Typhoid fever. An epidemic with remarkably few clinical signs and symptoms.

A major common-source, foodborne epidemic of typhoid fever occurred in San Antonio, Tex, in the fall of 1981, involving 80 verified cases. We summarize the clinical course of our 34 patients who had a nonspecific symptom complex that included at the initial examination fever (32 patients, 93%), headache (19 patients, 57%), diarrhea (11 patients, 33%), and anorexia (ten patients, 30%). The most common initial diagnoses were urinary tract and upper respiratory tract infections. The subsequent isolation of Salmonella typhi from blood cultures was usually unexpected. Physical findings were different from two previous series originating in the United States. Hepatomegaly was noted in only 7% (two patients), splenomegaly was noted in 13% (four patients), and rose spots were noted in 5% (two patients) of the patients. Liver function test results, however, were abnormal in 32 (95%) of the 34 patients (mean SGOT, 155 IU/mL). Typhoid fever, as seen in this outbreak, was notable for its nonspecific and mild manifestation and uniformly favorable outcome.

High-dose ketoconazole therapy and adrenal and testicular function in humans.

Ketoconazole, an oral antifungal, when given in conventional doses, transiently blocks testosterone synthesis and adrenal response to corticotropin. Higher therapeutic doses (ie, 800 to 1,200 mg/day), even once daily, caused more prolonged blockade. In some men, the serum testosterone concentrations were always subnormal. Bound and free testosterone values were equally diminished. Oligospermia and azospermia after prolonged therapy were noted. Impotence and decreased libido were found. Gynecomastia appeared more common than with lower doses. Depressed response to corticotropin was pronounced. Urine cortisol excretion was depressed. The blockade appeared related to the serum ketoconazole concentration. Instances of normal hormone levels or responsiveness were associated with low ketoconazole concentrations. The hormonal effects were generally unrelated to duration of therapy, although there may have been partial reversal with continued therapy. These effects appeared reversible with discontinuation of therapy. Patients receiving ketoconazole should be considered potentially unable to mount an adrenal stress response and may require testosterone supplementation.

Oral ciprofloxacin therapy for chronic contiguous osteomyelitis caused by aerobic gram-negative bacilli.

Twenty adult patients with chronic contiguous osteomyelitis caused by aerobic gram-negative bacilli were enrolled in an open, prospective cooperative study to determine the effect of oral ciprofloxacin therapy in a dosage of 750 mg every 12 hours. There were 14 men and six women, with a mean age of 55 years. Fifteen of the 20 patients had undergone previous unsuccessful attempts at therapy; seven of the 20 patients had clinically important underlying diseases. Osteomyelitis involved the sternum in three patients and the bones of the lower extremity in 17 patients. Initial surgical debridement was performed in 15 of 20 patients. The predominant organism isolated was Pseudomonas aeruginosa, which was found as a single pathogen in 13 patients and as part of a polymicrobic flora in three patients. Based on posttreatment follow-up of seven to 21 months, clinical cure was achieved in 13 of 20 (65 percent) patients and bacteriologic cure was achieved in 14 of 20 (70 percent) patients. Minimal inhibitory concentrations of ciprofloxacin against P. aeruginosa increased during therapy in four of 16 (25 percent) patients. Minor gastrointestinal side effects occurred in five patients. Oral ciprofloxacin was an effective and safe therapy in patients with chronic contiguous osteomyelitis due to aerobic gram-negative bacilli.

Amikacin therapy of patients with multiply antibiotic-resistant Serratia marcescens infections: development of increasing resistance during therapy.

Over a recent 22 month period, 222 patients in two adjacent hospitals became infected with a multiply antibiotic-resistant strain of Serratia marcescens; 13 were bacteremic. Nineteen patients with clinically significant infections received amikacin. Nine of 11 patients with urinary tract infections were cured. In contrast, only one of eight patients with pneumonia or other deep tissue infections was cured and four died. These eight patients were severely ill; many had infections with multiple microorganisms. In four of five patients in whom the infection failed to clear promptly. Serratia strains became increasingly resistant to amikacin during therapy and these strains contributed to the death of two of these patients. Amikacin proved useful in treating patients with infections due to gentamicin-resistant S. marcescens organisms, especially urinary tract infections. However, the capacity of some strains of S. marcescens to develop resistance to amikacin may limit the usefulness of this antibiotic in the treatment of deep tissue infections which involve this microorganism.

Randomized trial of ciprofloxacin compared with other antimicrobial therapy in the treatment of osteomyelitis.

