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Recent reports have documented human herpesvirus 6 (HHV-6) as a cause of high fever, bone marrow depression, and rash in liver transplant recipients in the absence of another known pathogen. We describe a 49-year-old liver transplant recipient who developed confusion, occipital headache, and involuntary movements of the limbs 3 weeks after orthotopic liver transplantation. HHV-6 was detected in the peripheral blood using a rapid culture assay. Examination of cerebrospinal fluid by polymerase chain reaction for HHV-6 was also positive. No other pathogens were identified. The patient improved after commencement of intravenous ganciclovir therapy. This case suggests HHV-6 needs to be considered in the differential diagnosis of unexplained confusion in liver transplant recipients.

Background: Early cytomegalovirus (CMV) reactivation infections have been found to be associated with a number of stress responses such as severe bacterial infection. Intraoperative hypothermia is known to be a significant physiological stressor. Hence, we sought to evaluate a relationship between intraoperative hypothermia during liver transplantation and early CMV infection., Methods: Relationships between intraoperative hypothermia and early CMV infection were assessed using univariate and multivariate analysis., Results: There were 11 of 100 patients who had CMV infection detected within the first 30 days after the transplant and 16 of 100 in the next 3 months after the transplant. The median intraoperative temperature (34.4 degrees C) of those who subsequently developed early CMV infection was significantly lower than that in patients who did not develop early CMV infection (35.3 degrees C; P = 0.032). Multivariate analysis showed that only hypothermia was an independent predictor of early CMV infection (odds ratio 2.8, 95% confidence intervals 1.2-6.4; P = 0.047)., Conclusions: Intraoperative hypothermia during liver transplantation increases the risk of CMV infection in the 1st month postoperatively and active warming seems to reduce this risk.

Antibiotic options for patients with methicillin resistant Staphylococcus aureus infections are severely limited. Unfortunately, infections with S. aureus with reduced susceptibility to vancomycin and teicoplanin have been recently reported for the first time. Commonly used laboratory methods for determining antibiotic susceptibility may be inadequate for detecting reduced susceptibility to vancomycin. Even though no confirmed cases have yet been detected in Australia, a high index of suspicion must be maintained for the occurrence of such organisms. Strategies for prevention of the spread of S. aureus with reduced susceptibility to vancomycin should be prepared by Australian hospitals prior to their first cases being identified. This article outlines the background to this developing issue and discusses laboratory methods and findings, with some current recommendations for diagnostic laboratories.

Background: Precise diagnosis of central nervous system (CNS) lesions in liver transplant recipients remains problematic. Brain biopsies are often not feasible as a result of coagulopathy. We sought to determine whether selected clinical or radiologic characteristics can predict the likely etiology of CNS lesions in liver transplant recipients and thus obviate the need for diagnostic brain biopsies., Methods: A 4-year prospective, observational, cohort study was conducted at liver transplant centers at four geographically diverse medical institutions. A total of 1730 consecutive liver transplant recipients were evaluated for CNS lesions; 60 patients with radiologically documented CNS lesions comprised the study sample., Results: Vascular events (52%, 31/60), infections (181%, 11/60), immunosuppressive associated leukoencephalopathy (12%, 7/60), central pontine myelinolysis (8%, 5/60), and malignancy (3%, 2/60) were the predominant etiologies of CNS lesions. CNS lesions were most likely to occur within 30 days of transplantation (43%, 26/60); central pontine myelinolysis, subdural hematoma, acute infarcts, and Aspergillus brain abscesses were the predominant etiologies during this time. All brain abscesses were fungal; 73% (8/11) of these patients concurrently had documented extraneural (pulmonary) infection as a result of the same fungal pathogen. Thus, a diagnostic brain biopsy is not warranted in these patients. Patients on dialysis were more likely to have ischemic or infectious CNS lesions (P=0.03). Vascular events were more likely to occur in repeat transplant recipients (P=0.03). Twenty-five percent (15/60) of the CNS lesions occurred more than 1 year after transplantation; small vessel ischemic lesions, malignancy, or non-Aspergillus fungal brain abscesses accounted for all such lesions., Conclusions: A presumptive etiologic diagnosis can be established in a vast majority of CNS lesions in liver transplant recipients based on identifiable presentation that includes time of onset, unique risk factors, and neuroimaging characteristics. Empiric therapy of brain abscesses in liver transplant recipients should include antifungal and not antibacterial agents.

