Spectrum of excess mortality due to carbapenem-resistant Klebsiella pneumoniae infections.

Patients infected or colonized with carbapenem-resistant Klebsiella pneumoniae (CRKp) are often chronically and acutely ill, which results in substantial mortality unrelated to infection. Therefore, estimating excess mortality due to CRKp infections is challenging. The Consortium on Resistance against Carbapenems in K. pneumoniae (CRACKLE) is a prospective multicenter study. Here, patients in CRACKLE were evaluated at the time of their first CRKp bloodstream infection (BSI), pneumonia or urinary tract infection (UTI). A control cohort of patients with CRKp urinary colonization without CRKp infection was constructed. Excess hospital mortality was defined as mortality in cases after subtracting mortality in controls. In addition, the adjusted hazard ratios (aHR) for time-to-hospital-mortality at 30 days associated with infection compared with colonization were calculated in Cox proportional hazard models. In the study period, 260 patients with CRKp infections were included in the BSI (90 patients), pneumonia (49 patients) and UTI (121 patients) groups, who were compared with 223 controls. All-cause hospital mortality in controls was 12%. Excess hospital mortality was 27% in both patients with BSI and those with pneumonia. Excess hospital mortality was not observed in patients with UTI. In multivariable analyses, BSI and pneumonia compared with controls were associated with aHR of 2.59 (95% CI 1.52-4.50, p <0.001) and 3.44 (95% CI 1.80-6.48, p <0.001), respectively. In conclusion, in patients with CRKp infection, pneumonia is associated with the highest excess hospital mortality. Patients with BSI have slightly lower excess hospital mortality rates, whereas excess hospital mortality was not observed in hospitalized patients with UTI.

Tigecycline therapy for carbapenem-resistant Klebsiella pneumoniae (CRKP) bacteriuria leads to tigecycline resistance.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an increasing global threat. Here, we describe the prevalence and impact of tigecycline use in a cohort of patients with CRKP bacteriuria nested within a multicentre, prospective study. In the 21-month study period, 260 unique patients were included. Tigecycline was given to 80 (31%) patients. The use of tigecycline during the index hospitalization was significantly associated with the subsequent development of tigecycline resistance in the same patient (OR, 6.13; 95% CI, 1.15-48.65; p 0.03). In conclusion, the use of tigecycline with CRKP bacteriuria is common, and is associated with the subsequent development of tigecycline resistance.

HIV nephropathy and the Duffy antigen/receptor for Chemokines in African Americans.

BACKGROUND AND OBJECTIVES: HIV nephropathy (HIVAN) is markedly racially biased in its distribution, occurring in about 10% of HIV infected African Americans according to some studies. Based upon previous laboratory and epidemiological studies, the Duffy promoter polymorphism, which occurs almost exclusively in individuals of African descent, has been postulated to be the predisposing factor. We aimed to explore that relationship by directly genotyping individuals with HIV nephropathy to determine the proportion homozygous for this mutation to test the hypothesis it was responsible for the genetic component of this disease. We anticipated that if the polymorphism was associated with HIV nephropathy all individuals would be homozygous for this mutation. METHOD: Individuals with HIVAN proven on biopsy were identified from previous studies and a pre-existing clinical database. This diagnosis was confirmed by an experienced pathologist examining the biopsies in a blinded fashion. PCR and RFLP strategies were used on the biopsy samples to genotype for the Duffy promoter polymorphism. The cases were compared to a control population of HIV seronegative African Americans. RESULTS: Twenty African American individuals with HIV nephropathy were successfully genotyped. Only nine were homozygous for the promoter mutation. Nine were heterozygous and two homozygous wild type. Furthermore, the frequency of the polymorphism did not differ from the background rate in the African American population (OR = 0.788 95% confidence intervals 0.378-1.64). CONCLUSION: The Duffy promoter polymorphism was not disproportionately represented in persons with HIVAN calling into question any significant role in the pathogenesis of HIVAN.

