Therapeutic options for the management and prevention of Mycobacterium avium complex infection in patients with the acquired immunodeficiency syndrome.

Atypical mycobacteria that cause disseminated disease result in significant morbidity and mortality among patients with advanced human immunodeficiency viral infection. Although significant progress has been made with respect to our understanding of the epidemiology, microbiology, and pathogenesis of Mycobacterium avium complex (MAC) infections in patients with the acquired immunodeficiency syndrome (AIDS), treatment and prevention strategies are still emerging. A series of case-controlled studies and clinical trials evaluated various combinations of traditional and investigational antimycobacterial agents, and demonstrated modest clinical and microbiologic success in the treatment of disseminated MAC infection. Prevention studies proved rifabutin and clarithromycin to be rational prophylaxis agents. Continued identification of optimum combination regimens remains essential to curtail the increasing frequency of disseminated MAC disease in patients with AIDS.

Overview of issues related to medical compliance with implications for the outpatient management of infectious diseases.

Noncompliance with therapeutic drug regimens is a public health problem with major health and economic implications. Reported rates of noncompliance for all types of drugs range from 13% to 93% among adults and from 25% to 82% among children. In recent years, sophisticated techniques for evaluating noncompliance have evolved, as has our understanding of factors associated with noncompliance. A key factor is the prescribed dosing schedule for a drug. Studies indicate that there is a direct relationship between frequency of dose and compliance. A study of compliance with short-term regimens of oral antibiotic therapy found mean compliance rates of 80%, 69%, and 38% for administration once a day (QD), twice a day (BID), and three times a day (TID), respectively. Pharmacoeconomic analyses of dose-related compliance have demonstrated that significant savings can be achieved with QD dosing of antihypertensive medication. Although similar analyses have not been performed for drug regimens used in the treatment of infectious diseases that are usually treated on an outpatient basis, it is probable that comparable savings will be attained when economic analyses of dose/compliance relationships in short-term antibiotic therapy for such common disorders as sinusitis, pharyngitis, otitis media, urinary tract infections, and community-acquired pneumonia are undertaken.

The role of fluoroquinolones in sexually transmitted diseases.

The management of sexually transmitted diseases (STDs) has reached a new level in the era of antibiotic resistance and human immunodeficiency virus infection. To date, no single antimicrobial is capable of eradicating the commonly encountered STD pathogens including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum. Among the marketed fluoroquinolones, ciprofloxacin, ofloxacin, lomefloxacin, and enoxacin all provide excellent in vitro activity (MIC90 < 0.06 micrograms/ml) and excellent in vivo efficacy against N. gonorrhoeae, including multiply resistant isolates (penicillinase-producing N. gonorrhoeae and chromosomally mediated resistant N. gonorrhoeae). Ofloxacin is the only fluoroquinolone approved by the Food and Drug Administration for chlamydial infection. All of the quinolones lack reliable in vitro activity against Ureaplasma urealyticum, a cause of nongonococcal urethritis. Although limited data suggest the usefulness of ciprofloxacin and ofloxacin in the treatment of pelvic inflammatory disease, these drugs cannot currently be recommended for single-agent therapy. Haemophilus ducreyi infections, however, can be managed effectively with the fluoroquinolones. Although their role continues to evolve, this class of drugs cannot be used equally to treat all STDs, and notably, no quinolone to date inhibits T. pallidum.

Antimicrobial tissue penetration in a rat model of E. coli epididymitis.

Following induction of unilateral epididymitis by intratesticular injection of E. coli, a single intraperitoneal dose of amdinocillin, ampicillin, doxycycline, tobramycin, or trimethoprim/sulfamethoxazole was administered to five groups of rats. The animal was sacrificed serially and concentrations of antibiotic in serum, infected epididymides, and non-infected epididymides were determined by high performance liquid chromatography. The ratio of infected to non-infected tissue area under the curve values was 1.05 for trimethoprim, 1.58 for sulfamethoxazole, 1.67 for amdinocillin, 2.01 for tobramycin, 2.25 for doxycycline, and 2.58 for ampicillin. Except for trimethoprim, infected tissue concentrations were significantly greater than compared to uninfected epididymal levels (p less than 0.05). Antibiotic concentrations in infected epididymides compared to serum revealed overall penetration of 34% for amdinocillin, 66% for sulfamethoxazole, 70% for ampicillin, 76% for tobramycin, 256% for trimethoprim, and 257% for doxycycline. In a rat model of epididymitis, trimethoprim and doxycycline demonstrated the greatest degree of epididymal penetration compared to serum. All antibiotics except trimethoprim had significantly greater penetration into infected tissue when compared to non-infected epididymal tissue.