Tuberculosis is a serious opportunistic infection in transplant recipients. On the basis of the compilation of published reports in the literature, the incidence of Mycobacterium tuberculosis infection in organ transplant recipients worldwide ranged from 0.35% to 15%. Nonrenal transplantation (P = .004), rejection within 6 months before the onset of tuberculosis (P = .02) and type of primary immunosuppressive regimen (P = .007) were predictors of M. tuberculosis infection occurring within 12 months after transplantation. Thirty-three percent (155) of 476 transplant patients with tuberculosis had disseminated infection; receipt of OKT3 or anti-T cell antibodies (P = .005) was a significant predictor of disseminated tuberculosis. Overall, the mortality rate among 499 patients was 29%; disseminated infection (P = .0003), prior rejection (P = .006), and receipt of OKT3 or anti-T cell antibodies (P = .0013) were significant predictors of mortality in patients with tuberculosis. Clinically significant hepatotoxicity due to isoniazid occurred in 2.5%, 4.5%, and 41% of renal, heart and lung, and liver transplant recipients, respectively. The diagnosis and effective management of tuberculosis after transplantation warrant recognition of the unique epidemiological and clinical characteristics of tuberculosis in transplant recipients.

Prostatitis due to vancomycin-resistant enterococci has not been previously described. Reported here is a case of chronic prostatitis due to Enterococcus faecium, resistant to vancomycin, ampicillin, ciprofloxacin and doxycycline, in a 42-year-old liver transplant recipient. Treatment with a combination of rifampin and nitrofurantoin for 6 weeks resulted in long-lasting cure. Other antimicrobial agents active in vitro against vancomycin-resistant enterococci, such as quinupristin/ dalfopristin and chloramphenicol, are unlikely to achieve sufficient prostatic tissue levels to be successfully utilized for treatment of this condition.

Objective: To determine the risk factors for aminoglycoside toxicity in the elderly., Design: Prospective observational study., Setting: Acute care teaching hospital serving predominantly veterans., Participants: Consecutive patients aged 70 years and over receiving aminoglycosides., Interventions: None., Measurements and Main Results: Thirteen (15%) of 88 patients developed aminoglycoside-related nephrotoxicity and 3 (3.4%) developed otovestibular toxicity. Multivariate analysis showed that increasing duration of aminoglycoside therapy was the only factor significantly associated with development of toxicity. Elevated baseline serum creatinine level (p = .02) and use of allopurinol (p = .03) were risk factors specifically for nephrotoxicity. Only 2 (3.9%) of 51 patients receiving aminoglycosides 7 or fewer days developed nephrotoxicity, as compared with 11 (30%) of 37 receiving the drugs for 8 to 14 days and 4 (50%) of 8 treated for more than 14 days., Conclusions: Although toxicity is common in elderly patients treated with aminoglycosides, limiting the duration of aminoglycoside therapy to less than a week can substantially reduce risk of toxicity.

Background: Mycophenolate mofetil (MMF) is a new immunosuppressive agent that is gaining widespread use in solid organ transplantation recipients. A comprehensive assessment of infectious complications after its use after liver transplantation has never been assessed., Methods: Bacterial, fungal, and viral infections occurring after transplantation were compared for a cohort of consecutive liver transplant recipients who received MMF (because of suspected tacrolimus-related nephrotoxicity or neurotoxicity) and a cohort who did not receive the drug. All patients received a tacrolimus-based primary immunosuppressive protocol., Results: Biopsy-proven acute rejection episodes within the first 6 months after transplant occurred in 6% of MMF-treated patients but in 30% of those who did not receive MMF (P=0.07). No significant differences were found in occurrence of cytomegalovirus infection or disease, Pneumocystis carinii, Aspergillus, or other fungal infection and hepatitis C virus recurrence between MMF-treated and untreated patients. Bacterial infections were more common in MMF-treated patients, but this cohort had a prolonged intensive care unit stay compared with patients who did not receive MMF. None of the MMF-treated patients with bacterial infection had leukopenia., Conclusions: MMF use does not appear to be associated with an significantly increased risk of infection occurring after liver transplantation and is associated with fewer episodes of acute rejection.

