Does aminoglycoside therapy cause significant acute kidney injury in febrile neutropenia?

Int J Antimicrob Agents. 2011 Jan;37(1):78-81

Authors: Hajkowicz KM, Post JJ

Owing to concern about aminoglycoside-related acute kidney injury (AKI) in therapy for febrile neutropenia, the aim of this study was to ascertain the incidence, severity and persistence of AKI secondary to aminoglycoside use for febrile neutropenia at an adult tertiary referral hospital. All admitted adults with neutropenia in a 27-month period were reviewed. Cases of febrile neutropenia due to chemotherapy who received an aminoglycoside were identified and renal function was assessed up to Day 30 after aminoglycoside administration. Transient renal impairment (TRI) was defined as any temporary rise in serum creatinine of >44?mol/L within 30 days; and persistent, significant renal impairment (PSRI) was defined as an elevation of serum creatinine of >44?mol/L at Day 30, or death from renal failure or need for dialysis. The Acute Kidney Injury Network (AKIN) stage for all episodes was also determined. Amongst 554 episodes of neutropenia, 148 episodes of chemotherapy-related febrile neutropenia with aminoglycoside treatment were identified. PSRI occurred in six episodes [4.1%; 95% confidence interval (CI) 1.9-8.6%] and TRI occurred in seven episodes (4.7%; 95% CI 2.3-9.4%). No PSRI was attributable to aminoglycoside therapy alone (0%; 95% CI 0-3.2%). Severe sepsis was the main cause of PSRI. Aminoglycoside therapy was the main contributing cause of TRI in two episodes (1.4%; 95% CI 0.2-5.3%). In conclusion, PSRI is a rare complication of aminoglycoside therapy for febrile neutropenia at this institution. AKIN stage 1 AKI is a common complication of febrile neutropenia episodes in which aminoglycosides are administered.

PMID: 21163406 [PubMed - in process]

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Vancomycin-associated nephrotoxicity: a critical appraisal of risk with high-dose therapy.

Int J Antimicrob Agents. 2010 Dec 2;

Authors: Wong-Beringer A, Joo J, Tse E, Beringer P

The recent emergence of meticillin-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin has prompted clinicians to prescribe vancomycin therapy targeting high trough concentrations (15-20mg/L). Relevant studies (n=12) analysing the occurrence of nephrotoxicity with high-dose therapy were reviewed. Most studies were retrospective and the temporal relationship between elevated trough levels and development of nephrotoxicity was unclear, precluding a definitive cause-effect analysis. Available data suggest an association between vancomycin trough level and risk of nephrotoxicity as a function of intensity and duration of therapy (>7 days), compounded by concomitant receipt of nephrotoxins, vasopressor therapy and underlying physiological impairment. In separate studies in which a high trough concentration was measured prior to the onset of nephrotoxicity, the frequency of occurrence was 21-28% in patients with concomitant risks compared with 7% in patients without risks. A similar comparison between risk and no-risk groups who attained a standard trough concentration (10-15mg/L) indicates the rates of occurrence as 9-21% vs. 2%. Onset of nephrotoxicity ranged from 4 days to 8 days from the start of therapy. The degree of renal dysfunction was modest, with a reported decrease of 35-45% in creatinine clearance from baseline. Resolution occurred in >70% of patients by the time of discharge. Future studies should detail clearly the temporal relationship between drug exposure and onset of nephrotoxicity, confounding risk factors, extent of injury and time course of recovery, and should also determine the relative risk versus benefit of high-dose vancomycin versus alternative agents.

PMID: 21130609 [PubMed - as supplied by publisher]

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Preparation of liposomal vancomycin and intracellular killing of meticillin-resistant Staphylococcus aureus (MRSA).