Pharmacokinetic evaluations of low- and high-dose zidovudine plus high-dose acyclovir in patients with symptomatic human immunodeficiency virus infection.

The pharmacokinetics of zidovudine were evaluated in 41 patients with Centers for Disease Control HIV class IVA infection. The patients were assigned escalating doses of zidovudine (300, 600, or 1,500 mg daily) and were randomized to receive either zidovudine alone or zidovudine with a high dose of acyclovir (4,800 mg per day). Single and multiple intravenous- and oral-dose pharmacokinetic studies were performed on days 1 and 7 and weeks 6 and 12 of therapy. Zidovudine concentrations were analyzed by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by noncompartmental methods. Zidovudine concentrations in serum declined in a biphasic manner, with half-lives ranging from 1 to 2 h, and were independent of acyclovir administration or length of zidovudine therapy. The median time of peak concentrations in serum following oral doses was 0.75 h (range, 0.25 to 3 h). Accumulation of zidovudine in serum was not observed, but the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve increased proportionally with increased zidovudine doses. Mean day 7 oral Cmax values were 0.20 +/- 0.12, 0.55 +/- 0.33, and 1.0 +/- 0.5 micrograms/ml for 17 patients receiving total daily doses of, respectively, 300, 600, and 1,500 mg of zidovudine alone, whereas Cmax values were, respectively, 0.27 +/- 0.18, 0.43 +/- 0.33, and 1.2 +/- 0.80 micrograms/ml for 15 comparably treated recipients of zidovudine plus acyclovir (P was not significant). The median bioavailability of oral zidovudine was 67% (42 to 120%) and did not vary with dosage. Absolute and apparent total body clearances were similar among the patients given the various zidovudine doses regardless of whether there was concomitant acyclovir therapy. Drug-related toxicities were observed more frequently in the subjects who received high doses of zidovudine than they were in those who received median and low doses of zidovudine (P=0.03). Overall, acyclovir did not influence the disposition of zidovudine over a wide range of zidovudine doses. No unusual toxicities could be attributed to the zidovudine and high-dose acyclovir combination during the 12-week observation period.

Acquired immunodeficiency syndrome. Cerebrospinal fluid findings in patients before and during long-term oral zidovudine therapy.

Fifty-two patients with acquired immunodeficiency syndrome were enrolled in this study to evaluate the relationship between cerebrospinal fluid (CSF) zidovudine concentrations and neurologic and human immunodeficiency virus (HIV) culture findings. Paired HIV-CSF culture and neurologic measurements were available in 30 and 45 patients, respectively. Twenty-nine patients were assessable for zidovudine CSF concentrations. Patients underwent lumbar puncture and neurologic testing before and after 8 weeks or more of oral zidovudine therapy (600 to 1500 mg/d). After 8 weeks of therapy, the frequency of HIV isolation from CSF cultures was unchanged. Significant neurologic improvement by examination was noted in 61.5% (32/52) of the patients. The median CSF zidovudine concentration among 29 patients was 0.047 mg/L (range, 0.015 to 0.198 mg/L). No correlation between CSF zidovudine concentration, cumulative dose, or HIV isolation from CSF and persistence or resolution of neurologic symptoms or signs was observed. The mechanisms by which zidovudine improves neurologic function are unclear and appear unrelated to direct clearance of virus from CSF.

Bacterial epididymitis in the rat: a model for assessing the impact of acute inflammation on epididymal antibiotic penetration.

A rat model of bacterial epididymitis was developed and characterized for use in assessing the impact of acute epididymal inflammation on antibiotic penetration into the epididymis. A 0.2 ml. intratesticular injection of a 0.5 McFarland standard suspension of E. coli resulted in histologically confirmed acute epididymitis in all animals studied. Inflammatory changes were detectable as early as 24 hours following inoculation and were progressive to the last assessment point at 11 days. Early testicular infarction was observed in association with epididymal inflammation. Serial transcrotal ultrasounds of infected animals showed progressive increase in epididymal size and a late decrease in testicular size. Serum and epididymal drug concentrations were assayed following a single dose of the antibiotic amdinocillin. Fifteen minutes following the peak serum level, the drug concentration in infected epididymis was 2.3-fold higher than the contralateral, non-infected epididymis. These data suggest that acute inflammation enhances antibiotic penetration into the infected epididymis. The model described provides a rapid, reproducible method to study epididymal drug delivery in normal and diseased states.

