Impact of voluntary vs enforced compliance of third-generation cephalosporin use in a teaching hospital.

STUDY OBJECTIVE: The purpose of this study was to assess and compare the impact of voluntary compliance and enforced compliance with institutional guidelines for initiating third-generation cephalosporin therapy. DESIGN: An audit of third-generation cephalosporin use during a 6-month period shortly after ceftriaxone and ceftazidime were added to the hospital formulary already containing cefotaxime was performed. During this period, compliance to institutional guidelines for initiating therapy was voluntary. A follow-up audit during a similar 6-month period was performed to assess compliance with institutional guidelines shortly after an enforcement policy was placed in effect. The results of these two audits were compared to assess usage patterns of these cephalosporins, compliance rates with institutional guidelines for initiating therapy, use of susceptibility testing to guide therapy, effect of use of these drugs on susceptibility patterns within the hospital, and third-generation cephalosporin costs during periods when institutional policy was unenforced and enforced. RESULTS: Only 24.2% of 66 courses of third-generation cephalosporins were initiated in compliance with institutional guidelines during the initial audit period. Susceptibility testing revealed an organism susceptible to a first-generation cephalosporin in 13 courses but in only six instances was a switch to the more narrow-spectrum antibiotic performed. At the time routine susceptibility testing to ceftazidime and ceftriaxone was instituted, 92% of Enterobacter cloacae were sensitive to ceftriaxone and 89% of Pseudomonas aeruginosa were sensitive to ceftazidime. Fifteen months later, when voluntary compliance to institutional policy was terminated, 70% of E cloacae were sensitive to ceftriaxone and 73% of P aeruginosa were sensitive to ceftazidime. During the last 6 months of this period, pharmacy expenditures totaled $50,000. The second audit revealed 85.4% of 48 courses of treatment complied with guidelines for initiating therapy. Since enforcement was instituted, sensitivity of E cloacae to ceftriaxone has risen to 88% and sensitivity of P aeruginosa to ceftazidime has increased to 80%. Pharmacy expenditures decreased to $23,000.

Osteomyelitis in the feet of diabetic patients. Long-term results, prognostic factors, and the role of antimicrobial and surgical therapy.

Fifty-one diabetic patients with osteomyelitis of the foot were studied to determine potential prognostic factors and the role of antimicrobial therapy. Most of the patients were elderly, with diminished pulses, a sensory neuropathy, and a polymicrobial infection. Twenty-seven patients had a good outcome, defined as clinical resolution at the time of the last follow-up examination, without the need for amputation. The mean duration of follow-up for these patients was 19 months. Fifteen patients had a below-knee amputation, and nine had a toe amputation. The absence of necrosis and/or gangrene, the presence of swelling, and the use of antimicrobial therapy active against the isolated pathogens for at least four weeks intravenously, or combined intravenously and orally for 10 weeks, predicted a good outcome. Diabetic foot osteomyelitis, in the absence of extensive necrosis or gangrene, usually responds to antimicrobial therapy without the need for an ablative surgical procedure.

Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Mycoses Study Group.

PURPOSE: This study assesses the efficacy and safety of fluconazole therapy in patients with acquired immunodeficiency syndrome (AIDS) and mild to moderately severe manifestations of disseminated histoplasmosis. PATIENTS AND METHODS: This was a multicenter, open-label, nonrandomized prospective trial. All patients had AIDS and disseminated histoplasmosis. Patients were treated with 1,200 mg of fluconazole given by mouth once on the first day, then 600 mg once daily for 8 weeks, and those patients who improved clinically were then assigned fluconazole maintenance therapy 200 mg once daily for at least 1 year. Interim analysis revealed a high failure rate (10 of 20, 50%), causing revision of the protocol to increase the fluconazole dose to 1,600 mg given once on the first day, then 800 mg once daily, and the duration to 12 weeks for induction therapy and then 400 mg daily for 1 year for maintenance therapy. MEASUREMENTS AND MAIN RESULTS: Thirty-six of 49 patients (74%; 95% confidence interval [CI]: 59% to 85%) with mild to moderately severe clinical manifestations who entered into the revised study responded to 800 mg of fluconazole daily for 12 weeks as induction therapy. Of the seven patients who failed induction therapy because of progression of histoplasmosis, one died of the infection. Of 36 patients who entered into the maintenance phase of the study receiving 400 mg of fluconazole daily for 1 year, 11 (30.5%) relapsed, including one who died (2.8%). Two of the 49 patients (4.1%) were removed because of grade 4 adverse events, alkaline phosphatase elevation for one and aspartate aminotransferase elevation in the other. The relapse-free rate at 1 year was 53% (95% CI: 32% to 89%), prompting closure of the study. CONCLUSIONS: Fluconazole 800 mg daily is a safe and moderately effective induction therapy for mild or moderately severe disseminated histoplasmosis in patients with AIDS. On the basis of historic comparison, fluconazole 400 mg daily is less effective than itraconazole 200 to 400 mg daily or amphotericin B 50 mg given weekly as maintenance therapy to prevent relapse.

Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 2. Analogues of 3-aminopyridin-2(1H)-one.

A series of nonnucleoside 3-aminopyridin-2(1H)-one derivatives was synthesized and evaluated for HIV-1 RT inhibitory properties. Several analogs proved to be potent and highly selective antagonists with in vitro IC50 values as low as 19 nM in the enzyme assay using rC.dG as template-primer. Two compounds from this series, 3-[[(4,7-dimethylbenzoxazol-2-yl)methyl]-amino]-5-ethyl-6-methy lpyridin-2(1H)-one (34, L-697,639) and the corresponding 4,7-dichloro analogue (37, L-697,661) inhibited the spread of HIV-1 IIIb infection by 95% in MT4 cell culture at concentrations of 25-50 nM and were selected for clinical trials as antiviral agents.

Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 4. 3-[2-(Benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one and analogues.

A new series of potent specific 2-pyridinone reverse transcriptase (RT) inhibitors was developed based on the preliminary development lead 3-[(phthalmido)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (3), a non-nucleoside derivative which exhibited weak antiviral activity in cell culture against HIV-1 strain IIIB. One compound, 3-[(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (9,L-696,229), which was a highly selective antagonist of the RT enzyme (IC50 = 23 nM) and which inhibited the spread of HIV-1 IIIB infection by > 95% in MT4 human T-lymphoid cell culture (CIC95 = 50-100 nM), was selected for clinical evaluation as an antiviral agent.

Synthesis and evaluation of 2-pyridinone derivatives as specific HIV-1 reverse transcriptase inhibitors. 3. Pyridyl and phenyl analogs of 3-aminopyridin-2(1H)-one.

In an ongoing effort to develop novel nonnucleoside, specific human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors, a series of 3-[(pyridylmethyl)amino]- and 3-[(phenylmethyl)amino]-2-pyridinone derivatives was synthesized and tested for HIV-1 RT inhibitory activity. The more potent compounds have a 2'-methoxy group and 4'- and/or 5'-aliphatic substituents on the pyridyl and phenyl rings. Several of the more potent compounds were also evaluated for antiviral activity in MT-4 cell culture. From this series of compounds, 3-[N-[(5-ethyl-2-methoxy-6-methyl-3-pyridyl)methyl]amino]-5-ethyl-6- methylpyridin-2(1H)-one (6) was selected for clinical evaluation.

Treatment and long-term follow-up of foot infections in patients with diabetes or ischemia: a randomized, prospective, double-blind comparison of cefoxitin and ceftizoxime.

The efficacy and safety of ceftizoxime and cefoxitin were compared in a randomized, double-blind study of therapy for lower extremity infections in patients with diabetes mellitus or peripheral vascular disease. Overall clinical responses were satisfactory in 82% (23/28) of patients treated with ceftizoxime and in 68% (17/25) of patients treated with cefoxitin. The difference was not statistically significant. Ceftizoxime had superior in vitro activity against Enterobacteriaceae, especially Enterobacter cloacae, whereas cefoxitin had better activity against the Bacteroides fragilis group. Relapses of infection were common in both groups during long-term follow-up; only about one third of patients in either group maintained satisfactory outcomes after one year. More than half of the patients in both groups responded to one or more courses of medical therapy and avoided major amputations for one year following entry into the study.

Osteomyelitis. A commonsense approach to antibiotic and surgical treatment.

Therapy for osteomyelitis requires a multidisciplinary approach. A precise microbiologic diagnosis and adequate debridement of necrotic tissue are essential. Acute hematogenous osteomyelitis usually responds to antimicrobial therapy. The presence of an abscess or a metaphyseal cavity in hematogenous osteomyelitis and evidence of spinal cord compression in vertebral osteomyelitis require surgical treatment. Chronic osteomyelitis usually implies that dead bone is present, which requires surgical debridement. Because of the chronicity of the infection and various presentations and surgical approaches, antibiotic treatment must be individualized. In general, however, at least 4 weeks of therapy is required.