Int J Antimicrob Agents. 2010 Dec 2;

Authors: Pumerantz A, Muppidi K, Agnihotri S, Guerra C, Venketaraman V, Wang J, Betageri G

Meticillin-resistant Staphylococcus aureus (MRSA) can persist in alveolar macrophages and contribute to clinical failure of intravenous vancomycin to cure pneumonia. In this study, it was shown that vancomycin in standard solution is unable to kill intracellular MRSA within macrophages. The intracellular viability of MRSA inside macrophages treated with two different formulations of encapsulated liposomal vancomycin prepared using a hydration-dehydration method was then determined. In contrast to the observations with standard vancomycin, treatment with conventional non-pegylated liposomal vancomycin (lacking any surface modification) resulted in a sufficient concentration of antibiotic inside the intracellular compartment of the macrophages to exert a marked bactericidal effect against MRSA. On the other hand, treatment of infected macrophages with surface-pegylated liposomes resulted in no impact on MRSA survival, and this lack of an inhibitory effect may likely reflect delayed phagocytosis owing to the ‘stealth’ effect by pegylation. This study indicates the potential for a novel liposomal delivery system that may improve clinical vancomycin treatment outcomes by targeting intracellular MRSA infection.

PMID: 21130608 [PubMed - as supplied by publisher]

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Confronting multidrug-resistant Acinetobacter baumannii: a review.

Int J Antimicrob Agents. 2010 Dec 2;

Authors: Neonakis IK, Spandidos DA, Petinaki E

Multidrug-resistant Acinetobacter baumannii (MDR-AB) infections are difficult to treat owing to the extremely limited armamentarium. The present review reports all available treatment options against MDR-AB, including single molecules, combination schemes, and alternative modes of antimicrobial administration. Additionally, a group of recently reported peptides with anti-MDR-AB activity is described.

PMID: 21130607 [PubMed - as supplied by publisher]

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Aminoglycoside-containing antibiotic combinations for the treatment of bacterial endocarditis: an evidence-based approach.

Int J Antimicrob Agents. 2010 Dec 2;

Authors: Leibovici L

This review deals with the question of whether the addition of an aminoglycoside to an antibiotic with activity against Gram-positive bacteria is safe and effective for the treatment of endocarditis. Aminoglycosides are more toxic than other drugs used in combination therapy for endocarditis, e.g. rifampicin. In the four randomised controlled trials that included patients with endocarditis and reported on this outcome, the relative risk for nephrotoxicity was 2.22 (95% CI 1.11-4.35). Given the high rates of significant nephrotoxicity we should ask whether sufficient evidence exists for the efficacy of combination therapy for the treatment of endocarditis. No randomised controlled trials have been conducted for most of the patients and pathogens for which combination therapy is recommended. In the few randomised controlled trials that have addressed the question, the addition of an aminoglycoside did not decrease fatality rate, clinical failure, need for operation or bacteriological failure. In clinical practice I would choose any option that is within the accepted boundaries (guidelines, textbooks, common practice) and does not include an aminoglycoside. Large randomised clinical trials are needed to answer this question; they need to include about 600 patients per patient/pathogen group and thus a multicentre, probably international, effort is needed.

PMID: 21130606 [PubMed - as supplied by publisher]

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New perspectives on immunomodulatory therapy for bacteraemia and sepsis.

Int J Antimicrob Agents. 2010 Dec 1;

