Aminoglycoside-induced nephrotoxicity

In severe gram-negative infections aminoglycosides generally remain the first-line antibiotic. Their use is limited by the high risk of side effects and, especially, nephrotoxicity. High peak levels are crucial for antibacterial activity, whereas toxic side effects are determined by the more prolonged trough levels. Thus, aminoglycosides should not be given by intramuscular injection because the peak levels achieved are inadequate, whilst long-lasting elevated plasma trough levels result. On administration of a daily single dose intravenously high antibacterial efficacy can be combined with low nephrotoxicity. Besides the dose-dependent bactericidal effect, the post-antibiotic effect of aminoglycosides is of importance. The main site of nephrotoxicity are the proximal tubule epithelial cells. Renal toxicity is usually reversible after discontinuation of drug therapy. Toxic acute renal failure is not uncommon (5-35%) and usually dependent on the underlying disease, preexisting renal function, hydration state, age, cumulative dose, additional medication, previous therapy with aminoglycosides and the choice of the specific aminoglycoside. By implementing a single daily dose regimen in conjunction with adequate hydration, alkalization therapy with bicarbonate, monitoring of plasma trough levels and minimization of the duration of therapy (5 days), development of renal impairment can be prevented in the large majority of patients. Hence, acute renal failure has become an avoidable, and much less frequently observed complication of aminoglycoside therapy due to these measures.     

Inhibition by anion channel blockers of ischemia-evoked release of excitotoxic and other amino acids from rat cerebral cortex

In febrile neutropenic patients with high-grade hematologic malignancies, empirical antimicrobial intervention is mandatory. Large randomized clinical trials have elucidated the benefit of broad-spectrum beta lactam antibiotics used as single drugs or in combination with aminoglycosides in order to provide activity against gram-negative aerobes as well as against streptococci and Staphylococcus aureus. As a result, infection-related mortality was reduced to less than 10% also in patients undergoing intensified remission induction or consolidation therapy for acute leukemias. Distinct subgroups of patients have been identified who need an empirical modification of antimicrobial treatment i.e., patients with catheter-related infections, patients with pulmonary infiltrates, and patients with unexplained fever not responding to first-line antibiotics. In two consecutive, prospectively randomized trials conducted by the Paul Ehrlich Society it was demonstrated that empirical antifungal therapy is beneficial for second-line treatment in patients with persistent unexplained fever and should be part of the first-line approach in patients with lung infiltrates. The empirical addition of glycopeptides, however, should be restricted to patients with catheter-related infections due to coagulase-negative staphylococci.     

Trade-off between segregational stability and metabolic burden: a mathematical model of plasmid ColE1 replication control

Gastrointestinal surgical problems often mimic symptoms and signs of nonsurgical conditions that occur during pregnancy. This mimicry presents a particular challenge to diagnosis because avoiding a delay in treatment is critical to successful management. Some of these conditions, such as acute appendicitis and biliary colic, are common in younger women; however, the anatomic and physiologic changes of pregnancy can alter their usual manner of presentation. Many elective and urgent operations can be performed during pregnancy with minimal risk to the mother and fetus. The mother's condition should always take priority because her proper treatment usually benefits the fetus as well.     

Respiratory syncytial virus infection in childhood

Respiratory syncytial virus is the most frequent cause of respiratory tract infections in infants and is responsible for annual winter epidemics of acute bronchiolitis. Over the last decades medical therapy has remained unchanged and controversial, despite intensive research. Inhaled bronchodilators are often not effective and should be discontinued if no beneficial response can be documented. Steroids and ribavirin are not indicated in previously healthy infants with acute RSV bronchiolitis. There is some evidence, however, that certain risk groups may benefit from their use. With good supportive care the mortality from RSV infection is now low. Postinfectious alterations in lung function are usually transient and reversible. High-risk infants can be protected from severe RSV infections by monthly infusions of RSV immune globulins. This treatment modality has, however, not gained wide acceptance because of the benign nature of the disease and the high costs and side effects of regular immune globulin infusions. An international consensus statement on the treatment of RSV bronchiolitis may help to reduce the wide differences in clinical practice.     

