Richard B. Roberts

Impaired Production of Lymphokines and Immune (Gamma) Interferon in the Acquired Immunodeficiency Syndrome

To examine the cellular immune defect that predisposes patients with the acquired immunodeficiency syndrome (AIDS) to opportunistic infections, we tested T lymphocytes from 16 patients for the capacity to secrete macrophage-activating products (lymphokines) including gamma interferon. Mononuclear cells from 10 of 11 patients did not generate an effective lymphokine in response to mitogen, and 11 of 16 produced subnormal levels of gamma interferon (less than 300 U per milliliter). In addition, upon stimulation with specific microbial antigen, cells from none of 14 patients generated active lymphokines, and cells from 13 to 14 completely failed to secrete gamma interferon. However, the antimicrobial function of monocytes from the patients was intact, and once stimulated with normal lymphokines or gamma interferon alone, macrophages derived from patients monocytes responded with enhanced and effective intracellular antimicrobial activity. These results suggest that impaired lymphokine production may predispose patients with AIDS to opportunistic infections, and they provide a rationale for using gamma interferon as immunotherapy.

Cryptosporidiosis in Homosexual Men

Between April 1982 and June 1983, cryptosporidiosis was diagnosed in six homosexual men. Four patients with the acquired immunodeficiency syndrome had lymphopenia, cutaneous anergy, and profoundly impaired cellular immunity; their cryptosporidiosis was severe, unremitting, and refractory to all therapy. Two patients without other opportunistic infections or Kaposis sarcoma had moderately impaired cellular immunity but not lymphopenia or anergy; their enteric illness was self-limited. Cryptosporidium recently had been recognized as a human pathogen that is transmitted through fecal-oral contamination. The severity of human cryptosporidiosis appears to be determined primarily by immunocompetence of the patient. These six homosexual men, with different degrees of immunologic impairment, had two clinically divergent forms of cryptosporidiosis. Their cases raise questions about human transmission of Cryptosporidium and the prognostic significance of this disease in patients who are at high risk for developing the acquired immunodeficiency syndrome.

Ribavirin disposition in high‐risk patients for acquired immunodeficiency syndrome

Ribavirin is a broad‐spectrum antiviral drug that has in vitro activity against human immunodeficiency virus. To determine the kinetics of ribavirin, 17 symptom‐free homosexual men with lymphadenopathy were studied. Single doses of ribavirin, 600, 1200, or 2400 mg, were given orally or intravenously. The plasma ribavirin concentration‐time profiles were well fitted by a three‐compartment open model. Ribavirin followed linear kinetics over the dose range studied. The mean 1‐hour postinfusion concentrations after intravenous ribavirin, 600, 1200, and 2400 mg, were 8.0, 19.7, and 37.1 μmol/L, respectively. The mean ± SD plasma β‐phase half‐life, terminal‐phase (γ) half‐life, and volume of distribution at steady state were 2.0 ± 1.1 hours, 35.5 ± 14.0 hours, and 647 ± 258 L, respectively. The mean ribavirin renal clearance and total body clearance were 99 ± 30 and 283 ± 37 ml/min, respectively. After an oral dose of 600,1200, and 2400 mg, the mean peak plasma ribavirin concentrations (which occurred 1.5 hours after administration) were 5.1, 9.9, and 12.6 μmol/L, respectively. The mean absorption half‐life and bioavailability of ribavirin were 0.5 hour and 45%. Ribavirin had no plasma protein binding and the drug accumulated within red blood cells. In conclusion, ribavirin is incompletely absorbed from the gastrointestinal tract, its renal excretion accounts for approximately one third of the drugs elimination, and drug accumulation (>threefold) will result with repetitive dosing at the 6‐ to 8‐hour dosing interval currently used.

Mycobacterium avium-M. intracellulare isolates from patients with or without acquired immunodeficiency syndrome.

Susceptibility testing and serotyping were performed on 57 isolates of Mycobacterium avium-M. intracellulare from patients with acquired immunodeficiency syndrome (AIDS) and 75 isolates from patients without AIDS. Susceptibility patterns and serotypes of AIDS isolates were significantly different from those of non-AIDS isolates. These results may partially explain the poor therapeutic response of M. avium-M. intracellulare infections in AIDS patients.

Antimicrobial Therapy of Experimental Enterococcal Endocarditis

The successful therapy of enterococcal endocarditis requires prolonged administration of synergistic antibiotic combinations. Controversy has arisen regarding optimal therapy (i) when the organism possesses high-level streptomycin resistance, and (ii) when the patient is allergic to penicillin. This study examines these questions in vitro and in a rabbit model of enterococcal endocarditis. The combination of penicillin with either streptomycin or gentamicin increased the rate of bacterial killing in vitro and in vivo when compared with penicillin alone (P < 0.05) when the test strain was relatively susceptible to streptomycin (minimal inhibitory concentration, 128 μg/ml). Only the combination of penicillin and gentamicin was consistently more effective than penicillin alone (P < 0.01) when the test strain was highly resistant to streptomycin (minimal inhibitory concentration > 150,000 μg/ml). The combination of vancomycin and streptomycin was more rapidly bactericidal than vancomycin alone in vitro and in the animal model against the streptomycin-susceptible strain (P < 0.01). The relative rate of in vitro bacterial killing by various antibiotics and combinations was predictive of the efficacy of these drugs in eradicating enterococci from cardiac vegetation in experimental endocarditis.

