rifampin (43 mg/kg), was significantly superior to the double combination of ticarcillin plus tobramycin (p less than 0.01). Although treatment with rifampin (43 mg/kg) alone yielded results similar to treatment with the triple combination in mice infected with three of the four isolates, rifampin-resistant mutants (minimal inhibitory concentration greater than 1000 micrograms/ml) of P. aeruginosa were frequently isolated from surviving mice (26% of mice sampled). In contrast, in mice treated with the triple combination, rarely were rifampin-resistant mutants isolated (3% of mice sampled). Rifampin alone was active against P. aeruginosa isolates only when peak serum concentrations of rifampin exceeded the rifampin minimal bactericidal concentration of the infecting isolate. The addition of rifampin to a "standard" therapy of antipseudomonal penicillin plus aminoglycoside may be useful in the treatment of serious P. aeruginosa infection.

Isolation of Legionella pneumophila from blood with the BACTEC system: a prospective study yielding positive results.

In a prospective study of 16 patients with Legionnaires disease confirmed by cultural isolation of Legionella pneumophila from the respiratory tract, 38% (6 of 16) had positive blood cultures. Daily subcultures were made onto buffered charcoal-yeast extract plates from 6B aerobic and 7C anaerobic BACTEC blood culture bottles (Johnston Laboratories, Inc., Towson, Md.). Isolation of L. pneumophila was achieved from both aerobic and anaerobic bottles. L. pneumophila growth indices failed to exceed the BACTEC threshold limits; thus, the organism would have been overlooked despite its presence in the blood culture bottles. Bacteremic patients had statistically significant higher quantities of L. pneumophila isolated from sputum and visualized on direct fluorescent antibody stains. Thus, the potential exists for improved diagnosis of Legionella infection by a relatively noninvasive procedure (blood culture) with an instrument already in use in many hospital laboratories.

In-vitro synergy testing of triple antibiotic combinations against Staphylococcus epidermidis isolates from patients with endocarditis.

In-vitro synergy testing was performed against ten blood or valve isolates of Staphylococcus epidermidis taken from patients with endocarditis. A three-dimensional microtitre checkerboard method was used for evaluation of vancomycin-rifampicin-gentamicin. The triple combination of vancomycin plus rifampicin plus gentamicin was found to be synergistic in 70% of the isolates. Vancomycin plus rifampicin was not synergistic. Oral agents including dicloxacillin, rifampicin, and fusidic acid were also evaluated. Four methicillin-resistant isolates were relatively resistant to dicloxacillin (MIC greater than 0.79 mg/l) but all four isolates were susceptible to fusidic acid alone and rifampicin alone. The triple combination of dicloxacillin plus fusidic acid plus rifampicin was found to be synergistic in 50% of the isolates and generally superior to any two-drug combination raising the possibility of an effective oral combination of antibiotics.

Addition of rifampin to carboxypenicillin-aminoglycoside combination for the treatment of Pseudomonas aeruginosa infection: clinical experience with four patients.

Four patients infected with Pseudomonas aeruginosa were treated with the triple therapy of carboxypenicillin (carbenicillin or ticarcillin), aminoglycoside (gentamicin or tobramycin), and rifampin. Two patients had P. aeruginosa endocarditis, one had bacteremia associated with granulocytopenia, and one had neurosurgical meningitis. In all four cases, the clinical condition of the patient deteriorated on combined antipseudomonal penicillin and aminoglycoside therapy. All patients had persistent blood cultures (throughout a 3- to 30-day period) or cerebrospinal fluid cultures (throughout a 24-day period) while receiving penicillin-aminoglycoside therapy. Rifampin, 600 mg every 8 h orally, was added to the penicillin-aminoglycoside regimen. All four patients defervesced within 24 h after the initiation of rifampin. In addition, all four patients experienced sterilization of blood and cerebrospinal fluid cultures within 24 h of therapy. The emergence of rifampin-resistant P. aeruginosa was not observed. Ultimately, two patients survived their infection; the other two patients succumbed to complications of their underlying disease. This clinical experience should provide a stimulus for a controlled evaluation of rifampin as a component of multiple drug therapy directed against P. aeruginosa.

Staphylococcus aureus nasal carriage and infection in patients on hemodialysis. Efficacy of antibiotic prophylaxis.

We conducted a five-year prospective controlled study of prophylaxis of Staphylococcus aureus nasal carriage and infection among patients in a hemodialysis unit. Carriers tended to have chronic colonization with a single phage type. S. aureus infections occurred significantly more frequently in carriers than in noncarriers and, in 93 percent of the infected carriers, were caused by the same phage type as that carried in the nares. Neither intravenous vancomycin nor topical bacitracin was found to be efficacious in eradicating nasal carriage. However, oral rifampin given for five days decreased S. aureus carriage over a one-month follow-up period, but within three months colonization of the nares recurred in most carriers, often with an S. aureus of the original phage type. Carriers were then randomly assigned to receive either rifampin or no prophylaxis. Rifampin was readministered at three-month intervals if culture of the anterior nares yielded S. aureus. Infections with S. aureus occurred significantly more frequently in carriers given no prophylaxis than in those given a full course of rifampin. S. aureus resistant to rifampin was isolated from the anterior nares of four patients, but these isolates were not implicated in any infections. The incidence of infection at the dialysis access site, skin, and soft tissue of patients on hemodialysis can be decreased by interventions directed at nasal carriage of S. aureus.

