Efforts to regulate antibiotic misuse in hospitals: A history.

Today, most hospitals have implemented regulatory programs designed to curtail the antimicrobial misuse that has fueled resistance. In this paper, I trace the history of resistance and efforts to mitigate antibiotic overuse in the hospital. Medical investigators in the 1950s argued that the difficulties posed by resistant bacteria in the hospital were even more worrisome than the problems that antibiotics were intended to solve. These investigators sought to reform physician habits that they believed, left unchecked, would accelerate resistance and hasten the end of the antibiotic era. When their methods of education failed to change physician's prescribing habits voluntarily, external restrictions were imposed. Today's antimicrobial stewardship programs represent the newest version of a series of efforts that began in the mid-twentieth century to reform antibiotic misuse and to control resistant microbes in the hospital.

Historical and contemporary features of infections due to Clostridium novyi.

Clostridium novyi is an anaerobic bacterium that resides in the soil in nature and that may cause severe clinical infections in humans. It is named after Frederick Novy, who incidentally discovered the anaerobic organism responsible for septicemia in rabbits. In this paper, we explore the circumstances surrounding the identification of the organism. In particular, we address who Novy was and what he was trying to do when he first described the organism in the 1890s. We then address what is known about the biological features of the organism today, as well as the clinical syndromes that are now recognized to be associated with the microbe. Finally, we review efforts that have been made to use the organism for potential beneficial purposes for humans.

Mycobacterium avium complex immune reconstitution inflammatory syndrome: long term outcomes.

BACKGROUND: To describe long term outcomes of Mycobacterium avium complex (MAC) immune reconstitution inflammatory syndrome (IRIS). METHODS: Cases of MAC IRIS were retrospectively identified at four HIV clinics (Michigan, Maryland, Rhode Island, and Indiana) from 1996-2004. Patients were included if they were initially diagnosed with AIDS and found to have evidence of focal MAC infection documented by tissue culture or PCR after initiating HAART, and at least 6 months of follow up. RESULTS: Among the 20 patients included, the mean age was 40 years, mean CD4 cell count was 24/mm3 at pretreatment baseline and 100/mm3 at time of MAC IRIS diagnosis. Sites of disease included lymph nodes (15 patients [8 peripheral, 8 abdominal and 1 peripheral and abdominal]), gastrointestinal tract (7) and liver (3). Sixteen patients (80%) responded to treatment and were disease free after a mean of 17.4 months of therapy for MAC IRIS; IRIS therapy was withdrawn in 6 without relapse. Four patients (non-responder group) had persistent or relapsing disease despite 27 months of ongoing MAC IRIS treatment. At the time of resolution or last follow-up, the mean CD4 cell count and viral load was 143/mm3 and 7,000 c/mL for responders, and 65/mm3 and 17,000 c/mL for non-responders, respectively. Most patients with peripheral adenopathy were responders (7/8; 88%); many with abdominal adenopathy (4/8; 50%) were nonresponders. CONCLUSION: The majority of patients with MAC IRIS eventually responded to treatment. Our sample size was not adequate to perform statistical analysis, but there was a tendency towards adequate CD4 response to HAART and peripheral rather than intraabdominal adenopathy among responders.

Long-term efficacy and safety of tipranavir boosted with ritonavir in HIV-1-infected patients failing multiple protease inhibitor regimens: 80-week data from a phase 2 study.

BACKGROUND: BI 1182.2, an open-label, randomized, multicenter, phase 2 study, evaluated efficacy and tolerability of the protease inhibitor (PI) tipranavir (TPV; 500 mg twice daily or 1000 mg twice daily) administered with ritonavir (100 mg twice daily) in combination with 1 nucleoside reverse transcriptase inhibitor and 1 nonnucleoside reverse transcriptase inhibitor in multiple PI-experienced HIV-1-infected patients. METHODS: Forty-one patients were evaluated in 2 arms: low-dose (19 patients) or high-dose (22 patients) ritonavir-boosted tipranavir (TPV/r). Primary endpoints were change from baseline in HIV-1 RNA concentrations at weeks 16, 24, 48, and 80 and percentage of patients with plasma HIV-1 RNA levels lower than the limit of quantitation. Safety was evaluated by adverse events (AEs), grade 3/4 abnormalities, and serious AEs. RESULTS: Of all patients, 59% were still receiving TPV/r (14 in low-dose arm and 10 in high-dose arm) at week 80. Patients in both arms had a median >2.0-log10 reduction in plasma viral load. Intent-to-treat analysis demonstrated that a similar proportion of patients in the high-dose and low-dose groups achieved plasma HIV-1 RNA levels <50 copies/mL at week 80 (43% vs. 32%; P = 0.527). The most frequently observed AEs were diarrhea, headache, and nausea. CONCLUSION: TPV/r combined with other active antiretroviral agents can provide a durable treatment response for highly treatment-experienced patients.

Magnitude and duration of elevated gastric pH in patients infected with human immunodeficiency virus after administration of chewable, dispersible, buffered didanosine tablets.