There is considerable confusion as to how to monitor serum aminoglycoside levels when using once-daily dosing. At least five methods are in use in Australia. We prospectively assessed 100 consecutive once-daily courses of gentamicin or tobramycin, during which 120 pre-dose and 213 sets of immediate post-dose and six hour post-dose levels were taken. By using the six hour post-dose level we were able to compare dosage recommendations made using methods known as ALADDIN, DOSECALC and the Australian Antibiotic Guidelines nomogram (AAGN). There were statistically significant differences in the doses recommended by each method. When comparing each of the three methods, at least 25% of dosage recommendations differed by more than 80 mg per dose. Although we have not been able to determine the clinical significance of these differences, we are concerned that methods used in dosage adjustment of aminoglycosides differ so widely in their recommendations. Presumably the ALADDIN method, which utilises two post-dose levels to determine an area under aminoglycoside concentration-time curve, gives more accurate pharmacokinetic information than methods which rely on a single level. Comparative cost-effectiveness studies of different methods, although in practice difficult to perform, should be undertaken to resolve the optimal management of patients receiving aminoglycosides once-daily.

Twenty-three horses and three humans in Queensland, Australia, were infected with a novel member of the Paramyxoviridae family of viruses in two geographically distinct outbreaks. Two of the humans died-one died of rapid-onset respiratory illness, and the other died of encephalitis. The third infected human developed an influenza-like illness and made a complete recovery. All infected humans had close contact with sick horses. Since the two outbreaks occurred at sites 1,000 km apart and no known contact between the two groups of humans and horses occurred, extensive testing of animals and birds common to the two areas was conducted. Fruit bats (Pteropus species) were found to carry a virus identical to that found in the infected humans and horses. Although there was no contact between the infected humans and the bats, some form of close contact between the horses and bats is the likely mode of infection.

Chlamydia pneumoniae is a recently reported, but common, respiratory tract pathogen. The organism has been detected by electron microscopy, immunocytochemistry, polymerase chain reaction (PCR) and recently culture within atherosclerotic plaques, suggesting a possible association between C. pneumoniae infection and atherosclerosis. Interestingly this association has not been found by all researchers. We examined 17 carotid endarterectomy specimens, 16 carotid arteries and 16 coronary arteries from autopsy specimens. They were examined by PCR for the presence of C. pneumoniae. In none of the 49 atherosclerotic samples examined was C. pneumoniae detected. The sensitivity of our PCR assay was rigorously tested and found to detect consistently fewer than ten elementary bodies. The association between C. pneumoniae and atherosclerosis is intriguing but has not yet been demonstrated in Australian patients.

Background: Intravesical bacillus Calmette-Guerin (BCG) is widely used in the management of bladder cancer but because it is a living organism, local and disseminated infection may result., Methods: A prospective assessment of complications of this therapy in 200 patients in Queensland was performed. A review of management of complications of intravesical BCG was also carried out., Results: Major side effects were rare. Cystitis was the most common side effect, being seen to some degree in all patients, although only forcing cessation of BCG therapy in two patients. Two patients developed persistent cystitis necessitating institution of isoniazid and rifampicin. Two patients had culture-proven bladder infection that presented several months after the BCG treatment. These patients also responded to two-drug antituberculous therapy. While low-grade fever is very common with this therapy, seven patients (3.5%) had fevers of > 39 degrees C within 48 h of receiving BCG. Fevers may be an indication of severe disseminated mycobacterial infection, which has a high mortality, so it needs to be treated aggressively. Alternatively bacterial sepsis with gram-negative bacterial pathogens or a hypersensitivity reaction to BCG may cause this degree of fever, and cannot be rapidly distinguished from fulminant mycobacterial infection. One patient in the present series developed pneumonia attributed to mycobacterial dissemination., Conclusions: The key to appropriate management of complications of BCG therapy is awareness of their possibility, even months or years after the therapy has been given. Appropriate empirical therapy in acute situations and mycobacterial culture in chronic situations can then be performed.

The choice of empirical treatment for community-acquired pneumonia (CAP) is highly controversial. Our survey of 42 Australian emergency department doctors showed that monotherapy with a third-generation cephalosporin was the preferred regimen for severe CAP (14/42; 33%). We argue that cheaper regimens with a narrower spectrum are likely to be just as effective as third-generation cephalosporins and will have fewer adverse effects on the microbial ecology of hospitals. We suggest penicillin or ampicillin (to cover pneumococci--even if penicillin "resistant"--and Haemophilus influenzae), plus a macrolide (e.g., azithromycin or erythromycin; to cover Legionella and other "atypical" pathogens), plus a single large dose of an aminoglycoside (e.g., gentamicin; to cover gram-negative bacilli such as Klebsiella pneumoniae) as empirical therapy for severe CAP.