The Effect of Penicillin on Acute Rheumatic Fever and Valvular Heart Disease

THE control of symptoms of acute rheumatic fever is easily attained by several methods of therapy, but no form of treatment has had a marked effect on acute carditis and valvular heart disease, the two complications that determine the ultimate prognosis. Since the initiating event of the acute rheumatic episode is infection by the Group A streptococcus, it appeared logical to attempt to alter the course of established rheumatic fever by removing the original inciting agent. To accomplish this objective, 49 patients with acute rheumatic fever received large doses of penicillin, and 48 patients received no antibiotic and served as .xa0.xa0.

Ribavirin pharmacodynamics in high‐risk patients for acquired immunodeficiency syndrome

Ribavirin was administered orally in escalating doses for 2 or 4 weeks to 15 symptom‐free, human immunodeficiency virus seropositive homosexual men with generalized lymphadenopathy. Reverse transcriptase activity was inhibited during therapy when steady‐state plasma concentrations were >6 µmol/L. These concentrations were achieved with 1200 or 2400 mg/day for 2 weeks or a loading dose of 2400 mg/day for 3 days followed by 600 mg/day for 4 weeks. Drug accumulation occurred at all doses. The elimination half‐life appeared to be approximately 2 weeks. Reversible adverse reactions, principally resulting in central nervous system symptoms and anemia, correlated with dose and duration of therapy. Immunologic enhancement of T‐lymphocyte—mediated mitogen‐induced responses was observed in the majority of patients who had reduction in reverse transcriptase activity. However, specific T4 + lymphocyte—mediated antigen‐induced responses increased to within the normal range in only three patients. Significant enhancement appeared to correlate with the severity of baseline antigen‐induced functional impairment. These data indicate that oral ribavirin can be given for at least 1 month with acceptable toxicity at doses that appear to inhibit human immunodeficiency virus replication.

Recurrent peritonitis in a patient on dialysis and prophylactic vancomycin

resistant S aureus laboratory mutant and in several coagulase-negative staphylococcal isolates. Between January and June, 1997, the patient received 30 g of intraperitoneal vancomycin. In spite of this extensive exposure, the same S epidermidis strain with resistance to vancomycin was recovered from each of the dialysate samples after 3 weeks of vancomycin prophylaxis, demonstrating that the vancomycin prophylaxis did not produce bacteriological cure. In fact, the episodes of recurrent S epidermidis peritonitis stopped only after removal of the dialysis catheter. It is ominous that the dialysis-catheter site was contaminated by two different bacterial species each carrying a distinct vancomycin-resistance mechanism. Heterogeneous cultures of meticillin-resistant S epidermidis represent potential reservoirs of staphylococci with vancomycin MIC values above therapeutically achievable levels. The ease with which selection of these subpopulations occurred in the laboratory suggests that they may also emerge in patients patients by echocardiography. Preliminary results (follow-up 1 month to 1 year) indicate recovery of sinus rhythm in all cases, with a normal sinoatrial node response to gentle exercise and no requirement for permanent pacing. Because atrial fibrillation is a prominent cause of thromboembolism and significantly reduces cardiac performance, we are evaluating this surgically simple and effective method of restoring sinus rhythm as an adjunct to routine mitral valve surgery in a prospective randomised controlled trial.

Penicillin-Resistant Streptococcus pneumoniae in Metropolitan New York Hospitals: Case Control Study and Molecular Typing of Resistant Isolates

During the 4-month period from January to April, 1998, 476 patients with Streptococcus pneumoniae infections were detected in 12 metropolitan New York hospitals and 112 penicillin-resistant (PRP) isolates (24%) were identified in 11 institutions. A case control study of 100 patients with penicillin-resistant and susceptible pneumococci from four of the widely dispersed hospitals revealed a high incidence of underlying medical illnesses in adult patients (74%), a preponderance of patients with pneumonia (63%), and a majority of patients who had underlying risk factors for pneumonia or invasive disease (51%). In this limited case control study, no difference was noted between cases and controls regarding known risk factors for penicillin-resistant pneumococcal infections. The percentage of single-patient PRP isolates varied among individual hospitals but the mean percentages of PRP from the four participating University Medical Centers and seven community hospitals were similar: 26% and 22% respectively. By E-test, 60% and 26% were high-level penicillin and ceftriaxone resistant, respectively. Pulsed-field gel electrophoresis identified 26 chromosomal macrorestriction patterns among the 103 PRP isolates available for analysis, but almost half (50 isolates or 48%) of these belong to two drug-resistant internationally spread clones, SP(23)-1 and SP(9/14)-3, that were detected in all hospitals and were recovered from invasive and noninvasive sites in both children and adults.

Comparison of ceforanide and cephalothin prophylaxis in patients undergoing total joint arthroplasty.

One hundred one patients undergoing total hip and knee arthroplasty were randomly assigned to receive either two 1 gm doses of ceforanide or five doses of cephalothin perioperatively. Simultaneous plasma and cancellous bone specimens were obtained intraoperatively and assayed for antibiotic concentration. Ceforanide plasma and bone levels remained sustained over six hours. Cephalothin plasma and bone levels obtained three to four hours post administration were 91% lower than levels obtained one hour post-dose. Patients were examined for infection for up to 18 months following surgery. None of the patients developed an infected implant. The sustained plasma and bone levels achieved with ceforanide obviate the need for intraoperative dosing necessary with other agents.