STUDY OBJECTIVES: To test the hypothesis that gastric pH would be elevated above pH 3.0 for at least 2 hours after administration of chewable, dispersible, buffered didanosine tablets. Doses tested were 200 mg (two 100-mg tablets) and 400 mg (two 200-mg tablets). We also sought to compare these doses with regard to maximum gastric pH (pHmax), time to pHmax (TpH-max), time that gastric pH exceeds 3.0 (TpH>3), and area under the gastric pH versus time curve for pH greater than 3.0 (AUCT>pH 3). DESIGN: Prospective, parallel-group, dose-comparison, gastric pH study. SETTING: General Clinical Research Center, University of Michigan Hospitals, Ann Arbor, Michigan. PATIENTS: Nineteen patients infected with human immunodeficiency virus, aged 30-62 years, and receiving long-term didanosine therapy. INTERVENTION: Patients underwent continuous gastric pH monitoring, using the Heidelberg capsule radiotelemetric pH monitoring device. After documentation of a fasting baseline gastric pH below 3.0, patients were given 180 ml of water (control phase), and gastric pH was allowed to return to baseline. After administration of a single, oral dose of didanosine 200 mg or 400 mg with 180 ml of water, gastric pH was recorded until pH remained below 3.0 for 10 minutes. MEASUREMENTS AND MAIN RESULTS: A mean pHmax of 8.6 (range 6.3-9.5) was achieved with a TpH-max of 4.1 minutes (range 1-12.0 min). Mean TpH>3 was 24.9 minutes (range 15-55 min), with an AUCT>pH 3 of 2.6 pH x min(-1) (range 1.2-6.9 pH x min(-1)). The two doses of didanosine tested did not differ significantly in mean gastric pH parameters. CONCLUSIONS: After administration of chewable, dispersible, buffered didanosine tablets, 200 or 400 mg, the mean duration of elevated gastric pH (TpH>3) was less than 30 minutes, with a range of 15-55 minutes. Characterization of the magnitude and duration of elevated gastric pH may allow for earlier administration of other pH-sensitive drugs. The short duration of elevated gastric pH may help explain the wide variability in didanosine bioavailability observed clinically.

Increase in prevalence of Pneumocystis carinii mutations in patients with AIDS and P. carinii pneumonia, in the United States and China.

This study of Pneumocystis carinii dihydropteroate synthase (DHPS) mutations in patients with AIDS who have P. carinii pneumonia compares the change in the prevalence of such mutations in the United States, where sulfa-drug prophylaxis is widespread, to that in China, where it is infrequent. The DHPS gene from 145 US patients presenting during 1983-2001 and from 15 Chinese patients presenting during 1998-2001 was amplified by polymerase chain reaction and was sequenced. In the United States, 40% of patients had DHPS mutations; 38% received sulfa-drug prophylaxis. Mutation prevalence increased to 70% during 2000-2001, from 25% during 1994-1995 (P<.01). In China, 7% of patients had DHPS mutations; none received sulfa-drug prophylaxis. The prevalence of P. carinii DHPS mutations has markedly increased in the United States but remains low in China.

Capacity of neutrophils and monocytes from human immunodeficiency virus-infected patients and healthy controls to inhibit growth of Mycobacterium bovis.

We compared the differences in growth inhibition of Mycobacterium bovis by monocytes and neutrophils from human immunodeficiency virus (HIV)-infected persons (n = 12; mean CD4 count = 451/mm(3)) and healthy controls (n = 6). Phagocytes from all HIV-infected patients were incubated with or without exogenous granulocyte-macrophate colony-stimulating factor (GMCSF; 500-1000 U/mL). In two of the HIV-infected patients, phagocytes were incubated with or without interleukin (IL)-2 or IL-8 (500-1000 U/mL). Compared with that in HIV-infected patients, the reduction of M. bovis growth at 24 hours was 81% greater among monocytes and 69% greater among neutrophils from healthy controls (P =.03 and.04, respectively). Among HIV-infected patients, we noted greater mycobacterial reduction in monocytes (49%, P =.04) and neutrophils (42%, P =.05) from the early-stage patients (mean CD4 count = 760/mm(3)) compared with that in late-stage patients (mean CD4 count = 172/ mm(3)). Incubation with GM-CSF, IL-2, or IL-8 did not augment mycobactericidal activity. These findings suggest that the capacity of neutrophils and monocytes from HIV-infected patients to inhibit the growth of M. bovis is impaired, and this impairment is more pronounced in later stages of HIV infection.

Pneumocystis carinii pneumonia in patients in the developing world who have acquired immunodeficiency syndrome.

We review Pneumocystis carinii pneumonia (PCP) in patients in the developing world (i.e., Africa, Asia, the Philippines, and Central and South America) who have acquired immunodeficiency disease (AIDS). During the first decade of the AIDS pandemic, PCP rarely occurred in African adults. More recent reports have noted that PCP comprises a significantly greater percentage of cases of pneumonia than it did in the past. This trend dramatically contrasts with that observed in industrialized nations, where a reduction in the number of cases of PCP has occurred as a result of the widespread use of primary P. carinii prophylaxis and highly active antiretroviral therapy. Throughout the developing world, the rate of coinfection with Mycobacterium tuberculosis and PCP is high, ranging from 25% to 80%. Initiation of treatment when PCP is in an advanced stage may account for the high mortality rates (20%-80%) associated with pediatric PCP in the developing world.