Liposomal amphotericin B. Therapeutic use in the management of fungal infections and visceral leishmaniasis

Incorporation of amphotericin B into small unilamellar liposomes (AmBisome) alters the pharmacokinetic properties of the drug, but allows it to retain significant in vitro and in vivo activity against fungal species, including Candida, Aspergillus and Cryptococcus, and parasites of the genus Leishmania. Used as prophylaxis against fungal infections in immunocompromised patients, liposomal amphotericin B appeared to reduce the incidence of both fungal colonisation and proven fungal infections, but did not affect overall survival. Empirical therapy with liposomal amphotericin B in immunocompromised adults or children with suspected fungal infections was at least as effective as therapy with conventional amphotericin B. In the largest noncomparative studies, liposomal amphotericin B produced mycological eradication in 40 and 83% of patients with proven Candida infections and 41 and 60% with proven Aspergillus infections; however, these studies included relatively few patients. Mycological eradication rates of 67 to 85% in patients with cryptococcal meningitis have been reported. Liposomal amphotericin B is an effective treatment for visceral leishmaniasis in immunocompetent adults and children, including those with severe or drug-resistant disease. The drug also produces good response rates in immunocompromised patients; however, relapse rates in these patients are high. Liposomal amphotericin B is generally well tolerated. Few patients require discontinuation or dose reduction of the drug because of adverse events. The most frequently reported adverse events are hypokalaemia, nephrotoxicity and infusion-related reactions; however, these occur significantly less often after liposomal amphotericin B than after the conventional formulation of the drug. The acquisition cost of liposomal amphotericin B is higher than that of conventional amphotericin B. Cost-effectiveness analysis did not clearly show an economic benefit for empirical liposomal amphotericin B antifungal therapy in adults; however, one model suggested that initial empirical therapy with the liposomal formulation in children may cost less per cure than initial therapy with the conventional formulation. Liposomal amphotericin B appears to be an effective alternative to conventional amphotericin B in the management of immunocompromised patients with proven or suspected fungal infections. Use of the drug is facilitated by its greatly improved tolerability profile compared with conventional amphotericin B. Because of this, liposomal amphotericin should be preferred to conventional amphotericin B in the management of suspected or proven fungal infections in immunocompromised patients with pre-existing renal dysfunction, amphotericin B-induced toxicity or failure to respond to conventional amphotericin B. Liposomal amphotericin B may also be considered for first- or second-line treatment of immunocompetent patients with visceral leishmaniasis.     

Fungal infections of the hand

Fungal infections of the upper extremity are of four main types--cutaneous, subcutaneous, deep, and systemic. Cutaneous infections are caused by organisms capable of metabolizing keratin. They involve the skin and nails but do not penetrate deeper. Most cutaneous infections respond to topical or local therapy. Subcutaneous infections (at least in North America) are most commonly caused by Sporothrix schenckii. Diagnosis is often delayed because associated secondary bacterial colonization may be mistaken for the primary infectious agent. Treatment with systemic antifungal agents is usually successful. Deep infections are usually caused by direct inoculation or, rarely, hematogenous spread of fungi. Systemic fungal infections are of two types--those that occur in normal hosts and those that occur primarily in immunocompromised patients. For both deep and systemic fungal infections, permanent impairment is likely. Diagnosis of deep and systemic fungal infections is often delayed. Treatment of such infections usually requires a combination of surgical excision and systemic antifungal therapy.     

Macrolide antibiotics

The macrolides remain excellent antibiotics for many infections particularly those involving intracellular and/or respiratory pathogens. Erythromycin is still an effective drug for many acute orofacial infections. The newer macrolides, azithromycin and clarithromycin, should also prove efficacious although there is very little current data on their use in orofacial infections. They have the advantages over erythromycin of less GI toxicity, higher tissue concentrations, greater gram-negative spectrum, and once or twice daily dosing for better patient compliance. Macrolide concentration in inflammatory cells and transport to the site of infection is a distinct advantage over other antibiotics. Both erythromycin and clarithromycin are associated with significant drug interactions but azithromycin is devoid of such potential toxicity. Azithromycin is less effective against gram-negative cocci than erythromycin and clarithromycin and attains very high tissue concentrations for a very long time, but whether either of these characteristics is clinically significant for orofacial infections is presently unknown.     