Antiviral therapy for HIV patients with renal insufficiency.

Patients with HIV infection and HIV-related opportunistic infections are treated extensively with a spectrum of drugs. Introduction of new antiretroviral drugs, such as protease inhibitors and nonnucleoside reverse transcriptase inhibitors in addition to nucleoside reverse transcriptase inhibitors, has created exciting dimensions in treatment strategies. Renal dysfunction is also common in HIV-infected patients. Because some drugs used in HIV are primarily excreted unchanged by the kidney, dose adjustments are necessary in patients with renal insufficiency. Drugs such as foscarnet, cidofovir and adefovir are directly nephrotoxic, whereas acyclovir can crystallize in the kidneys, and indinavir may cause nephrolithiasis. This paper reviews the impact of renal insufficiency on pharmacokinetics of antiviral drugs used in HIV disease and discusses dosage recommendations needed to avoid toxicity. Finally, we summarize the effects of dialysis on removal of these drugs.

Treatment of mucocutaneous herpes simplex virus infections unresponsive to acyclovir with topical foscarnet cream in AIDS patients: a phase I/II study.

The efficacy and toxicity of foscarnet cream for the treatment of mucocutaneous herpes simplex virus lesions or lesions that were clinically unresponsive to systemic acyclovir treatment (median, 30.5 days) in AIDS patients were studied in a phase I/II, open-label, nonrandomized multicenter trial. In the study, 20 patients with advanced stages of AIDS were treated with foscarnet 1% cream five times a day for a mean duration of 34.5 days. Response of index lesions (n = 20) was judged to be completely healed (8 lesions), excellent (4 lesions), or good (1 lesion) in 65% of lesions. The median time to first negative herpes simplex virus culture of index lesion was 8 days. Among 15 patients with pain at baseline, 11 had complete resolution of pain and 2 had at least a 50% reduction. Clinical adverse events included skin ulceration (4 patients), application site reactions (3 patients), fever (3 patients), and headache (3 patients). Five (25%) patients developed new lesions due to herpes simplex virus at sites other than those being treated topically while enrolled in the study. Topical foscarnet 1% cream appears to be a safe and effective treatment for acyclovir-unresponsive mucocutaneous herpes simplex virus infection in AIDS patients.

The utility of clinical and radiographic features in the diagnosis of cytomegalovirus central nervous system disease in AIDS patients.

BACKGROUND: Polymerase chain reaction (PCR) assays of cerebrospinal fluid (CSF) for cytomegalovirus (CMV) DNA have facilitated the diagnosis of CMV-associated central nervous system disease in AIDS patients. We attempt to correlate clinical and radiographic features that are associated with CMV PCR- positivity in CSF from AIDS patients with neurologic disease. METHODS AND RESULTS: A retrospective case controlled comparison was made of CMV PCR-positive and PCR-negative patients. RESULTS: CMV PCR-positive patients were significantly more likely to have nystagmus, prior CMV retinitis, and CSF protein levels.90 mg/dL. Of patients with 0, 1, and $2 of these features, 5.6%, 55.2%, and 88.9%, respectively, were PCR-positive. Ependymal enhancement was present by magnetic resonance imaging in 9 of 12 PCR-positive, and in 8 of 30 PCR-negative patients. CONCLUSION: These clinical and radiographic features may serve as useful adjuncts toward the establishment of the diagnosis of CMV-associated neurologic disease in AIDS patients.

A phase I/II evaluation of oral L-2-oxothiazolidine-4-carboxylic acid in asymptomatic patients infected with human immunodeficiency virus.

