Earl H. Freimer

T lymphocyte abnormalities in disseminated histoplasmosis

Disseminated histoplasmosis is associated with depression of T cell-mediated immunity and in some cases anergy. In this report, two patients with disseminated disease are described. Both had a depression of T cell-mediated immunity as well as other abnormalities of immune response. In one, a patient with relapse, a marked depression in the ratio of T helper to T suppressor cells was noted. Neither patient had any predisposing condition known to be associated with disseminated disease.

Treatment of skin and soft tissue infections with imipenem/cilastatin

Ninety-eight adult patients with skin and soft tissue infections caused by a variety of bacterial pathogens were treated with imipenem/cilastatin (71), cefazolin (21), or moxalactam (six) at three medical centers. Favorable clinical responses were observed in 87 of the 90 evaluable cases (97 percent). Most etiologic pathogens were eradicated during treatment including five of seven which demonstrated in vitro resistance to the therapeutic agent. Strains that persisted during treatment were not associated with therapeutic failure except in one cefazolin-treated patient who was infected with Bacteroides fragilis. All three drugs were well tolerated and no specific patterns of adverse reactions were observed.

Rupture of a pulmonary artery mycotic aneurysm associated with candidal endocarditis

Candidal endocarditis can develop if candidemia occurs during Swan-Ganz catheterization. Candida endocarditis may persist for many months and is fatal unless the infected valve is resected. Herein is reported the first case of rupture of a mycotic pulmonary artery aneurysm caused by chronic candidal endocarditis. The endocarditis followed Swan-Ganz catheterization and aneurysm progressed despite appropriate medical and surgical therapy.

Ceftizoxime elimination kinetics in continuous ambulatory peritoneal dialysis

We investigated the kinetics of ceftizoxime, a β‐lactamase stable cephalosporin, in eight subjects undergoing continuous ambulatory peritoneal dialysis (CAPD). A single 500‐mg or 1‐gm dose was injected IV, or a 500‐mg dose was given intraperitoneally in the CAPD fluid during a 6‐hr dwell time. The ceftizoxime (500 mg) serum kinetic parameters were as follows: peak concentrations, 21 to 46 mg/l; volume of distribution, 0.27 l/kg; elimination rate constant, 0.0784 hr−1; plasma clearance, 1.66 l/kg hr−1; and t½, 10.2 hr. The t½ after 1 gm was 12 hr. Dialysate ceftizoxime concentrations rose rapidly between 0.25 and 2 hr and slowly over the next 4 hr, but only 4.04 ± 7.5 and 7.4 ± 2.9 mg ceftizoxime/hr was eliminated by the peritoneal route over a 6‐hr dwell time after 500 mg or 1 gm IV. This represents only 4% to 5% of the dose. After intraperitoneal instillation, the antibiotic appeared in the serum within 15 min in all four subjects, and the peak serum concentrations ranged from 12 to 19.8 mg/l (mean ± SD = 16.4 ± 3.3) between 5 and 6 hr. Approximately 78% of ceftizoxime was absorbed from the peritoneal dialysis fluid during a single 6‐hr dwell time. Rate constant for absorption, ka, was 0.3959 hr−1 and absorption t½ was 1.75 hr (as calculated by the residual equation). These data suggest that ceftizoxime has bidirectional exchange characteristics through the peritoneal membrane. Instillation of ceftizoxime in CAPD fluid alone may permit rapid absorption to reach therapeutic serum concentrations.

Clinical Studies of Cefazolin and Comparison with Other Cephalosporins

Cefazolin, a new cephalosporin derivative, was studied in the treatment of 105 hospitalized patients with a variety of infections including endocarditis, pneumonia, and urinary and soft tissue infections, and was found to be effective in 104 patients. Cefazolin was also tested in vitro and shown to be effective against staphylococci, pneumococci, Escherichia coli, Klebsiella sp., and Proteus mirabilis by agar dilution method. It was shown to produce high serum levels when administered in a 250- to 1,000-mg intramuscular dose and was well tolerated and free from renal toxicity. Comparison of the results of this study with those from our prior studies on cephaloridine revealed equivalent antibiotic potency, good tolerance to both the agents when given intramuscularly, superior, average blood levels with cefazolin, equal clinical efficacy, and absence of renal toxicity with cefazolin (unlike cephaloridine). Similarly, the results of treatment of pneumococcal pneumonia with intramuscular cefazolin were found to be superior to those for oral cephalexin.