Infective endocarditis, defined as pathologically or clinically definite by the Duke criteria, was observed in 14 transplant recipients at our institutions. In addition, we reviewed 32 previously reported cases in solid organ transplant recipients. The spectrum of organisms causing infective endocarditis was clearly different in transplant recipients than in the general population; 50% of the infections were due to Aspergillus fumigatus or Staphylococcus aureus, but only 4% were due to viridans streptococci. Fungal infections predominated early (accounting for six of 10 cases of endocarditis within 30 days of transplantation), while bacterial infections caused most cases (80%) after this time. In 80% (37) of the 46 cases in transplant recipients, there was no underlying valvular disease. Seventy-four percent (34) of the 46 cases were associated with previous hospital-acquired infection, notably venous access device and wound infections. Three patients with S. aureus endocarditis had had an episode of S. aureus bacteremia > 3 weeks prior to the diagnosis of endocarditis and had received treatment for the initial bacteremia of < 14 days' duration. The overall mortality rate was 57% (26 of 46 patients died), with 58% (15) of the 26 fatal cases not being suspected during life. Endocarditis is an underappreciated sequela of hospital-acquired infection in transplant recipients.

Donovanosis is a genital ulcer disease that occasionally has extragenital manifestations. This report describes a case of disseminated donovanosis in a 54-year-old woman from northern Australia who had subsequent thoracic vertebral osteomyelitis and spinal cord compression. Malignancy and vertebral tuberculosis were the major differential diagnoses. The patient had no genital lesions at the time of diagnosis of extragenital donovanosis but had undergone a hysterectomy, thus raising the possibility of prior disease of the uterine cervix (most previous cases have been associated with primary cervical disease). Despite treatment with doxycycline, she had no significant neurological improvement. Donovanosis disseminated to bone has been reported in 18 cases in the last 55 years. Awareness of donovanosis in the differential diagnosis of osteomyelitis and prompt pelvic examinations enabling early diagnosis of occult cervical disease are the most important measures in preventing morbidity and mortality due to disseminated donovanosis.

Pulmonary nodules present a diagnostic dilemma in liver transplant recipients because of the broad differential diagnosis involved. Eleven of 155 (7.1%) liver transplant recipients at the Veterans Affairs Medical Center, Pittsburgh, developed pulmonary nodules. The underlying etiology included aspergillosis (3 cases), cryptococcosis (2), metastatic hepatocellular carcinoma (1), posttransplant lymphoproliferative disorder (1), Staphylococcus aureus (1), squamous cell carcinoma (1), adenocarcinoma of unknown primary site (1), and undifferentiated carcinoma (1). A review of the literature revealed 22 other liver transplant recipients with pulmonary nodules. There appears to be a definite relationship between time since transplantation and etiology of the nodule. Aspergillosis and bacterial infections appear early (within the first month), whereas nocardiosis, coccidiomycosis, tuberculosis, and cryptococcosis occur from 3 to 24 months posttransplantation. Metastatic hepatocellular carcinoma is a relatively common cause of pulmonary nodule and appears from 2 months to 2 years posttransplantation. Detection of skin lesions (indicating nocardiosis or cryptococcosis) and positive serologic tests may further narrow the diagnosis. However, radiographic appearances of nodules of differing etiology are relatively nonspecific, necessitating biopsy in virtually all cases.

Tacrolimus is being increasingly used as an immunosuppressive agent in transplant recipients. The drug is metabolized by the cytochrome P-450 3A system, thus antimicrobials that inhibit or induce these enzymes can alter levels of tacrolimus in the bloodstream. Tacrolimus is potentially nephrotoxic and neurotoxic; the likelihood of toxicity rises as blood levels of the drug increase. Increased tacrolimus levels and subsequent toxicity have been produced by a number of antimicrobial agents that inhibit the cytochrome P-450 3A system. Conversely, drugs with the potential to induce the cytochrome P-450 3A system can reduce the levels of tacrolimus in the blood, leading to increased risk of acute rejection in transplant recipients. Antimicrobial agents that can have adverse effects on renal function may add to the nephrotoxicity of tacrolimus. The potential for drug interactions should be reviewed before antimicrobial agents are prescribed to patients treated with tacrolimus.