Thirty adults (mean age, 52 years) were enrolled in a randomized, comparative trial of oral ciprofloxacin (750 mg twice daily) and other antimicrobial therapies. Etiologic agents included Enterobacteriaceae (18 isolates), Pseudomonas aeruginosa (16 isolates), and Staphylococcus aureus (four isolates). Seven of 14 (50 percent) ciprofloxacin-treated infections are cured at up to 13 months follow-up and three infections appear improved. Treatment failure or relapse has occurred in four patients. Sixteen patients received other antimicrobial therapy and 11 patients (65 percent) remain without infection and have healed wounds, with follow-up from one to 13 months. One patient has had a relapse, while improvement is apparent in four patients. Complications that occurred in this group included drug-related neutropenia (two patients), diarrhea (two patients), drug allergy (one patient), and catheter-related staphylococcal cellulitis (one patient). Oral ciprofloxacin therapy for chronic osteomyelitis caused by susceptible organisms appears to be as effective as other antimicrobial therapies.

Toxoplasmosis presenting as panhypopituitarism in a patient with the acquired immune deficiency syndrome.

A 57-year-old man with a prior episode of lymphatic toxoplasmosis presented with signs of anterior panhypopituitarism, which was confirmed by standard endocrinologic evaluation. The diagnosis of central nervous system toxoplasmosis was established by brain biopsy after nondiagnostic serologic and radiographic studies. At autopsy, the anterior pituitary was necrotic, with Toxoplasma abscesses in neighboring brain structures. Clinical and laboratory data met the criteria for the acquired immune deficiency syndrome. Although this is the first reported case of toxoplasmosis presenting as panhypopituitarism, future cases may be identified since central nervous system toxoplasmosis is being recognized more frequently in patients with immunodeficiency.

Antifungal agents used in systemic mycoses. Activity and therapeutic use.

The development of the polyene antibiotic, amphotericin B, provided for the first time a drug which was clinically effective in many serious mycotic diseases. Unfortunately, it requires parenteral administration and is often toxic, factors which limit the total cumulative dose which can be given. Efforts to utilise combinations of amphotericin B with other agents were best realised with amphotericin B/flucytosine in cryptococcal meningitis, and to a lesser degree in systemic candidiasis. More recently, the introduction of new imidazoles has extended the range of applications of these drugs to fungal diseases. Two members of this group, miconazole and ketoconazole, are promising agents. Miconazole is a parenterally administered agent for patients acutely ill with candidiasis and other mycotic infections. It may be the drug of choice for Petriellidium boydii infections and it is an attractive alternative to amphotericin B for intrathecal administration to patients with fungal meningitis. Ketoconazole offers much less toxicity, the advantage of oral administration, and the possibility of indefinitely prolonged therapy. However, it does not attain high concentrations in either the urine or cerebrospinal fluid. With the imidazoles, we have entered a new era of antifungal therapy which may produce even better antifungal agents than those currently available.

Ketoconazole treatment of coccidioidal meningitis.

Fifteen patients with coccidioidal meningitis were treated with high doses of ketoconazole for up to 4 years. Five patients were treated with ketoconazole alone. One clinically failed, one developed hepatotoxicity, and three achieved remission of meningitis. One patient received intrathecal AMB in addition to ketoconazole for only 2 weeks before continuing on ketoconazole alone. He improved, but discontinued ketoconazole because of nausea and vomiting, and suffered a lethal relapse. Nine patients received ketoconazole in combination with prolonged courses of intrathecal AMB. Two patients were failures from nausea and vomiting, and the remaining seven either improved or experienced remission. The clinical responses appeared to be similar in patients receiving high-dose ketoconazole, either alone or combined with AMB, suggesting that there is no clinically significant antagonism of the drugs. Nausea and vomiting are significant limitations of high-dose ketoconazole. Ketoconazole alone is effective in some patients with coccidioidomycotic meningitis.

Dengue outbreaks in Guánica-Ensenada and Villalba, Puerto Rico, 1972-1973.

Epidemics of dengue fever occurring in Puerto Rico in 1963 to 1964 and 1969 were caused by dengue-3 and dengue-2 (DN-2) viruses, respectively, but endemic dengue transmission has never been documented on the Island. Since the 1969 epidemic, a surveillance system has detected DN-2 activity on the Island during each of the years 1970 through 1973, which suggests endemic persistence of the virus. This report describes the investigation of localized outbreaks of DN-2 in Guanica-Ensenada (1972) and Villalba (1973), and presents epidemiological, serological, and virological data from the outbreaks. Analysis of geographic distribution of dengue activity in Puerto Rico in recent years indicates that the DN-2 transmission in 1970 to 1973 may represent a long tail-off of the 1969 epidemic rather than the emergence of a truly endemic situation.