Authors: Opal SM

Systemic immune dysregulation is generally acknowledged to be the fundamental molecular mechanism that underlies the pathophysiology of severe sepsis and septic shock. In the presence of a systemic infection, microbial pathogens and their soluble mediators induce generalised immune activation and coagulation activation, leading to severe sepsis and septic shock. For decades, immune-based therapies have been devised with the specific intent of inhibiting the pro-inflammatory events that are thought to precipitate the septic process. Despite a clear therapeutic rationale based upon the available experimental evidence, anti-inflammatory therapies targeting the innate or acquired immune response have largely been unsuccessful in clinical trials of sepsis. Compelling evidence now exists that a prolonged state of sepsis-induced immune suppression follows the initial period of stabilisation and resuscitation in many critically ill patients. Sepsis-related immune suppression is evidenced by histological findings of markedly enhanced lymphocytic and monocytic apoptosis, poor response to neoantigens and recall antigens, and increased incidence of infections by opportunistic pathogens. Candidiasis, cytomegalovirus activation and secondary infections by relatively avirulent bacterial pathogens such as Stenotrophomonas and Acinetobacter spp. are commonplace in septic patients during prolonged Intensive Care Unit stays. Immunological tools to detect sepsis-induced immunosuppression are now available, and novel immunoadjuvants are in development to re-establish immune competence in sepsis patients. The intelligent use of immunomodulatory agents in sepsis will necessitate a personalised medicine approach to treat each patient at the appropriate time and with the optimal therapy.

PMID: 21129935 [PubMed - as supplied by publisher]

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Selection of the vascular catheter: can it minimise the risk of infection?

Int J Antimicrob Agents. 2010 Dec 2;

Authors: Bouza E, Guembe M, Muñoz P

Data regarding the prevention of catheter-related bloodstream infection (CRBSI) by making the correct decisions about when to place a central line, the appropriate selection of catheter composition and the size and number of lumens, a suitable choice of insertion site and the technique used are not well reported in recent medical literature. There is no clear evidence that the composition of the catheters presently on the market makes a significant difference to the risk of infection. Several prospective studies suggest that femoral vein location represents the highest risk of infection, followed by jugular vein and subclavian vein positioning, however, most articles do not correct for basic confounding variables. Several papers have reported that arterial catheters have a similar risk of infection as central venous catheters (CVCs). The slight increase in infection risk when using multi-lumen catheters is probably offset by their improved convenience. Current evidence does not support routine tunnelling of short-term catheters until its efficacy is evaluated at different placement sites, using specific catheters and situations and in relation to other preventive interventions. Cuffing is usually applied only to long-term tunnelled catheters. The available evidence suggests that chlorhexidine-silver sulfadiazine, minocycline-rifampicin CVCs and antifungal-coated catheters are useful in decreasing the incidence of CRBSI when other measures are not effective.

PMID: 21130605 [PubMed - as supplied by publisher]

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Conventional and molecular techniques for the early diagnosis of bacteraemia.

Int J Antimicrob Agents. 2010 Dec 1;

Authors: Paolucci M, Landini MP, Sambri V

Bloodstream infections account for 30-40% of all cases of severe sepsis and septic shock, and are major causes of morbidity and mortality. Diagnosis of bloodstream infections must be performed promptly so that adequate antimicrobial therapy can be started and patient outcome improved. An ideal diagnostic technology would identify the infecting organism(s) and their determinants of antibiotic resistance, in a timely manner, so that appropriate pathogen-driven therapy could begin promptly. Unfortunately, despite the essential information it provides, blood culture, the gold standard, largely fails in this purpose because time is lost waiting for bacterial or fungal growth. Several efforts have been made to optimise the performance of blood culture, such as the development of technologies to obtain rapid detection of microorganism(s) directly in blood samples or in a positive blood culture. The ideal molecular method would analyse a patient’s blood sample and provide all the information needed to immediately direct optimal antimicrobial therapy for bacterial or fungal infections. Furthermore, it would provide data to assess the effectiveness of the therapy by measuring the clearance of microbial nucleic acids from the blood over time. None of the currently available molecular methods is sufficiently rapid, accurate or informative to achieve this. This review examines the principal advantages and limitations of some traditional and molecular methods commercially available to help the microbiologist and the clinician in the management of bloodstream infections.

PMID: 21129933 [PubMed - as supplied by publisher]

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Catheter-related bloodstream infections: catheter management according to pathogen.