Diagnosis of Legionnaires' disease. An update of laboratory methods with new emphasis on isolation by culture.

A prospective clinical study of 40 cases of legionnaires' disease combined with serial laboratory examinations enabled us to present an update as well as new recommendations concerning the use of diagnostic tests for legionnaires' disease. Transtracheal aspirate specimens are the optimal specimen for recovery of Legionella pneumophila by culture as well as the most sensitive method for early diagnosis. In addition, with recent improvements in culture media and methodology, L pneumophila can now be readily isolated from sputum. Examination of respiratory specimens by direct immunofluorescence (DFA) is useful, but the sensitivity is much less than that of culture. The yield from DFA examination directly correlates with the number of L pneumophila recoverable by cultural methods; thus, the DFA test result may be negative in an early or mild case of legionnaires' disease. Antibody titers were elevated in 27% of cases within one week of onset of pneumonia and may, therefore, be useful in early diagnosis in selected patients.

Effect of calcium, magnesium, and zinc on ticarcillin and tobramycin alone and in combination against Pseudomonas aeruginosa.

Correlation between in vitro and in vivo test results for synergy between carboxypenicillins and aminoglycosides against Pseudomonas aeruginosa is poor. Although the divalent cation content of culture media is known to affect aminoglycoside susceptibility testing for P. aeruginosa, this effect of divalent cations has not been examined for synergy testing of carboxypenicillin-aminoglycoside interaction against P. aeruginosa. The minimal inhibitory concentrations (MICs) of tobramycin and ticarcillin and the interaction of these drugs in combination were studied by a microtitration method for 36 strains of P. aeruginosa in Mueller-Hinton broth with varying supplements of calcium, magnesium, and zinc. The supplementation of Mueller-Hinton broth to 50 or 100 mg of calcium per liter had a significant effect in increasing the tobramycin MIC (P less than 0.01), as well as decreasing the degree of synergy between ticarcillin and tobramycin (P less than 0.01). Supplementation to 20 mg of magnesium per liter, 1.0 mg of zinc per liter, or both did not significantly affect tobramycin MIC or the interaction of tobramycin and ticarcillin. Supplementation to 50 or 100 mg of calcium per liter rendered any additional effect of magnesium and zinc on aminoglycoside MIC and aminoglycoside-carboxypenicillin interaction negligible. If these results for ticarcillin and tobramycin are confirmed for other carboxypenicillins and aminoglycosides, then the Mueller-Hinton broth used for P. aeruginosa aminoglycoside susceptibility and synergy testing may need to be supplemented only with calcium at a concentration of 50 mg/liter.

Measurement of serum and tissue concentration of moxalactam using high pressure liquid chromatography.

We describe a sensitive high pressure liquid chromatographic (HPLC) procedure for the analysis of the new beta-lactam antibiotic moxalactam. Conditions are described for either measurement of total drug concentration or the concentration of the individual isomers. The proteins in a 1.0 ml plasma sample are denatured with isopropyl alcohol which is then extracted into a chloroform reagent, leaving the drug in the aqueous phase. An aliquot is then injected into a mu-bondapak phenyl column. A similar extraction procedure was employed for tissue homogenates. Linear regression analysis and comparison of the HPLC assay with the microbiological assay gave a correlation coefficient of 0.97. Analysis of tissue samples indicated that significant concentrations of moxalactam were obtained at the site of infection.

Intraocular candidiasis in patients with candidemia. Clinical implications derived from a prospective multicenter study.

PURPOSE: Intraocular infection caused by Candida species can have devastating visual consequences. With the emergence of Candida as a major nosocomial pathogen, the authors investigated the prevalence of ocular lesions in patients with candidemia and evaluated risk factors for eye involvement. METHODS: This study is a prospective, multicentered, observational design. One hundred eighteen patients with candidemia were evaluated by the infectious disease service and received indirect ophthalmologic examination within 72 hours of a reported positive blood culture. Ocular findings were classified on the basis of objective, pre-determined criteria. Candida chorioretinitis was defined as the presence of focal, white, infiltrative chorioretinal lesions without vitreal involvement. Candida endophthalmitis was defined as chorioretinitis with extension into the vitreous or intravitreal "fluff balls." RESULTS: In contrast to previous studies of patients with candidemia citing prevalence rates of endophthalmitis approaching 40%, no patients were shown to have endophthalmitis. Candida chorioretinitis was seen in 9% of the patients, all of whom received antifungal agents. The observation that chorioretinitis never progressed to endophthalmitis suggests that systemic antifungal agents provided adequate ocular therapy. Risk factors for Candida chorioretinitis include fungemia with Candida albicans (versus nonalbicans species), multiple positive blood cultures, visual symptoms, and immunosuppression. Twenty percent of patients had nonspecific ocular lesions not directly related to infection. CONCLUSION: Patients with candidemia who have the risk factors noted above warrant formal ophthalmologic examination.