Treating bone and joint infections with teicoplanin: hospitalization vs outpatient cost issues.

The relative cost of outpatient parenteral antibiotic treatment of bone and joint infections with the investigational drug teicoplanin was compared with the cost of inpatient treatment. A private practice infectious disease group used teicoplanin to treat 49 patients (53 treatment courses) with bone and joint infections. The outpatient treatment program "saved" $403,680 compared with inpatient treatment, based on per diem reimbursements of $700 for inpatient treatment and $220 for outpatient treatment. Any cost analysis should be interpreted carefully because accurate calculation of outpatient treatment savings requires distinguishing among actual costs, charges, and reimbursements. In addition, there may be hidden costs related to lack of efficacy, toxicity, or litigation. Consideration should also be given to whoever is the beneficiary of the savings. Is it the indemnity insurance company, the provider, or the patient? Specific characteristics of the treatment, including ease of use, effectiveness, and monitoring requirement, may affect the savings. Our study showed that teicoplanin allows once-daily dosing, is easily administered, is generally efficacious, and has minimum requirements for blood level monitoring. These characteristics improve the cost effectiveness of using the drug in an outpatient treatment program.

Risk factors of ventricular fibrillation during rapid amphotericin B infusion.

Amphotericin B causes reversible concentration-dependent loss of intracellular potassium in vitro and hyperkalemic ventricular arrhythmias in dogs. Hyperkalemic ventricular arrhythmias associated with amphotericin B infusion have not been well documented in humans. Ventricular fibrillation with progressive hyperkalemia (up to 8 to 8.4 meq/liter) occurred twice in an anuric patient during rapid infusion of high-dose amphotericin B (1.4 mg/kg over 45 min). The peak amphotericin B concentration in serum at the end of infusion was 6.7 micrograms/ml. Prolonged infusion (3 h) and concurrent hemodialysis each prevented the development of hyperkalemia and ventricular arrhythmia. In two anuric patients receiving 4-h infusions of amphotericin B during dialysis (0.7 and 1.0 mg/kg), peak amphotericin B concentrations in serum were lower, 1.6 +/- 0.1 and 2.7 +/- 0.7 micrograms/ml, respectively; serum potassium levels were maintained in the normal range; and venous access for outpatient therapy was convenient. Peak concentrations of amphotericin B in serum were also lower (1.7 +/- 0.7 micrograms/ml) in eight patients with normal renal function who received lower doses (0.7 +/- 0.2 mg/kg) over 45 min; there were only slight increases in the serum potassium level (from 3.9 +/- 0.9 to 4.4 +/- 0.6 meq/liter, P less than 0.05). We recommend that rapid infusion of amphotericin B not be used in patients with impaired potassium excretion unless accompanied by hemodialysis and careful potassium monitoring.

Combination of oral flucytosine and ketoconazole as therapy for experimental cryptococcal meningitis.

Current therapy for cryptococcal meningitis often is ineffective, toxic, and inconvenient. Ketoconazole has been shown to penetrate into brain tissue of mice and cerebrospinal fluid of humans and to improve the course of human coccidioidal meningitis. Ketoconazole, flucytosine, and amphotericin B, alone and in two-drug combinations, were used to treat cryptococcal meningitis in mice injected intracranially with Cryptococcus neoformans. Mortality was assessed, and numbers of cryptococci in brain and liver were counted. By both of these parameters, the combination of flucytosine and ketoconazole produced results superior to those of either agent used alone. The standard combination of amphotericin B and flucytosine also showed an additive effect in this model. However, the combination of amphotericin B and ketoconazole consistently showed no additive effect. None of the combinations of drugs was antagonistic. Our results indicate a possible role for therapy with a combination of oral flucytosine and ketoconazole as part of the treatment for cryptococcal meningitis.

Ketoconazole therapy of murine cryptococcal meningitis.

Currently, even optimal therapy of cryptococcal meningitis is associated with appreciable mortality, drug toxicity, and prolonged hospitalization. Ketoconazole, a new oral imidazole, has therefore been evaluated in a murine model of cryptococcosis. Cryptococcal meningitis was induced in BALB/c mice by intracranial injection of Cryptococcus neoformans. The mice developed infection characterized by diffuse meningitis and extracerebral dissemination. Oral ketoconazole therapy prolonged survival of infected mice, but most mice ultimately succumbed to infection. Ketoconazole dramatically reduced the cryptococcal counts in the liver, but had minimal effect on counts in the brain. Paralleling these results were high concentrations of ketoconazole found in lung, spleen, and heart muscle and lower concentrations (2 to 5 micrograms/ml) found in the brain. The detection of biologically active drug in the brain, and the prolongation of survival afforded by ketoconazole, suggest a potential role for this agent in the theory of cryptococcal meningitis.