Pharmacokinetics of imipenem-cilastatin in patients with renal insufficiency undergoing continuous ambulatory peritoneal dialysis.

In six patients with end-stage renal disease, a single bolus of imipenem-cilastatin (500 mg each) was given either intravenously or intraperitoneally in a randomized crossover protocol such that each patient received the drug by both routes at a 2- to 3-week interval. Drug levels in plasma and the peritoneal dialysis fluid were analyzed at frequent intervals, and various pharmacokinetic variables were calculated for a one-compartment open model. Data obtained in the present study suggest that while no significant difference in peak plasma levels or volume of distribution were noted, the following variables were significantly different for imipenem as compared with cilastatin: elimination half-life, total plasma clearance, area under the concentration-time curve, and percent drug excretion in the peritoneal dialysis fluid. The elimination half-life of imipenem (3.28 h) or cilastatin (8.84 h) in our patients was in the same range as observed in patients with minimal renal function undergoing hemodialysis. The dose of imipenem-cilastatin should be reduced appropriately in patients with end-stage renal disease undergoing peritoneal dialysis.

Pathogenesis and treatment of endocarditis

The rabbit model has been invaluable for in vivo studies in the pathogenesis and treatment of bacterial endocarditis. Both of the features of the mature bacterial vegetations in this rabbit model, i.e., absence of phagocytosis and decreased metabolic activity, provide evidence to support the concept that a rapidly bactericidal antimicrobial agent provides the optimal approach to the successful treatment of endocarditis. Imipenem, a carbapenem with a very broad spectrum of in vitro activity, has been shown to be rapidly bactericidal in animals and highly effective in the treatment of experimental bacterial endocarditis. In addition, twenty-six patients with endocarditis, caused largely by Staphylococcus aureus, have been successfully treated with imipenem/cilastatin.

Comparative In Vitro Activities of N-Formimidoyl Thienamycin and Moxalactam Against Nonfermentative Aerobic Gram-Negative Rods

N-Formimidoyl thienamycin was the most active drug against strains of Pseudomonas aeruginosa with a 90% minimum inhibitory concentration of 1.25 μg/ml. With the exception of P. maltophilia, thienamycin was as active or more active than moxalactam against other species of pseudomonads and against other genera of nonfermenters.

Treatment of serious infections with moxalactam.

In 93 hospitalized patients, 111 bacterial infections were treated with moxalactam. Eighty-three infections responded well to therapy, nine infections failed to respond to therapy or relapsed, and nine infections showed superinfection with resistant bacteria. The great majority of bacteria isolated had mean inhibitory concentrations below levels readily achieved in plasma, cerebrospinal fluid, bile, abscess fluid, and peritoneal fluid. Among the commonly identified bacteria, only Pseudomonas aeruginosa, enterococci, and Staphylococcus epidermidis had variable sensitivity to moxalactam.

In Vitro Evaluation of the New Oral Cephalosporin Cefatrizine: Comparison with Other Cephalosporins

Cefatrizine (BL-S640), a semisynthetic, orally administered cephalosporin, was found to have an in vitro spectrum of activity comparable to those of four other cephalosporins tested. It is as effective as cephalexin, the other orally administered cephalosporin evaluated, against most species, and it appears to be more effective than cephalexin against many Enterobacter, Haemophilus, and Proteus strains isolated in our hospital. It is not inactivated by the plasmid-determined β-lactamases of 14 strains of ampicillin-resistant Salmonella typhimurium or the ampicillin resistance determinant of an H. influenza strain from the Center for Disease Control. No synergy was observed between cefatrizine and gentamicin, kanamycin, carbenicillin, or polymyxin when tested against selected strains.