Zidovudine disposition during hemodialysis in a patient with acquired immunodeficiency syndrome.

Zidovudine (azidothymidine, AZT) disposition was examined during a hemodialysis session in an HIV-infected male with mesangial proliferative glomerulonephritis. Serum concentrations of zidovudine and its glucuronidated inactive metabolite (G-ZDV) were measured by HPLC. Zidovudine pharmacokinetics were similar to previous reports in patients with normal renal function, however, G-ZDV concentrations were significantly elevated (23-440 times zidovudine concentration). Hemodialysis did not appreciably reduce zidovudine or G-ZDV levels. Significance of chronically elevated G-ZDV levels is unknown.

Choosing cephalosporins for the formulary.

Proper selection of antibiotics for any formulary requires cooperation and communication with members of the pharmacy and therapeutics (P&T) committee and departments of infectious diseases, microbiology, and epidemiology. Ideally, P&T members need to know their institution's incidence and sources of infection (hospital- or community-acquired), antibiotic cure rates, and the adverse effects profiles of antimicrobial agents used. In addition, members need to be briefed on the findings of antibiotic utilization reviews performed. In vitro activity should be compared among similar classes of antibiotics and, when possible, local resistance rates should be considered. The pharmacokinetic properties of an antibiotic, such as peak concentration, protein binding, distribution characteristics, and elimination half-life, should be evaluated during the selection process, as should total cost of the drug, including costs associated with monitoring therapy. The three generations of cephalosporins are used as examples here to delineate differences in potency, pharmacokinetics, efficacy, and potential for causing adverse reactions during the ideal formulary evaluation process.

Pharmacodynamic evaluation of ofloxacin and trimethoprim-sulfamethoxazole in vaginal fluid of women treated for acute cystitis.

Vaginal colonization with Escherichia coli is an integral step in the development of acute cystitis, and persistent vaginal coliform colonization may also be a predisposing step to recurrent urinary tract infections. For this reason, we evaluated antibiotic concentrations in the vaginal fluid, serum, and urine and the vaginal colonization by E. coli of 56 women receiving either ofloxacin (200 mg orally twice a day) or trimethoprim-sulfamethoxazole (TMP-SMX) (160/800 mg orally twice a day) for the treatment of acute cystitis. Ofloxacin and trimethoprim both penetrated into vaginal fluid to a considerably greater extent than sulfamethoxazole. Among 33 patients given ofloxacin, the concentration of the drug in vaginal fluid during one dosage interval ranged from 1.6 to 21.6 micrograms/ml. In 21 women given TMP-SMX the range of drug concentrations in vaginal fluid was 2.6 to 32.5 micrograms/ml for TMP and 1.0 to 6.2 micrograms/ml for SMX. Treatment with both ofloxacin and TMP-SMX remarkably reduced vaginal colonization by E. coli during and up to 30 days after therapy. For the ofloxacin-treated women, eradication of vaginal E. coli was associated with a high ratio of drug concentration in vaginal fluid to that in serum. We conclude that ofloxacin and TMP both achieve high concentrations in vaginal fluid and are equally successful in eradicating E. coli from the vagina.

Development of antiviral agents for the treatment of human immunodeficiency virus infection.

Antiviral agents under investigation for the treatment of patients infected with the human immunodeficiency virus (HIV) are reviewed. Multiple mechanisms exist by which antiviral agents might inhibit the replication of HIV or eradicate its latent form in affected cells, or both. These mechanisms include (1) interference with the cell surface receptor for HIV, (2) prevention of uncoating of viral particles, (3) inhibition of reverse transcriptase, (4) prevention of integration and posttranscription processing, (5) interference with viral assembly, and (6) interference with virus release. Most agents developed thus far work by inhibiting HIV reverse transcriptase. Suramin, ribavirin, ammonium 21-tungsten-9-antimoniate (HPA-23), foscarnet (phosphonoformate, PFA), inosine pranobex (isoprinosine), peptide T, ampligen, AL 721, dideoxycytidine, and zidovudine (formerly azidothymidine) have antiretroviral activity in vitro. To date zidovudine is the only antiretroviral agent approved by the FDA as clinically effective. However, zidovudine has serious toxicities, including neutropenia and anemia; in some patients dosage reduction or cessation of therapy may be necessary. Because treatment with zidovudine does not cure HIV infection, numerous studies are under way with other anti-HIV agents. Ultimately, combinations of agents probably will be used to suppress or eradicate HIV. While the search for more efficacious and less toxic treatments continues, the development of zidovudine in such a short time provides hope that progress toward a cure will be made rapidly.