A randomized double-blind, placebo-controlled study was conducted in 37 asymptomatic HIV-infected individuals (mean CD4 count 707 cells/mm3) to characterize the safety, pharmacokinetics, and effect on blood thiols of three dosage levels of a cysteine prodrug, L-2-oxothiazolidine-4-carboxylic acid (OTC; Procysteine; Clintec Technologies, Deerfield, IL). Single-dose administration of OTC resulted in measurable plasma levels at all dosages, with a mean peak plasma concentration of 734 +/- 234 nmol/mL at the highest dosage studied. After 4 weeks of administration three times daily, a statistically significant increase was seen in whole blood glutathione in the 1,500 mg and 3,000 mg dose groups compared with the placebo group. A significant increase in whole blood cysteine and peripheral blood mononuclear cell (PBMC) glutathione was not seen during the study period.

Polymerase chain reaction detection and clinical significance of varicella-zoster virus in cerebrospinal fluid from human immunodeficiency virus-infected patients.

Varicella-zoster virus (VZV) causes ocular and other central nervous system (CNS) disease in human immunodeficiency virus (HIV)-infected persons. To study the prevalence of CNS disease due to VZV, cerebrospinal fluid (CSF) specimens from 84 consecutive HIV-infected patients with new neurologic symptoms were tested for VZV DNA by a polymerase chain reaction (PCR) assay. Six patients were PCR-positive for VZV in CSF; 3 additional patients were subsequently identified who were not part of the serial population sample. Among these 9 patients, all had clinical presentations consistent with ocular and other CNS disease due to VZV; 4 were without zoster on presentation. Sustained improvement in association with antiviral therapy was observed in 3. Therefore, VZV DNA was detected in the CSF of 7% of HIV-infected patients presenting with neurologic symptoms; the diagnosis of VZV-related CNS disease was facilitated by this assay; improvement in association with antiviral therapy was observed in some patients.

Prednisone improves renal function and proteinuria in human immunodeficiency virus-associated nephropathy.

PURPOSE: To determine if prednisone ameliorates the course of human immunodeficiency virus-associated nephropathy (HIV-AN). PATIENTS AND METHODS: Twenty consecutive HIV-infected adults with biopsy-proven HIV-AN (n = 17) or clinical characteristics of HIV-AN (n = 3) with serum creatinine concentrations > 177 mumol/L (2 mg/dL) or proteinuria > 2.0 g/d or both were prospectively evaluated and treated with prednisone at a dose of 60 mg/d for 2 to 11 weeks, followed by a tapering course of prednisone over a 2- to 26-week period. Serum creatinine concentration, 24-hour protein excretion, serum albumin, and steroid-related adverse effects were assessed before and after treatment. RESULTS: Nineteen patients had serum creatinine concentrations > 117 mumol/L (2 mg/dL). Two of them progressed to end stage renal disease (ESRD) in 4 to 5 weeks. In 17 patients serum creatinine levels decreased from 717 +/- 103 mumol/L (8.1 +/- mg/dL) (mean +/- SE) to 262 +/- 31 mumol/L (3.0 +/- 0.4 mg/dL) (P < 0.001). Five patients relapsed after prednisone was discontinued and were retreated. In these 5 the serum creatinine declined from 728 +/- 107 mumol/L (8.2 +/- 1.2 mg/dL) to 344 +/- 47 mumol/L (3.9 +/- 0.5 mg/dL) (P < 0.01) in response to the second course of prednisone. Twelve of 13 tested patients showed a reduction in 24-hour urinary protein excretion with an average decrement from 9.1 +/- 1.8 g/d to 3.2 +/- 0.6 g/d (P < 0.005). Serum albumin increased from 24.4 +/- 3.6 g/L to 29.3 +/- 2.6 g/L (P = NS) in the 11 patients with paired 24-hour urine collections for whom pre- and post-treatment determinations were available. In one non-azotemic patient with nephrotic syndrome, protein excretion declined from 15.2 to 2.2 g/day and the serum albumin increased from 4.0 g/L to 31.0 g/L. The 20 patients have been followed for a median of 44 weeks (range 8 to 107). Eight ultimately required maintenance dialysis. Eleven died from complications of HIV disease 14 to 107 weeks after institution of prednisone; none was receiving prednisone at the time of death. Seven are alive and free from ESRD a median of 25 weeks (range 8 to 81) from the initiation of prednisone therapy. Six patients developed a total of seven serious infections while receiving prednisone, including Mycobacterium avium-complex infection in 2 and CMV retinitis in 3. CONCLUSION: Prednisone improves serum creatinine and proteinuria in a substantial proportion of adults with HIV-AN. Corticosteroid-related side effects are not prohibitive. A prospective, randomized controlled trial is required to confirm these preliminary results.