Group A beta-hemolytic streptococcal infections

GABHS is the most common bacterial cause of tonsillopharyngitis, but this organism also produces acute otitis media; pneumonia; skin and soft-tissue infections; cardiovascular, musculoskeletal, and lymphatic infections; bacteremia; and meningitis. Most children and adolescents who develop a sore throat do not have GABHS as the cause; their infection is viral in etiology. Other bacterial pathogens produce sore throat infrequently (e.g., Chlamydia pneumoniae and Mycoplasma pneumoniae), and when they do, other concomitant clinical illness is present. Classic streptococcal tonsillopharyngitis has an acute onset; produces concurrent headache, stomach ache, and dysphagia; and upon examination is characterized by intense tonsillopharyngeal erythema, yellow exudate, and tender/enlarged anterior cervical glands. Unfortunately only about 20% to 30% of patients present with classic disease. Physicians overdiagnose streptococcal tonsillopharyngitis by a wide margin, which almost always leads to unnecessary treatment with antibiotics. Accordingly, use of throat cultures and/or rapid GABHS detection tests in the office is strongly advocated. Their use has been shown to be cost-effective and to reduce antibiotic overprescribing substantially. Penicillin currently is recommended by the American Academy of Pediatrics and American Heart Association as first-line therapy for GABHS infections; erythromycin is recommended for those allergic to penicillin. Virtually all patients improve clinically with penicillin and other antibiotics. However, penicillin treatment failures do occur, especially in tonsillopharyngitis in which 5% to 35% of patients do not experience bacteriologic eradication. Penicillin treatment failures are more common among patients who have been treated recently with the drug. Cephalosporins or azithromycin are preferred following penicillin treatment failures in selected patients as first-line therapy, based on a history of penicillin failures or lack of compliance and for impetigo. GABHS remain exquisitely sensitive to penicillin in vitro. There are several explanations for penicillin treatment failures, but the possibility of copathogen co-colonization in vivo has received the most attention. Treatment duration with penicillin should be 10 days to optimize cure in GABHS infections. A 5-day regimen is possible and approved by the United States Food and Drug Administration for cefpodoxime (a cephalosporin) and azithromycin (a macrolide). Prevention of rheumatic fever is the primary objective for antibiotic therapy of GABHS infections, but a reduction in contagion and faster clinical improvement also can be achieved. Development of streptococcal toxic shock syndrome and necrotizing fasciitis ("flesh-eating bacteria") are rising concerns. The portal of entry for these invasive GABHS strains is far more often skin and soft tissue than the tonsillopharynx.     

AIDS: infections of the retina and choroid

Various viral, bacterial, parasitic and fungal agents have been found to cause infections of retina and choroidea in HIV-infected patients. Usually these infections are opportunistic infections caused by the profound immunodeficiency, which is a result of the decay of lymphocytes by HIV. Before the HIV epidemic only rare cases of cytomegalovirus (CMV) retinitis were known in the literature. Now CMV retinitis has become the most common infection of the eye in AIDS patients. Ocular toxoplasmosis in HIV-infected patients can have a severe clinical appearance without treatment. Spontaneous recovery, as it usually occurs in otherwise healthy patients, does not take place in HIV-infected patients, so that a lifelong maintenance therapy is mandatory. Pneumocystis carinii chorioiditis was unknown before the HIV epidemic. In 1987 Pneumocystis carinii were found in the choroidea and two years later the clinical appearance could be described. Infections of choroidea and retina associated with AIDS may not be seen as isolated diseases. Commonly other organs are infected by the same or another organism. In case of AIDS-associated eye infections other organs should be checked for opportunistic disease. Diagnosis can be difficult. Because most of all intraocular infections associated with AIDS are CMV retinitis, an effective therapy can be initiated in most cases and in the follow-up a diagnosis can finally be made. Serological testing may be inconclusive because of occasional false-negative findings. Treatment often only suppresses the infections and so ongoing maintenance therapy may be necessary, as in the cases of CMV retinitis and Toxoplasma retinochorioiditis. A variety of different diseases, which can be treated by a multitude of different substances with a lot of adverse effects and contraindications, can complicate the therapeutic modalities used for the management of each individual disorder. Additionally HIV-infected patients suffer from at least two or three different diseases and must be treated lifelong with plenty of substances, which often are given with higher doses than usual. Only by cooperation of HIV-experienced doctors of different specialities in hospitals and offices the complex subject of HIV infection can be managed.     