Int J Antimicrob Agents. 2010 Dec 1;

Authors: Leonidou L, Gogos CA

Central-line access is an essential part of modern healthcare practice; however, catheter-related bloodstream infection is a major problem that causes substantial morbidity and mortality, and excess length of stay and cost. The risk of infection depends on the type of device, the site of insertion, the underlying conditions and the appropriate prevention measures taken during catheter insertion. Management of catheter-related bloodstream infection involves deciding on catheter removal, antimicrobial catheter lock solution and the type and duration of systemic antimicrobial therapy. Systemic antimicrobial use is essential but, although generally effective in controlling sepsis, it often fails to sterilise the line, increasing the incidence of complications or recurrence. The decision regarding whether the catheter should be removed or retained is therefore crucial. One of the major factors to be considered is the type of organism involved in the catheter-related infection. This review outlines the epidemiology, pathogenesis, diagnosis, microbiology and management of catheter-related infections, mainly focusing on the management of the intravascular device according to the pathogen.

PMID: 21129929 [PubMed - as supplied by publisher]

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Biomarkers as a guide for antimicrobial therapy.

Int J Antimicrob Agents. 2010 Dec 1;

Authors: Reinhart K, Hartog CS

The use of biomarkers might help to avoid antibiotic misuse and overuse and to curb the rising incidence of microbial resistance. Amongst >100 biomarkers proposed for use as infection/sepsis markers, procalcitonin is the most frequently evaluated. It has been tested in 11 randomised controlled trials with more than 3500 patients and resulted in a considerable 35-70% reduction in antibiotic use without an apparent negative impact on patient outcome. Testing was carried out in hospital, Intensive Care Unit, emergency and primary care settings; most of the patients had lower respiratory tract infections and only smaller studies exist in surgical patients with infectious complications, immunocompromised patients and patients with sepsis. There are, however, concerns – trials designed to show non-inferiority of procalcitonin to standard management allowed rather large differences for mortality rates, in the range of 7.5-10%, thus clinically relevant excess mortality by procalcitonin-guided antibiotic therapy cannot be completely ruled out. Marker panels derived from transcriptomic or proteomic profiling hold promise in overcoming the limitations of procalcitonin for differentiating non-infectious from infection-associated inflammation. However, the utility of these novel diagnostic tools in the clinical setting remains to be proven.

PMID: 21129930 [PubMed - as supplied by publisher]

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Management of Gram-negative and fungal endocarditis.

Int J Antimicrob Agents. 2010 Dec 1;

Authors: Durante-Mangoni E, Tripodi MF, Albisinni R, Utili R

Infective endocarditis is infrequently caused by Gram-negative bacteria or fungi. Gram-negative organisms are responsible for <4% of cases, whilst fungal endocarditis accounts for <1.5% of culture-positive cases worldwide. Endocarditis due to Gram-negative organisms or fungi is a rare but severe disease. It often has a nosocomial origin, is caused by virulent and often resistant organisms and presents a high rate of complications and high mortality. In this article we present the most recent literature data and address the current management of Gram-negative and fungal infective endocarditis. We also discuss the major challenges of antimicrobial treatment and discuss some issues related to surgical decision-making in difficult-to-manage cases. We finally present our centre's experience with Gram-negative infective endocarditis, with a special focus on the demanding issues that the management of these complex and severely ill patients raise.

PMID: 21129927 [PubMed - as supplied by publisher]

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Pharmacokinetic/pharmacodynamic (PK/PD) considerations in the management of Gram-positive bacteraemia.

Int J Antimicrob Agents. 2010 Dec 1;

Authors: Scaglione F

Bloodstream infections are amongst the most serious infections of hospitalised patients and are associated with high mortality, especially amongst those with severe sepsis and septic shock. A range of organ dysfunctions, together with drug interactions and other therapeutic interventions (e.g. haemodynamically active drugs and continuous renal replacement therapies) may have a strong impact on antimicrobial drug pharmacokinetics in critically ill patients. Intrinsic pharmacokinetic (PK) and pharmacodynamic (PD) properties are the major determinants of the in vivo efficacy of antimicrobial agents. Knowledge of PK/PD parameters is essential in facilitating the translation of microbiological activity into clinical situations and ensuring a successful outcome. This review analyses the typical patterns of antimicrobial activity of classes of agent commonly utilised against Gram-positive pathogens in hospital settings, and their corresponding PK/PD parameters, focusing on the PK/PD dosing approach.