Invasive aspergillosis occurred in 26 liver transplant recipients since 1990 at five liver transplant centers. The median time to onset was 17 days after transplantation. Twenty-seven percent of the patients had undergone retransplantation. Invasive aspergillosis occurred significantly earlier after transplantation in smokers than in nonsmokers (P=0.017). Patients with late-onset aspergillosis (occurring after posttransplant day 90) were more likely to have had prior cytomegalovirus infection than those with early-onset aspergillosis (occurring within 90 days of transplantation) (67% vs. 10%, respectively, P=0.013). Only 8% of the patients had received additional corticosteroids or OKT3, which suggests that augmented immunosuppression may not be a relevant risk factor for invasive aspergillosis in the 1990s due to less frequent use of these agents. The median serum bilirubin level of the patients was 21.8 mg/dl, 85% of the patients had renal insufficiency, and 54% were on dialysis before the onset of invasive aspergillosis, which suggest that overall severity of illness, including poorly functioning hepatic allograft and renal failure may be the major determinants of disease occurrence. Overall mortality was 92% (24/26). No difference in mortality could be shown for the patients who received amphotericin B versus liposomal amphotericin B preparations (100% vs. 89%); however, the mean time to death after the initiation of therapy was 20 days in patients who received amphotericin B and 43 days in those who received liposomal amphotericin B preparations.

Background: In September, 1994, an outbreak of severe respiratory disease affected 18 horses, their trainer, and a stablehand in Queensland, Australia. Fourteen horses and one human being died. A novel virus was isolated from those affected and named equine morbillivirus (EMV). We report a case of encephalitis caused by this virus., Findings: A 35-year-old man from Queensland had a brief aseptic meningitic illness in August, 1994, shortly after caring for two horses that died from EMV infection and then assisting at their necropsies. He then suffered severe encephalitis 13 months later, characterised by uncontrolled focal and generalised epileptic activity. Rising titres of neutralising antibodies to EMV in the patient's serum at the time of the second illness suggested an anamnestic response. Distinctive cortical changes were shown on magnetic resonance neuroimaging and histopathological examination of the brain at necropsy. Immunohistochemistry and electronmicroscopy of brain tissue revealed pathology characteristic of the earlier cases of EMV infection. PCR on cerebrospinal fluid taken during the second illness, brain tissue, and serum retained from the original illness resulted in an amplified product identical to that previously described from EMV., Interpretation: The results of serology, PCR, electronmicroscopy, and immunohistochemistry strongly suggest that EMV was the cause of this patient's encephalitis, and that exposure to the virus occurred 3 months before the fatal illness.

In recent years, thalidomide has been used for the treatment of a variety of ulcerative and immunologic conditions. Several previous reports have suggested that thalidomide therapy is beneficial for patients with aphthous ulceration related to human immunodeficiency virus (HIV) infection. We describe the use of thalidomide in 20 HIV-infected patients with oropharyngeal, esophageal, and rectal ulceration. Nineteen patients had a dramatic response to thalidomide therapy, with both subjective and objective abatement in the signs and symptoms of their ulcerative disease. The standard treatment course was 200 mg of thalidomide for 14 days (the drug was administered at night). Four patients required additional courses of treatment because symptoms recurred after thalidomide therapy was stopped. Side effects due to thalidomide included rash (5 patients), peripheral neuropathy (1 patient), and excessive fatigue (1 patient). There did not appear to be any adverse immunologic effects in thalidomide-treated patients. The mechanism of the effect of thalidomide is uncertain, although recent studies have suggested that thalidomide selectively inhibits the production of tumor necrosis factor alpha.

Objective: To present a case of adult botulism acquired in Queensland., Clinical Features: After eating home-preserved asparagus, a 33-year-old man presented with internal and external ophthalmoplegia, bilateral facial nerve palsies, and descending muscle weakness culminating in a sudden respiratory arrest. Electrophysiological testing demonstrated normal nerve conduction velocities and an incremental response of evoked motor potentials on repetitive stimulation, confirming the clinical diagnosis of botulism., Intervention and Outcome: Treatment with trivalent antitoxin, oral treatment with vancomycin and supportive mechanical ventilation for four weeks resulted in complete clinical recovery. Plasmapheresis was also used but its contribution to the patient's improvement is dubious., Conclusions: Although botulism is rare in Australia, clinicians should be aware of the clinical presentation and the rapidity of confirmation of the diagnosis by electrophysiological testing. Patients should be nursed in an intensive care setting. Regular testing of vital capacity should be performed to determine the need for mechanical ventilation.