Patrick N. A. Harris

The emerging threat of multidrug-resistant Gram-negative bacteria in urology

Antibiotic resistance in Gram-negative uropathogens is a major global concern. Worldwide, the prevalence of Enterobacteriaceae that produce extended-spectrum β-lactamase or carbapenemase enzymes continues to increase at alarming rates. Likewise, resistance to other antimicrobial agents including aminoglycosides, sulphonamides and fluoroquinolones is also escalating rapidly. Bacterial resistance has major implications for urological practice, particularly in relation to catheter-associated urinary tract infections (UTIs) and infectious complications following transrectal-ultrasonography-guided biopsy of the prostate or urological surgery. Although some new drugs with activity against Gram-negative bacteria with highly resistant phenotypes will become available in the near future, the existence of a single agent with activity against the great diversity of resistance is unlikely. Responding to the challenges of Gram-negative resistance will require a multifaceted approach including considered use of current antimicrobial agents, improved diagnostics (including the rapid detection of resistance) and surveillance, better adherence to basic measures of infection prevention, development of new antibiotics and research into non-antibiotic treatment and preventive strategies.

β-lactam and β-lactamase inhibitor combinations in the treatment of extended-spectrum β-lactamase producing Enterobacteriaceae: time for a reappraisal in the era of few antibiotic options?

The spread of extended-spectrum β-lactamase (ESBL) genes in Enterobacteriaceae such as Escherichia coli or Klebsiella spp is a major challenge to modern medical practice. Carbapenems are the treatment of choice for serious infections caused by ESBL producers; however, carbapenem resistance has increased globally. ESBL producers might be susceptible to β-lactam-β-lactamase inhibitor (BLBLI) combination antibiotics such piperacillin-tazobactam or amoxicillin-clavulanate. These drugs are frequently avoided in serious infections caused by ESBL producers because of the inoculum effect in-vitro (especially for piperacillin-tazobactam), animal data suggesting inferior efficacy when compared with carbapenems, concerns about pharmacokinetic-pharmacodynamic drug target attainment with standard doses, and poor outcomes shown in some observational studies. Prospective cohort data and a meta-analysis suggest that BLBLIs are non-inferior to carbapenems in the treatment of bloodstream infections caused by ESBL producers. We examine why BLBLIs are perceived as inferior in the treatment of infection with ESBL producers, and discuss data that suggest these concerns might not be strongly supported by clinical evidence.