Pulmonary disease due to infection by Mycobacterium avium complex in patients with AIDS.

We reviewed the clinical, radiographic, and histologic features of nine patients with AIDS and pulmonary disease due to Mycobacterium avium complex (MAC). Pulmonary MAC disease was defined by (1) the isolation of MAC from two or more lower respiratory tract specimens or from a single lung biopsy sample, (2) an infiltrate revealed by chest radiography, and (3) the absence of other identified pulmonary pathogens or malignancies. Pulmonary MAC disease was present in five (2.5%) of 200 patients with disseminated MAC infection and in four additional patients without evidence of dissemination, as assessed by blood culture. The median CD4 cell count at the time of presentation was 90/microL. Pulmonary MAC disease was the initial AIDS-defining infection in five patients and presented within a median of 5 months after the initial infection in four patients. Radiographic patterns for these nine patients included consolidating or nodular infiltrates and cavitation. The histopathology of pulmonary MAC disease was characterized by granulomatous inflammation, often associated with necrosis and few evident organisms. The conditions of all patients treated with multidrug regimens clinically improved.

Effect of corticosteroid therapy on human immunodeficiency virus-associated nephropathy.

PURPOSE: Human immunodeficiency virus-associated nephropathy (HIV-AN) occurs predominantly in blacks and is characterized histologically by focal segmental glomerulosclerosis or mesangial proliferation and a lymphohistiocytic tubulointerstitial infiltrate. Patients manifest heavy proteinuria and, once azotemia occurs, progress rapidly to end-stage renal disease within 2 to 6 months. No treatment has been shown to be useful for HIV-AN. The purpose of this study was to determine the effect of corticosteroid agents on the progression of HIV-AN. PATIENTS AND METHODS: Four consecutive HIV-infected adults with fewer than 200 CD4 cells/microL, moderate to severe renal insufficiency, proteinuria greater than 2 g per 24 hours, and HIV-AN demonstrated by renal biopsy were treated with 60 mg of prednisone daily for 2 to 6 weeks. Patients were followed with respect to serum creatinine level, 24-hour protein excretion, adverse drug reactions, and the occurrence of opportunistic infections. RESULTS: CD4 counts ranged from 30 to 80 cells/microL before therapy with steroids. The mean (+/- SD) pretreatment serum creatine concentration was 9.1 +/- 5.7 mg/dL and decreased to 3.3 +/- 1.8 mg/dL (P < 0.05) after 2 to 6 weeks of corticosteroid therapy. Twenty-four hour protein excretion did not change (5.2 +/- 2.4 g pretreatment versus 4.6 +/- 4.1 g posttreatment). One patient was able to discontinue dialysis after 10 days. Two patients developed Mycobacterium avium-complex infections and steroid-associated psychosis. One of these patients developed a recurrence of genital herpes, and the other developed dermatomal zoster. None of the four required dialysis during a 1.5- to 5.5-month period of follow-up after cessation of steroid treatment. CONCLUSION: In selected patients with HIV-AN, short-term treatment with corticosteroid agents improves renal function and prevents the development of end-stage renal disease during a 1.5- to 5.5-month period of observation, but may be associated with an increased risk of opportunistic infection.

A phase I/II trial of intravenous L-2-oxothiazolidine-4-carboxylic acid (procysteine) in asymptomatic HIV-infected subjects.