Spectrum of disease caused by Rhodococcus equi in human immunodeficiency virus infection: Report of a case and review of the literature.

Since the first report of Rhodococcus equi infection in an acquired immune deficiency syndrome patient in 1986, seven additional cases have been described. A patient is described in whom the diagnosis was delayed due to misidentification of the organism as an atypical mycobacterial species. The literature regarding R equi infection in persons infected with the human immunodeficiency virus is reviewed. The most common presentation is one of a chronic, indolent pulmonary infiltrative disease (78%). Fever (78%), cough (67%), and hemoptysis (44%) are frequently present. Coexistent opportunistic illnesses are common (67%). In the laboratory identification of this organism, it is important to communicate the clinical setting to the microbiologist and to recognize the potential for the organism to be overlooked as normal flora or a contaminant, or misidentified as an organism with similar phenotypic characteristics (Nocardia species or a rapidly growing mycobacterium). Based on experience in foals, therapy with erythromycin and rifampin is suggested.

Diagnosis and treatment of osteomyelitis.

The diagnosis and therapy of osteomyelitis remains difficult despite recent advances. Clinical decision making is also difficult because of considerable variations in the types of disease observed and the lack of large comparative trials studying the variety of approaches.

Antimicrobial treatment of sinusitis.

Sinusitis is a common disease. Most cases of acute sinusitis involve the maxillary sinus and occur after viral infections of the upper respiratory tract. The usual pathogens are Streptococcus pneumoniae and Haemophilus influenzae. Moraxella (Branhamella) catarrhalis is also an important pathogen in children. Anaerobic infections are more common in chronic sinusitis. Fungi are frequently observed in granulocytopenic cancer patients but also can occur in apparently normal hosts. Many strains of H influenzae and M catarrhalis observed in patients with sinusitis produce beta-lactamases. Many antimicrobial regimens have proven successful in the treatment of sinusitis, including ampicillin, amoxicillin, trimethoprim-sulfamethoxazole, the tetracyclines, and cefuroxime axetil, but only the latter three drugs are active against most beta-lactamase-producing strains. Nosocomial sinusitis usually occurs in intensive care unit settings and is frequently associated with nasopharyngeal instrumentation. The pathogens observed in nosocomial sinusitis are gram-negative bacilli or staphylococci and frequently require therapy with broad-spectrum penicillins or cephalosporins, an aminoglycoside, or vancomycin.

Diagnosis of nosocomial pneumonia.

Nosocomial pneumonia occurs in 0.6% of hospitalized patients. The usual causative agents are gram-negative bacilli, Staphylococcus aureus, Streptococcus pneumoniae, and anaerobic bacteria. In immunocompromised hosts, the differential diagnosis also includes fungi, mycobacteria, viruses, Nocardia, and Pneumocystis carinii. Important risk factors for the development of nosocomial pneumonia include prolonged mechanical ventilation, thoracic or upper abdominal surgery, altered mental status, underlying immunosuppression, chronic obstructive pulmonary disease, and the use of antacids or histamine type 2 blockers. Colonization of the oropharynx and tracheal secretions with gram-negative aerobic bacteria is common in hospitalized patients with or without pneumonia. The diagnosis of nosocomial pneumonia is usually based on the clinical features of dyspnea, cough, fever, purulent sputum production, new pulmonary infiltrates, hypoxemia, and leukocytosis. However, the clinician must recognize that the presence of these features is neither sensitive nor specific in the diagnosis of nosocomial pneumonia. Microbiologic diagnosis is also difficult because blood cultures are usually negative, and cultures of tracheal secretions, although usually sensitive, are not specific. Invasive procedures may prove useful, but most have yet to be studied in large groups of patients with nosocomial pneumonia.

Outcome of medical treatment of bacterial abscesses without therapeutic drainage: review of cases reported in the literature.

The usual treatment of bacterial abscesses, except lung or tubo-ovarian abscesses, includes therapeutic drainage. Increasing evidence suggests that some abscesses respond to antimicrobial therapy without drainage. To study this issue, a MEDLINE search of the literature (1966-1994) was performed for cases of bacterial abscess in which treatment without definitive drainage was attempted. Four hundred sixty-five cases were identified. The most commonly involved organs were the liver, brain, and kidney. The success rate of antimicrobial therapy was 85.9%. Factors that predicted a less favorable outcome were abscess diameter of > or = 5 cm (odds ratio [OR] = 37.7; P = .0003), involvement of > or = 1 organism (OR = 5.2; P = .014), presence of gram-negative bacilli (OR = 3.4; P = .022), length of therapy of < 4 weeks (OR = 49.1; P < .0001), and use of an aminoglycoside as the only active agent (OR = 11.8; P = .008). Many bacterial abscesses can be treated without drainage; abscess size, the organisms involved, and therapy utilized may influence outcome.