Colistin resistance: a major breach in our last line of defence

In hospital practice, clinicians have been buoyed by the recent development of new antibiotics active against multidrug resistant Gram-negative bacilli. However, recently approved antibiotics like ceftazidime-avibactam or ceftolozane-tazobactam do not provide activity against all Gram-negative bacilli, with notable gaps in their coverage, including the notorious New Delhi metallo-β-lactamase 1-producing organisms and many strains of carbapenem resistant Acinetobacter baumannii. For this reason, the polymyxins (colistin and polymyxin B) remain the last line of defence against many Gram-negative bacilli. Colistin-resistant and even pan-drug-resistant Gram-negative bacilli have already been reported. Typically, colistin resistance is due to chromosomally mediated modulation of two-component regulatory systems leading to modifi cation of lipid A, resulting in reduced affi nity for the polymyxins. Clones of colistin-resistant organisms have spread in some hospitals, but have not seriously aff ected the use of polymyxins. These resistance genes are generally not transmissible between bacteria and so have not disseminated widely. In The Lancet Infectious Diseases, Yi-Yun Liu and colleagues describe plasmid-mediated colistin resistance for the fi rst time. The implications of this fi nding are enormous. The investigators reported that the plasmid bearing the colistin resistance mechanism was readily passed between Escherichia coli strains, including strains with known epidemic potential, such as ST131. Furthermore, the plasmid could be passed to Klebsiella pneumoniae and Pseudomonas aeruginosa strains. The plasmids were quite stable, implying that even in the absence of selection pressure by colistin, the plasmids would be maintained. It therefore seems inevitable that plasmid-mediated transfer of colistin resistance will seriously limit the lifespan of the polymyxins as the backbone of regimens against multiply resistant Gramnegative bacilli. How did this come about and is there anything we can do to limit the rate of spread of colistin resistance? Colistin has been used in agriculture since the 1950s. Indeed, in 2010 it was the fi fth most sold group of antimicrobials used in agriculture in Europe. Historical data on its use in agriculture in Asia are limited. However, it is clear that its current use is substantial. Liu and colleagues present data from China showing that E coli from pigs at slaughter and from retail chicken and pork have high rates of plasmid-mediated colistin resistance. The same mechanism was found in E coli and K pneumoniae isolates from Chinese patients in hospital. These fi ndings suggest that the links between agricultural use of colistin, colistin resistance in slaughtered animals, colistin resistance in food, and colistin resistance in human beings are now complete. One of the few solutions to uncoupling these connections is limitation or cessation of colistin use in agriculture. This will require substantial political will and we call upon Chinese leaders to act rapidly and decisively. Failure to do so will create a public health problem of major dimensions. Is plasmid-mediated colistin resistance a purely Chinese phenomenon? A recent report has described colistin resistance in E coli from a pig and a person in Laos. The pig and human colistin-resistant E coli isolates were indistinguishable by pulsed fi eld gel electrophoresis suggesting animal to human transmission. No known chromosomally encoded colistin resistance mechanisms were identifi ed in these isolates, raising the question as to whether they could also have unrecognised plasmidmediated colistin resistance mechanisms. As noted by Liu and colleagues, E coli bearing genes very similar to those that they describe causing plasmid-mediated colistin resistance have recently been detected in Malaysia. Given that substantial use of colistin in agriculture is highly likely throughout southeast Asia, it would hardly be surprising that plasmid-mediated colistin resistance will soon be detected in this region. At least one manufacturer of colistin for agriculture is based in India, raising the spectre of untreatable NDM-producing, colistin-resistant strains occurring in the Indian subcontinent. In 2012, WHO reclassifi ed colistin as critically important for human medicine. This classifi cation remains true despite the ongoing development of new antibiotics against multiply resistant Gram negative bacilli. There have been previous calls for curtailing the use of polymyxins in agriculture. We must all reiterate these appeals and take them to the highest levels of government or face increasing numbers of patients for whom we will need to say, “Sorry, there is nothing I can do to cure your infection”. Published Online November 18, 2015 http://dx.doi.org/10.1016/ S1473-3099(15)00463-6

Empiric piperacillin-tazobactam versus carbapenems in the treatment of bacteraemia due to extended-spectrum beta-lactamase-producing enterobacteriaceae

Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are a common cause of bacteraemia in endemic countries and may be associated with high mortality; carbapenems are considered the drug of choice. Limited data suggest piperacillin-tazobactam could be equally effective. We aimed to compare 30-day mortality of patients treated empirically with piperacillin-tazobactam versus a carbapenem in a multi-centre retrospective cohort study in Singapore. Only patients with active empiric monotherapy with piperacillin-tazobactam or a carbapenem were included. A propensity score for empiric carbapenem therapy was derived and an adjusted multivariate analysis of mortality was conducted. A total of 394 patients had ESBL-Escherichia.coli and ESBL-Klebsiella pneumoniae bacteraemia of which 23.1% were community acquired cases. One hundred and fifty-one received initial active monotherapy comprising piperacillin-tazobactam (n = 94) or a carbapenem (n = 57). Patients who received carbapenems were less likely to have health-care associated risk factors and have an unknown source of bacteraemia, but were more likely to have a urinary source. Thirty-day mortality was comparable between those who received empiric piperacillin-tazobactam and a carbapenem (29 [30.9%] vs. 17 [29.8%]), P = 0.89). Those who received empiric piperacillin-tazobactam had a lower 30-day acquisition of multi-drug resistant and fungal infections (7 [7.4%] vs. 14 [24.6%]), P<0.01). After adjusting for confounders, use of empiric piperacillin-tazobactam was not associated with increased 30-day mortality (OR 1.00, 95% CI; 0.45–2.17). Empiric piperacillin-tazobactam was not associated with increased 30-day mortality and may result in fewer multi-drug resistant and fungal infections when compared with a carbapenem.

Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial

BackgroundGram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections.Methods/DesignThe study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection.Trial registrationThe MERINO trial is registered under the Australian New Zealand Clinical Trials Register (ANZCTR), reference number: ACTRN12613000532707 (registered 13 May 2013) and the US National Institute of Health ClinicalTrials.gov register, reference number: NCT02176122 (registered 24 June 2014).

Comparable outcomes for β-lactam/β-lactamase inhibitor combinations and carbapenems in definitive treatment of bloodstream infections caused by cefotaxime-resistant Escherichia coli or Klebsiella pneumoniae

BackgroundExtended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae are often susceptible in vitro to β-lactam/β-lactamase inhibitor (BLBLI) combination antibiotics, but their use has been limited by concerns of clinical inefficacy. We aimed to compare outcomes between patients treated with BLBLIs and carbapenems for bloodstream infection (BSI) caused by cefotaxime non-susceptible (likely ESBL- or AmpC β-lactamase-producing) Escherichia coli and Klebsiella pneumoniae.MethodsAll adult patients with a BSI caused by cefotaxime non-susceptible E. coli or K. pneumoniae were included from May 2012-May 2013. We compared outcomes between patients who had definitive monotherapy with a carbapenem to those who had definitive monotherapy with a BLBLI.ResultsThere were 92 BSIs that fulfilled the microbiological inclusion criteria. 79 (85.9%) were caused by E. coli and 13 (14.1%) by K. pneumoniae. Four out of 23 (17.4%) patients treated with carbapenem monotherapy and 2 out of 24 (8.3%) patients treated with BLBLI monotherapy died (adjusted HR for survival 0.91, 95% CI 0.13 to 6.28; p = 0.92). The time to resolution of systemic inflammatory response syndrome (SIRS) criteria did not vary between the treatment groups (adjusted HR 0.91, 95% CI 0.32 to 2.59; p = 0.97). The length of hospital admission post-positive blood culture was slightly longer in patients treated with BLBLIs (median duration 15 vs. 11 days), although this was not significant (adjusted HR 0.62; 95% CI 0.27 to 1.42; p = 0.26). There were no significant differences in subsequent isolation of carbapenem resistant organisms (4.3% vs. 4.2%, p = 1.0), C. difficile infection (13.0% vs. 8.3%, p = 0.67) or relapsed BSI (0% vs. 2%, p = 0.23).ConclusionsBLBLIs appear to have a similar efficacy to carbapenems in the treatment of cefotaxime-resistant E. coli and K. pneumoniae bloodstream infections. Directed therapy with a BLBLI, when susceptibility is proven, may represent an appropriate carbapenem-sparing option.

Clinical features that affect indirect-hemagglutination-assay responses to Burkholderia pseudomallei.

ABSTRACT Melioidosis, a disease endemic to northern Australia and Southeast Asia, is caused by the soil saprophyte Burkholderia pseudomallei. The indirect hemagglutination assay (IHA) is the most frequently used serological test to help confirm exposure to the causative organism. However, despite culture-confirmed disease, patients often have a negative IHA result at presentation and occasionally fail to seroconvert in serial testing. We retrospectively examined results for all patients with culture-confirmed melioidosis from our laboratory between January 1996 and August 2008. One hundred forty patients had a recorded IHA titer at presentation, 71 of which were positive at a titer of 1:40 or greater. Fifty-three patients went on to have subsequent IHAs 1 month or more after presentation. The relationships between IHA responses and clinical features were examined. The presence of bacteremia was significantly associated with a negative IHA at presentation. The coexistence of diabetes was associated with the presence of a positive IHA at presentation. In total, 14 patients (26%) demonstrated persistently negative IHA titers upon serial testing. No clinical factors were found to be significantly associated with this phenomenon. Supplementary testing using melioidosis-specific immunoglobulin G by EIA demonstrated different effects, with only Aboriginal or Torres Straits Islander ethnicity being significantly associated with a positive EIA at presentation. Reasons for these findings are examined, and directions for future research are discussed.