Twenty-four asymptomatic, HIV-1-seropositive subjects with CD4 cell counts of > or = 400/microliters participated in a Phase I/II, dose escalation trial of intravenous L-2-oxothiazolidine-4-carboxylic acid (OTC: Procysteine). Four groups of six subjects each were consecutively assigned to receive OTC at an initial dose of 3, 10, 30, or 100 mg/kg, followed by the same dose given twice weekly for 6 weeks. Increases in whole-blood glutathione were observed in the highest dosage group after 6 weeks of therapy. No effects on changes in CD4 cell counts, viral load, or proviral DNA frequency were observed among the four dosage groups, although a decline in beta 2-microglobulin levels was apparent in the highest dosage group. One subject withdrew due to headaches; other probable adverse events including rash, flushing, pruritus, lightheadedness, and diminished concentration were self-limited.

Fluorimetric analysis of recombinant p15 HIV-1 ribonuclease H.

We have exploited the sole tryptophan residue (Trp535) in the ribonuclease H (RNase H) domain of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) to study features of the isolated polypeptide (p15 RNase H) by fluorescence spectroscopy. Incubation of purified p15 RNase H with a synthetic RNA/DNA hybrid was accompanied by an alteration in Trp535 fluorescence intensity. This property was used to determine an apparent binding constant (Kapp) of 3.5 x 10(6) M-1 for p15 RNase H complexed with poly(rA)/oligo(dT)12-18 and an occluded site size of 4 nucleotides. A cooperativity coefficient (omega) of 910 was also determined which indicated that nearly three logs of the Kapp were due to cooperativity effects. Recombinant p15 RNase H preparations containing mutations at position 478 (Glu478-->Gln478) or 539 (His539 -->Phe539), which are highly conserved between bacterial and retroviral RNases H, were also analyzed. Under the same conditions, these mutants failed to bind the RNA/DNA hybrid, although they were structurally similar to the wild type polypeptide. Fluorescence spectroscopy thus appears to be an alternative and sensitive means of analyzing functional properties of the purified RNase H domain of HIV-1 RT under a variety of conditions.

Cytomegalovirus ventriculoencephalitis in AIDS. A syndrome with distinct clinical and pathologic features.

Cytomegalovirus ventriculoencephalitis is a late and terminal complication of AIDS. Cytomegalovirus retinitis was diagnosed before the onset of encephalitis in all but 1 of the 7 patients in this series. A distinct clinical presentation was observed, with encephalitis often associated with cranial nerve deficits and gaze-directed nystagmus. Examination of CSF demonstrated pleocytosis with elevated protein and hypoglycorrhachia. Increased signal of periventricular white matter was visualized by MRI soon after the development of encephalitis, and progressive ventriculomegaly was detected by serial CT scanning. Cytomegalovirus ventriculoencephalitis developed in some patients while receiving ganciclovir or foscarnet maintenance therapy, and the response to higher doses of these agents was limited in the 2 patients so treated. Death ensued a median of 4 weeks after the onset of neurologic symptoms. Pathologic examination showed extensive necrotizing periventriculitis involving ependymal and subependymal regions with spread to the meninges and adjacent cranial nerve roots. The infection was associated with characteristic CMV inclusion-bearing cells. This entity should be considered in AIDS patients with encephalitis, particularly in the presence of cranial nerve impairment or ascending muscle weakness. With the improvement in survival of patients with AIDS it is expected that this manifestation of CMV infection will become increasingly common.

Purification and characterization of recombinant equine infectious anemia virus reverse transcriptase.

A 1.67-kb segment of the equine infectious anemia virus pol gene, encoding a 66-kDa reverse transcriptase (RT), was cloned and expressed in Escherichia coli. Recombinant RT, purified by a combination of metal chelate affinity chromatography and ion-exchange chromatography, displays both RNA-dependent DNA polymerase and RNase H activity. The affinity of purified RT for its replication primer, tRNA(3Lys) was equivalent to that observed for human immunodeficiency virus RT. Our data suggest that an additional domain between RT-RNase H and integrase on the equine infectious anemia virus pol open reading frame is not an integral component of the RT polypeptide.