Noninvasive positive pressure ventilation: what is its role in treating acute respiratory failure?

Noninvasive positive pressure ventilation (NIPPV) is a viable option in treating appropriately selected patients with acute respiratory failure. It is often well tolerated, and it avoids endotracheal intubation with its potential complications. Moreover, gas exchange is reportedly improved. Several issues relating to the use of NIPPV are unresolved, however. The optimal interface, best ventilator mode, and patient selection criteria have not been firmly established. Also, studies are needed to compare the efficacy, safety, and cost-effectiveness of NIPPV and standard endotracheal ventilation. Despite these unresolved issues, NIPPV clearly represents an important addition to the techniques available in managing acute respiratory failure. Except in situations in which immediate endotracheal intubation is required, it may become first-line therapy in elderly patients in whom resuscitation status is unsettled.     

Sperm-mediated gene transfer in mice

OBJECTIVE: The purpose of this study was to perform a preliminary test of the hypothesis that patients infected with the human immunodeficiency virus (HIV) have an increased risk for serious odontogenic infections in comparison with HIV-negative patients. STUDY DESIGN: To address the research purpose, we used a case-control study design. A case was a serious odontogenic infection requiring inpatient management. A control was a nonserious odontogenic infection that could be managed on an outpatient basis. The ratio of controls to cases was 2:1. HIV status was determined by record review. RESULTS: The sample was composed of 300 patients. Sixteen patients (5%) were HIV-positive. Overall, 37.5% of the HIV-positive patients had serious infections; this compared with 33% of the HIV-negative patients (odds ratio = 1.21; 95% confidence interval = 0.43-3.44; P = .79). CONCLUSIONS: The results of this pilot study suggest that HIV-positive patients do not have an increased risk for developing serious odontogenic infections.     

The value of ultrafast computed tomography in the investigation of pediatric chest disease

A significant number of open and comparative studies have now addressed the use of teicoplanin in the treatment of documented or presumed infection in patients with haematological and non-haematological malignancy. Available evidence suggests that teicoplanin is an effective agent against such infections, with an excellent safety profile. The use of teicoplanin and vancomycin may be justified as part of the initial management of clinically infected right atrial catheters in patients with malignancy. The first-line use of glycopeptides may also be appropriate in units where streptococcal and methicillin resistant staphylococcal infections are prevalent. However, such a policy should be reviewed regularly. Except in the above situations, a delay in the introduction of either teicoplanin or vancomycin in cancer patients does not appear to produce any excess mortality, but there may be some additional morbidity in terms of fever and malaise. The introduction of glycopeptides as second-line agents is indicated for sensitive, microbiologically documented infections and for patients who have not responded to empirical, first-line therapy. Non-inpatient treatment with teicoplanin is an area of ongoing interest and may be justified on both humanitarian and pharmacoeconomic grounds. The use of glycopeptides in the prophylactic setting remains controversial and should be avoided while the emergence of resistance, particularly in enterococci, should be monitored closely.     

Principles of acute treatment of Horton's disease. Role of high-dose corticosteroid therapy

Corticosteroid therapy, the elective treatment for temporal arteritis, can produce adverse effects on bone in this elderly population which usually occur late after acute high-dose administration. Such adverse effects are exceptional and generally have little impact as long as certain cortisone-sparing principles are followed: duration of acute treatments should be as short as possible; dosage can be tapered off rapidly, cutting the acute dose in half in 4 weeks; to titrate dosage, inflammatory proteins should be monitored (especially CRP because of its rapid kinetics and sometimes another protein with slower kinetics); this appears to be more useful for cortisone-sparing than the classical method based on clinical analysis and sedimentation rate; acute regimens should be accompanied by anticoagulation until figrinogen has returned to normal levels; clinical relapses during treatment are usually benign and can generally be controlled by raising the dose slightly; in case of failure due to an acute flare-up far from corticosteroid administration, it would be interesting to study the cortisone sparing effect of giving a 240 mg i.v. bolus of methylprednisolone followed by low-dose corticosteroids; if the relapse is only expressed in laboratory tests, holding the dose at same plateau for two weeks generally leads to spontaneous normalization. Intravenous bolus methlyprednisolone is well tolerated in this population of elderly patients. There is no recognized indication in the uncomplicated forms of temporal arteritis. The cortisone-sparing effect of this technique may result from the fact that the acute oral dose can be reduced. Complicated forms, particularly with ocular involvement, are recognized indications for bolus administration although the administration modalities have not yet been validated. In patients with overt ocular involvement, repeating emergency high-dose i.v. boluses every 6 to 8 hours warrants evaluation with the objective of recovering visual function.     