Multiple-dose pharmacokinetics of piperacillin and azlocillin in 12 healthy volunteers.

The pharmacokinetic profile of piperacillin and azlocillin after multiple-dose administration to healthy volunteers was studied. Twelve healthy volunteers received either piperacillin 4 g (as the sodium salt) or azlocillin 4 g (as the sodium salt) as a 20-minute infusion every six hours for five doses. After a one-week washout period, subjects received identical treatment with the alternate drug. Serum and urine concentrations of piperacillin and azlocillin were measured using a reversed-phase high-performance liquid chromatographic assay, and the pharmacokinetic analysis of serum concentration-versus-time data was performed using a computerized program. A standard open-model equation for i.v. infusions was used. Mean serum concentrations of piperacillin and azlocillin after dose 5 were 344 +/- 66 micrograms/mL and 414 +/- 86 micrograms/mL, respectively. The terminal elimination half-life of azlocillin (1.1 +/- 0.2 hr) was significantly longer than that of piperacillin (0.75 +/- 0.13 hr) (p less than 0.05). Total body clearance of azlocillin (125 +/- 25 mL/min) was significantly less than that of piperacillin (226 +/- 43 mL/min) after dose 5. Azlocillin showed accumulation between the first and fifth doses. Twelve hours after administration of dose 5, 75% of azlocillin and 57% of piperacillin were excreted unchanged into the urine. In healthy volunteers, azlocillin produced higher and more prolonged serum concentrations than piperacillin after administration of equivalent i.v. doses. Further studies are needed to determine the clinical importance of these observations.

Management of Stevens-Johnson syndrome.

A patient with Stevens-Johnson syndrome is described, and the literature concerning the etiology, pathophysiology, clinical manifestations, and management of Stevens-Johnson syndrome is reviewed. A 2 1/2-year-old girl was treated with phenobarbital and i.v. ampicillin, followed by oral amoxicillin, for an upper-airway infection, otitis media, and febrile seizures. The fever returned, and she was treated unsuccessfully with penicillin and cefaclor. She was admitted to the hospital and treated with i.v. ampicillin. Within 24 hours an erythematous maculopapular rash developed. Phenobarbital was discontinued and phenytoin was begun. Four days later bullous lesions developed; ampicillin and phenytoin were discontinued, and cefazolin and phenobarbital were given. By the eighth day severe sloughing of the skin occurred over 75% of her body, and mucosal sloughing was apparent. The patient's condition was diagnosed as Stevens-Johnson syndrome. Porcine xenografts were immediately grafted to 75% of her total body surface. Severe lesions of the mouth and pharynx made parenteral nutrient therapy necessary, and ocular complications required the care of an ophthalmologist. Although the skin had healed by 14 days after grafting, another 14 days of treatment for respiratory complications was required. Stevens-Johnson syndrome is a severe exfoliative dermatitis accompanied by fever, inflammation of the gastrointestinal mucosa, and severe purulent conjunctivitis. It is associated with high morbidity and mortality. The etiologic factors may be iatrogenic (e.g., various antibiotics and anticonvulsants), infectious, or idiopathic. Respiratory complications, leukopenia, infections, erosion of the gastrointestinal mucosa, fluid and electrolyte disturbances, and chronic ocular complications may occur.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro and in vivo studies of the effect of aztreonam on platelet function and coagulation in normal volunteers.