Ketoconazole therapy for systemic fungal infections: inadequacy of standard dosage regimens.

We treated 29 patients with ketoconazole for systemic mycoses. Twenty-two had coccidioidomycosis, 5 had histoplasmosis, and 2 had sporotrichosis. Of the 25 patients who received 200 mg/day, 16% improved on that dose. Of 17 patients who did not improve on 200 mg/day, 71% responded after the dose was increased to 400 or 800 mg/day. Treatment periods ranged from 21 days to more than 600 days. Five patients relapsed. In 2, ketoconazole had been reduced in dose or discontinued. In 3, the drug was still being given. Ketoconazole is effective in suppressing disease in various mycoses. However, patients may require high doses for prolonged periods to achieve maximal benefit.

Successful control of hepatitis B surface antigenemia in a dialysis unit without geographic or machine isolation.

Persistent hepatitis B infections among patients and frequent new hepatitis B infections among both patients and staff were a major problem in our dialysis unit during its first two and one-half years of operation. During this time the mean quarterly rate of conversion to HBsAg positivity among patients ranged from 0-60% (mean 12%); in staff it ranged from 0-13%. Control efforts, including strict temporal isolation, improved sanitary measures, and use of parallel plate dialyzers without geographic or machine isolation, were begun late in 1976. After a four-month lag, new HBsAg conversions ceased among the 30 patients and staff at risk, despite continued dialysis of eight HBsAg-positive patients (at least four of whom were HBeAg-positive). Over the succeeding three years the conversion rate was zero in both patients and staff. This experience suggests that conservative control measures without geographic separation of patients may be sufficient to control an established outbreak of hemodialysis-related hepatitis B. Controlled prospective trials of this hypothesis are warranted.

Interaction of chemotherapy and immune defenses in experimental murine cryptococcosis.

Congenitally athymic nude (nu/nu) and thymus-containing heterozygous (nu/X) mice were infected intraperitoneally with Cryptococcus neoformans over a wide range of challenge doses. Cryptococcal disease progressed more rapidly in nude mice than in their nu/X littermates. When nu/X mice were treated with amphotericin B, all survived an otherwise lethal dose of C. neoformans. At larger challenge doses, survival was prolonged in nu/nu mice treated with amphotericin B, but they later succumbed to cryptococcosis. At lower challenge doses, amphotericin B was curative in some nude mice. Therapy of nude mice with both amphotericin B and flucytosine further prolonged survival at high-dose challenge and increased the number of cures at low-dose challenge. These studies support an interaction of antifungal chemotherapy with thymus-dependent immune defense mechanisms. This interaction is most evident at high challenge doses, where antifungal chemotherapy cures nu/X mice but only modestly prolongs survival in nude mice.

Treatment of experimental murine candidiasis with liposome-associated amphotericin B.

Mice were challenged intravenously with Candida albicans, and then treated either with nothing (controls), amphotericin B-desoxycholate (AMB), or amphotericin B associated with liposomes (AMB-lipo). AMB-lipo permitted larger doses of amphotericin B to be given, and also appeared to have no severe toxicity in the animal model. High doses of AMB-lipo were protective, but at equal doses, AMB-lipo was not as effective as commercial AMB.

International outbreak of Salmonella Eastbourne infection traced to contaminated chocolate.

Between Dec. 4, 1973, and Feb. 15, 1974, 80 cases of infection due to Salmonella eastbourne, previously a rare isolated serotype in the United States, were reported from twenty-three States. An additional 39 cases were reported from seven Provinces in Canada during a similar period. A telephone case-control study implicated Christmas-wrapped chocolate balls manufactured by a Canadian company as the vehicle of transmission. S. eastbourne was subsequently isolated from several samples of leftover chocolate balls obtained from homes where cases occurred. Investigation of the factory revealed that the contaminated Christmas and Easter chocolates, and a few chocolate items for year-round sale, had been produced between May and October, 1973. Bacteriological testing of samples taken at the plant implicated cocoa beans as the probable source of the salmonella organisms which, in the low-moisture chocolate, were able to survive heating during production. This outbreak and the finding of salmonella of other serotypes in chocolates produced by another manufacturer suggest that chocolate-related salmonellosis may be a significant public-health problem.