Antibiotics: why they fail in patients who are critically ill.

Most of the failures of antimicrobial therapy can be related to advanced infections in patients with serious comorbid processes or altered immunity. However, some of the failures are related to the type of antimicrobial therapy used, the length of therapy, the pharmacokinetic or pharmacodynamic properties of the antimicrobial agent, the development of antimicrobial resistance, microbial factors that influence antimicrobial efficacy, and the site and type of infection. This report will review the common mechanisms by which antimicrobials fail.

Acute sinusitis.

Acute sinusitis is one of the most commonly observed entities in clinical practice. Despite the frequency of the disease, diagnosis and therapy often remain empiric. Most cases are secondary to sinus ostia obstruction associated with the common cold or allergies. Maxillary sinusitis is most common. Because of the proximity of vital anatomic structures and venous drainage systems, serious complications frequently arise from sphenoid, frontal, and ethmoid sinusitis. Clinical signs and symptoms most helpful in the diagnosis of maxillary sinusitis are the presence of a maxillary toothache, lack of improvement with decongestants, a purulent nasal discharge, cough, purulent secretions observed on nasal examination, abnormal transillumination, and sinus tenderness. Plain film radiographs are helpful, but do not adequately visualize the anterior ethmoid sinuses. Computed tomography provides superior visualization, but cost remains prohibitive for routine cases. Most maxillary sinusitis in adults is secondary to Streptococcus pneumoniae or Hemophilus influenzae. Moroxella catarrhalis is common in children. Staphylococcus aureus is observed more frequently in frontal or sphenoid disease. Most patients with acute sinusitis are treated without microbiological diagnosis and respond well to commonly used oral antimicrobials with activity against the usual pathogens. Complications of sinusitis include meningitis, periorbital infections, subdural empyema, epidural abscess, brains abscess, cavernous sinus thrombosis, and osteomyelitis.

Microbial etiology and clinical characteristics of distributive shock.

Although septic shock may be the most common cause of distributive shock, to our knowledge, no studies have defined the likelihood and type of infection among patients with distributive shock. We performed a retrospective study of 100 consecutive patients who were admitted to a city-county hospital with hemodynamic evidence of distributive shock. Forty-nine of 100 patients with distributive shock had microbiological documentation of infection. Six patients had clinical evidence of infection without microbiological documentation. Forty-five patients had no microbiological or clinical evidence of infection. Among patients with microbiologically documented infections, the incidence of infection due to aerobic gram-positive cocci equaled the incidence of infection due to aerobic gram-negative bacilli. Clinical parameters, such as the criteria for the systemic inflammatory response syndrome, were not useful in distinguishing the group with infections from the group without infections. In conclusion, many patients with distributive shock do not have evidence of infection.

Bactericidal capacity of neutrophils in rabbits with experimental acute and chronic abscesses.

Bacteria persist within abscesses despite the presence of neutrophils, and patients with abscesses have high rates of subsequent infections. A model was developed to study neutrophil function in rabbits with Staphylococcus aureus abscesses. Blood neutrophils from rabbits with 2-week-old (chronic) abscesses had diminished bactericidal capacity and decreased superoxide production compared with rabbits with 24-h (acute) abscesses. Rabbits with chronic abscesses did not produce serum opsonic factors that enhanced bacterial killing. A bactericidal assay performed with chronic abscess fluid in the suspending medium revealed inhibition of neutrophil killing. The inhibition could be replicated with a neutrophil lysate but not by an S. aureus supernatant. Rabbits with chronic abscesses have diminished blood neutrophil bactericidal capacity and superoxide formation, and the abscess fluid milieu is inhibitory to neutrophil function.

Haemophilus influenzae meningitis in an adult with initially normal cerebrospinal fluid.

We have described an adult patient with signs and symptoms of bacterial meningitis who had an initially unremarkable cerebrospinal fluid examination, but then had development of fulminant meningitis over the next 48 hours. Bacterial meningitis with normal CSF values has been previously reported in children, immunocompromised hosts, and alcoholics, and in patients with fulminant infections due to Neisseria meningitidis. We recommend that all patients with signs and symptoms compatible with bacterial meningitis and with normal results of CSF examination have close follow-up clinically over the next 48 hours with consideration of repeating the lumbar puncture.