The in vitro effects of aztreonam on platelet aggregation were compared with those of cefotaxime, moxalactam, piperacillin, and carbenicillin. In addition, the in vivo effects of intravenously administered aztreonam on blood coagulation and platelet function were examined in 10 normal male volunteers in a randomized crossover study. In vitro, at concentrations of greater than 6.25 mM (2.7 mg/ml), aztreonam inhibited ADP-induced platelet aggregation in a dose-dependent manner. The effect was less than that produced by equimolar concentrations of cefotaxime, moxalactam, piperacillin, or carbenicillin. At all concentrations tested, aztreonam and cefotaxime inhibited epinephrine-induced aggregation least. All antibiotics inhibited collagen-induced aggregation, but only at inordinately high concentrations (25 mM). In vivo studies in 10 male subjects, randomly infused intravenously with 2 g of aztreonam or saline placebo every 6 h for 21 consecutive doses in a single-blind crossover study, revealed no evidence of bleeding or visible adverse side effects. Although plasma coagulation and platelet adhesion remained within normal limits in all subjects throughout the study, inhibition of ADP-induced platelet aggregation significantly (P less than 0.0001) increased on days 3 and 6, but still was below 40%. With the exception of one subject who had a mean template bleeding time of 7.3 min (normal, 2 to 7 min at 95% confidence limits) on day 6 of aztreonam administration, all volunteers exhibited bleeding times within the normal range. No abnormalities in platelet morphology were observed. Mean peak serum aztreonam concentrations on days 1 and 6 were 90.1 +/- 16.7 and 95.9 +/- 13.7 micrograms/ml, respectively; accumulation did not occur. Thus, in normal volunteers, aztreonam produced no significant recognizable abnormalities of hemostasis after 6 days of maximal recommended doses.

Pneumonia caused by a relatively resistant strain of Streptococcus pneumoniae.

A patient with pneumonia caused by a relatively resistant strain of Streptococcus pneumoniae that did not respond to prolonged therapy with intravenous ampicillin is described, and general principles of treatment for such cases are reviewed. The patient was a 16-month-old, 10-kg girl who was admitted to a hospital for treatment of severe smoke inhalation and burns. The patient was intubated immediately, but her respiratory status remained unstable. Chest roentgenograms showed numerous episodes of pneumonia; the organism was later identified as Strep. pneumoniae. Despite empiric therapy with ampicillin and tobramycin followed by a prolonged course of ampicillin and subsequent treatment with cefazolin, the patient's respiratory status did not improve, and she continued to have elevated temperatures. Strep. pneumoniae isolated from her blood was identified as relatively resistant to penicillin but sensitive to chloramphenicol. After a seven-day course of chloramphenicol, the patient recovered and was later discharged. Relatively resistant Strep. pneumoniae (RRSP) infections often occur at sites where high antibiotic concentrations are not achieved, such as in the CNS. Prior antibiotic therapy may increase or have no effect on the incidence of RRSP. The mechanism for RRSP is unknown, and these infections often are not detected until a patient has failed to respond to conventional therapy. Also, the incidence of RRSP has not been determined because many hospitals do not perform susceptibility tests for pneumococcal isolates routinely. Vancomycin or chloramphenicol may be alternates to penicillin for the treatment of RRSP, but antibiotic sensitivities should be determined for each isolate to ensure susceptibility.

Pharmacokinetics and tolerance of ciprofloxacin after sequential increasing oral doses.

The pharmacokinetics and safety of orally administered ciprofloxacin (Bay o 9867) were examined in 12 healthy male volunteers who received sequential doses of 250, 500, 750, and 1,000 mg. The individual and mean data were best described by biexponential disposition and elimination, assuming an apparent zero-order rate of absorption. The peak serum concentrations determined from the individual data occurred at approximately 1.5 h after each dose and ranged from 0.42 to 4.2 micrograms/ml; the mean peak concentrations increased in proportion to the dose. The areas under the curve determined from the mean data were also proportional with respect to dose. The mean elimination half-lives calculated from pooled data were 4.1, 4.1, 6.9, and 6.3 h for doses of 250, 500, 750, and 1,000 mg, respectively. Longer half-lives but proportional area-under-the-curve values after the 750- and 1,000-mg doses implied that smaller fractions of ciprofloxacin were absorbed after these doses, although nonlinear kinetics could not be ruled out. The mean serum concentrations 12 and 24 h following each dose were greater than or equal to 0.08 and 0.01 micrograms/ml, respectively. The urinary concentrations ranged from 30 to 500 micrograms/ml for at least 12 h after administration and were greater than or equal to 9 micrograms/ml at 24 h following each dose. The urinary recovery level of unchanged ciprofloxacin over a 24-h period ranged from 28 to 44%. The mean renal clearances for each dose ranged from 300 to 500 ml/min. Ciprofloxacin was well tolerated, and no significant clinical or laboratory abnormalities were observed.