Prevalence of diabetes mellitus in odontogenic infections and oral candidiasis: an analysis of neutrophil suppression

The prevalence of diabetes mellitus (DM) in odontogenic infections and oral candidiasis was examined, and influences of DM on the clinical manifestations of the infections and neutrophil functions were investigated. Among 21 severe and 221 mild odontogenic infections, DM was detected in 5 cases in each group. Of 64 cases of symptomatic oral candidiasis, 8 cases were complicated with DM which was detected by blood examination during treatment. During the period of infection, the mean fasting blood sugar level was 16.0 +/- 4.4 and 9.8 +/- 1.2 mmol/l in the DM-complicated odontogenic infections and candidiasis, respectively. All white blood counts, C-reactive protein levels and erythrocyte sedimentation rates were more elevated in DM(+) odontogenic infection cases than in DM(-) ones. In DM(+) candidiasis, hyposalivation (0.79 +/- 0.54 ml/10 min) was observed. The polymorphonuclear leukocytes from diabetic patients, especially those with candidiasis, produced less free oxygen radicals and exhibited reduced phagocytosis and intracellular killing of Candida cells associated with this reduced O2- generation during the infection. These suppressed neutrophil functions increased after treatment but did not reach control levels. These results indicate that DM is a predisposing condition for odontogenic infections and oral candidiasis, that DM-complicated infections become severe because of neutrophil suppression, and that examination of blood sugar level should be essential for patients with oral infections.     

Urinary tract infections in children: why they occur and how to prevent them

Urinary tract infections (UTIs) usually occur as a consequence of colonization of the periurethral area by a virulent organism that subsequently gains access to the bladder. During the first few months of life, uncircumcised male infants are at increased risk for UTIs, but thereafter UTIs predominate in females. An important risk factor for UTIs in girls is antibiotic therapy, which disrupts the normal periurethral flora and fosters the growth of uropathogenic bacteria. Another risk factor is voiding dysfunction. Currently, the most effective intervention for preventing recurrent UTIs in children is the identification and treatment of voiding dysfunction. Imaging evaluation of the urinary tract following a UTI should be individualized, based on the child's clinical presentation and on clinical judgment. Both bladder and upper urinary tract imaging with ultrasonography and a voiding cystourethrogram should be obtained in an infant or child with acute pyelonephritis. Imaging studies may not be required, however, in older children with cystitis who respond promptly to treatment.     

The maxillary sinus and odontogenic cysts

An unilateral maxillary sinusitis is frequently caused by dental pathology. An odontogenic cyst in the maxillary sinus usually lacks accompanying symptoms of infection. In three patients, a 35-year-old man and two women aged 16 and 28, an odontogenic cyst in the maxillary sinus was diagnosed. Consultation of a maxillofacial surgeon is needed because orthopantomographic imaging is diagnostically most helpful. In these patients combined treatment by an ENT surgeon and a maxillofacial surgeon is important.     

Imaging and radiologic management of upper urinary tract infections

Most infections of the upper urinary tract respond promptly to antibiotic therapy and imaging is not necessary. Patients with urinary obstruction, diabetes, or immunocompromise are more likely to develop complicated infection, abscess, or have unusual organisms. Chronic granulomatous processes involving the kidney are usually related to recurrent bacterial infections. Again, stone disease or obstruction is often an underlying problem. In those patients who do not respond promptly to treatment or have a more complicated clinical picture, imaging can assess the severity and extent of disease. CT scan is the study of choice for diagnostic evaluation in these patients and directs percutaneous intervention when appropriate. Placement of drainage catheters is often curative but also may allow the patient to stabilize until surgical treatment is accomplished. One exception is the diagnosis of pyonephrosis, which may be accomplished more easily by ultrasound. In these cases, PCN placement is generally needed and is performed under fluoroscopic guidance. Ultimately, however, definitive surgical intervention often is needed to relieve the underlying obstruction.     