PMID: 21129926 [PubMed - as supplied by publisher]

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New antifungal agents for the treatment of candidaemia.

Int J Antimicrob Agents. 2010 Dec 1;

Authors: Muñoz P, Guinea J, Rojas L, Bouza E

Suspected or proven invasive candidiasis is an important indication for antifungal drugs and a leading cause of death. Prompt initiation of effective therapy has a marked effect on survival, but the indiscriminate application of different risk-factor-based prediction models is massively increasing the number of patients treated unnecessarily. Fluconazole resistance levels are <5% in most European centres and the use of low doses is still common. Candins are fungicidal, have efficacy against device-related infections, have few interactions and are well tolerated. Accordingly, the use of newer, more expensive drugs must be carefully balanced in each case. Campaigns directed towards stewardship in antifungal drug use must take into consideration the choice of the drug, the dose and route of administration, and the length of therapy. Early microbiological information and medical education may contribute to better use of these important drugs. We review the characteristics of the new antifungals used for the treatment of candidaemia.

PMID: 21129925 [PubMed - as supplied by publisher]

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Multidrug-resistant Gram-negative bacteria: how to treat and for how long.

Int J Antimicrob Agents. 2010 Dec 1;

Authors: Giamarellou H

The emergence of multidrug-resistant (MDR) Gram-negative bacilli creates a big problem for the treatment of nosocomial infections. As the pharmaceutical pipeline wanes, the only therapeutic options are two revived antibacterials (colistin and fosfomycin), a newer one (tigecycline) and an early-phase neoglycoside (ACHN-490). Polymyxins, known since 1947, are mostly represented by polymyxin E (colistin), which has recently gained a principal position in the management of the most difficult-to-treat MDR Gram-negative pathogens -Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. However, despite promising therapeutic results in 59-75% of cases, the reported studies share common drawbacks, i.e. the absence of a control group, their retrospective nature, variable dosing and duration of therapy, simultaneous administration of other antibiotics in >70% and a lack of resistance development monitoring. The necessity for well-designed prospective clinical trials is therefore urgent. Fosfomycin is active in vitro against MDR Enterobacteriaceae, including a high proportion of P. aeruginosa; however, clinical experience is lacking with the parenteral formulation in MDR infection and on the best combinations to prevent resistance development. Tigecycline, which is active against MDR Enterobacteriaceae and A. baumannii, has shown satisfactory clinical experience. However, dosage adjustment is required because of low blood levels. ACHN-490, which has promising in vitro activity against MDR K. pneumoniae, is still in early phase II trials in urinary tract infections. Meanwhile, the strict application of infection control measures is the cornerstone of nosocomial infection prevention, and antibiotic stewardship, exemplified by appropriate duration of therapy and de-escalation policies, should not be overlooked.

PMID: 21129924 [PubMed - as supplied by publisher]

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Emerging carbapenemases: a global perspective.

Int J Antimicrob Agents. 2010 Nov;36S3:S8-S14

Authors: Walsh TR

The celestial rise in antibiotic resistance among Gram-negative bacteria has challenged both the scientific and pharmaceutical sectors. The hallmark of this general increase is the unbridled dissemination of carbapenem resistance genes, namely KPC, OXA and metallo-?-lactamase variants. In particular, the media attention given to the NDM-1 metallo-?-lactamase has highlighted the global consequences of human behaviour on spreading antibiotic resistance.

PMID: 21129630 [PubMed - as supplied by publisher]

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