Continuous infusion of methohexital and alfentanil hydrochloride for general anesthesia in outpatient third molar surgery.

Three anesthetic techniques were compared in this study: 1) Intermittent Brevital boluses supplemented with fentanyl and midazolam all titrated to patient movement, 2) constant infusion of Brevital supplemented with fentanyl and midazolam all delivered in calculated mg/kg doses based on total body weight, and 3) constant infusion of methohexital (Brevital) and alfentanil (Alfenta) supplemented by midazolam (Versed), droperidol, and glycopyrolate (Robinul) delivered in calculated mg/kg doses based on lean body mass. Nitrous oxide was delivered in all cases via nasal mask in a 30% to 50% concentration. The mean total dose of Brevital in group 1 (intermittent Brevital bolus) was 0.17 mg/kg/min (SD = 0.07), group 2 (Brevital infusion) was 0.23 mg/kg/min (SD = 0.06), and group 3 (alfentanil/Brevital infusion) was 0.12 mg/kg/min (SD = 0.07). Mean total dose of alfentanil in group 3 equaled 1.58 mcg/kg/min (SD = 0.73). In group 1, 94% of the patients experienced moderate to severe movement intraoperatively. Twenty-three percent of the patients in group 2, and only 7% of group 3 exhibited moderate to severe movement. Emergence in group 3 averaged 4.5 minutes (SD = 1.6). Three patients (7%) in group 3 had postoperative nausea. Additional subjective findings in group 3 included easier airway maintenance during administration of the anesthetic, lack of unpleasant emergence phenomena such as crying, and prompt readiness for discharge. It was concluded that continuous alfentanil and Brevital infusion satisfied the objectives of safety, stability, predictability, and rapid recovery, while improving operating conditions (less patient movement) when compared with more traditional anesthetic techniques.

Attenuation of the hemodynamic responses to endotracheal intubation with preinduction intravenous labetalol.

Endotracheal intubation following anesthesia induction frequently produces hypertension and tachycardia. This study evaluated the efficacy of preinduction IV labetalol for attenuating the hemodynamic responses to intubation following thiopental and succinylcholine induction of anesthesia. Two hours after diazepam (10 mg by mouth), 60 patients were randomized in a double-blind manner and received IV saline or labetalol at doses of 0.25, 0.5, 0.75, or 1 mg/kg in a parallel design study. Five minutes later, thiopental (4 mg/kg) and succinylcholine (1 mg/kg) were administered, and the trachea was intubated in 2 minutes. Nitrous oxide (70%) anesthesia was maintained for 10 minutes. Hemodynamic parameters were grouped and analyzed for significance (p less than 0.05) by two-way repeated measures analysis of variance and t-test with Bonferroni adjustments. Baseline group demographics and hemodynamics were comparable. All doses of labetalol significantly attenuated the rate-pressure product increase immediately postintubation versus placebo. There was a dose-dependent attenuation of the increases in heart rate and the systolic, diastolic, and mean blood pressures versus placebo following intubation. IV labetalol at doses up to 0.75 mg/kg offers an effective pharmacologic means of attenuating preoperative hemodynamic responses to endotracheal intubation.

Thrombosis of the aorta caused by mucormycosis.

We have reported the case of a 57-year-old man with a myelodysplastic syndrome who had sudden paraplegia and paresthesias of both legs. Myelogram was normal, but an aortogram showed thrombosis of the abdominal aorta. Thrombectomy disclosed a clot composed of nonseptate hyphae with right angle branching, characteristic of the family Mucoraceae. Though angioinvasion and septic thrombosis are characteristic features of mucormycosis, aortic thrombosis has not previously been reported with this infection.