Antibiotic susceptibilities of mycoplasmas and treatment of mycoplasmal infections

Mycoplasmas are the smallest free-living microorganisms, being about 300 nm in diameter. They are bounded by a triple-layered membrane and, unlike conventional bacteria, do not have a rigid cell wall. Hence, they are not susceptible to penicillins and other antibiotics that act on this structure. They are, however, susceptible to a variety of other broad-spectrum antibiotics, most of which only inhibit their multiplication and do not kill them. The tetracyclines have always been in the forefront of antibiotic usage, particularly for genital tract infections, but macrolides are also widely used for respiratory tract infections. Indeed, in comparison with the tetracyclines, erythromycin, the newer macrolides, the ketolides and the newer quinolones have equal or sometimes greater activity. The two latter antibiotic groups also have some cidal activity. The antibiotic susceptibility profiles of several mycoplasmas of human origin are presented, those of Mycoplasma pneumoniae and Mycoplasma genitalium being similar. Apart from the penicillins, mycoplasmas are innately resistant to some other antibiotics, for example the rifampicins. In addition, some may develop resistance, either by gene mutation or by acquisition of a resistance gene, to antibiotics to which they are usually sensitive. Resistance of mycoplasmas to tetracyclines is common and due to acquisition of the tetM gene. The antibiotic susceptibility pattern may be influenced greatly by the source of the mycoplasma; for example, one recovered from a contaminated eukaryotic cell culture that has been subjected to extensive antibiotic treatment may have an antibiotic profile quite different from the same mycoplasmal species that has been recovered directly from a human or animal source. Mycoplasmas may be difficult to eradicate from human or animal hosts or from cell cultures by antibiotic treatment because of resistance to the antibiotic, or because it lacks cidal activity, or because there is invasion of eukaryotic cells by some mycoplasmas. Eradication may be particularly difficult in immunosuppressed or immunodeficient individuals, particularly those who are hypogammaglobulinaemic. The regimes that are most likely to be effective in the treatment of respiratory or genitourinary mycoplasmal infections are presented.     

Besides the liver, what does the virus of hepatitis attack?

I have reviewed some of the clinical and pathogenetic features of the extrahepatic syndromes of viral hepatitis B. They are important for three reasons: First, it is important to be able to reassure the patient with acute viral hepatitis that the troubling symptoms which he frequently fears are due to rheumatoid arthritis, are self-limited, are benign, and will disappear. Second, these syndromes will occur with occult liver disease or with no active liver disease. Frequently, patients will consult a dermatologist for a rash or a rheumatologist for arthritis. They will see a clinical immunologist for a severe vasculitis or a nephrologist for nephritis. They will have no apparent evidence of liver disease, and the etiologic agent will not be discovered unless it is searched for, that is, unless one is aware that an occult infection with the hepatitis B virus can cause these syndromes. The third important reason is that all of these syndromes previously have been thought to be idiopathic; several of them have been rather severe and even fatal. Now, with the advent of potential antiviral therapy for viral hepatitis, it becomes important to make a correct diagnosis because now, for the first time, one can think about antiviral therapy for some of these serious syndromes.     

Ciprofloxacin-associated acute renal failure in patients undergoing high-dose chemotherapy and autologous stem cell rescue

The broad spectrum of activity of ciprofloxacin makes it an ideal drug for the prophylaxis of bacterial infections in patients undergoing high-dose chemotherapy (HDC) with autologous stem cell rescue. We present two cases of ciprofloxacin-associated acute renal failure (ARF) in patients undergoing HDC. Maintaining a high index of suspicion for this complication will allow a prompt diagnosis, with discontinuation of the drug usually resulting in a reversal of renal failure. Renal biopsy usually reveals changes compatible with interstitial nephritis, but is not always possible in these patients due to severe thrombocytopenia following HDC. A brief course of steroid therapy may be beneficial although the role of glucocorticoids is difficult to ascertain in the absence of data regarding its efficiency in this clinical setting.