Bacteraemia caused by beta-haemolytic streptococci in North Queensland: changing trends over a 14-year period

Group A streptococci (GAS) are usually the predominant species in cases of bacteraemia caused by β haemolytic streptococci (BHS). An increasing worldwide incidence of invasive disease from non-group A BHS has been reported. Little is known about the changing trends in invasive disease caused by BHS in Australia. North Queensland has a relatively large indigenous population, who experience significantly higher rates of group A-related disease than the non-indigenous population. This prospective study examined changing trends of disease from large colony BHS that group with A, B, C and G antisera over a 14-year period at the single large tertiary referral hospital in the area. We identified 392 bacteraemic episodes caused by BHS. GAS were most commonly isolated (49%), with adjusted rates remaining stable over the period. There was a significant increase in the incidence of non-neonatal bacteraemia caused by group B streptococci (GBS) over the study period (r = 0.58; p 0.030), largely driven by infection in older, non-indigenous women. Rates of bacteraemia caused by group C streptococci also experienced a modest, but significant, increase over time (r = 0.67; p 0.009). GAS, which had no predominant emm type, were seen most commonly in indigenous subjects (52%). Mortality rates ranged from 3.2% (group G) to 10.3% (group C), with a rate of 7.9% associated with group A disease. The marked rise in GBS disease has been noted worldwide, but the relatively low incidence in indigenous Australian patients has not been described before, despite the burden of well-recognized risk factors for GBS disease within this group.

Prostate Biopsy-related Infection: A Systematic Review of Risk Factors, Prevention Strategies, and Management Approaches

A systematic review to identify risk factors for prostate biopsy-related infection, preventative strategies, and optimal management of infectious complications was conducted. Significant risk factors for postbiopsy infection include urogenital infection, antibiotic use, international travel, hospital exposure, bacteriuria, previous transrectal biopsy, and resistance of fecal flora to antibiotic prophylaxis (especially fluoroquinolones). Patients at risk may benefit from an adjusted biopsy protocol comprising transrectal biopsy under targeted prophylaxis, and/or the use of rectal disinfection techniques or using a transperineal approach. Management of biopsy-related infection should be based on individual risk and local resistance profiles with input from multiple specialties.

Atypical hand, foot, and mouth disease: eczema coxsackium can also occur in adults

We read with interest the case report by Henry Feder and colleagues describing an atypical vesiculobullous eruption in an infant with Coxsackievirus A6 and hand, foot, and mouth disease. Here, we report a case of an adult patient with preexisting eczema who presented with hand, foot, and mouth disease and atypical lesions distributed in areas of eczematous skin. A 25-year-old Malaysian woman with a history of mild asthma and eczema affecting her groin, lower abdomen, buttocks, and thighs presented with fever, sore throat, and rhinorrhoea for 1 day. She developed painful, non-pruritic vesicular lesions on her palms, and blisters and vesicles on the eczematous areas on her lower abdomen, groins, thighs, and buttocks. Subsequently, the soles of her feet and face were also involved (fi gure). She reported close contact with a niece and a nephew 1 week before the onset of her symptoms, both of whom were diagnosed with hand, foot, and mouth disease. Enterovirus was identified with RT-PCR from swabs of her throat, from faeces, and from the lesions on the right thigh. Limited sequencing of the VP1 coding region confi rmed the virus as Coxsackievirus A6. All samples were negative for varicella zoster virus and herpes simplex virus 1 and 2 by PCR. Her symptoms improved and she was discharged from hospital by the third day of admission without complications. Herpes simplex virus is known to cause superinfection of pre-existing skin disease — termed ec zema herpeticum. This phenomenon has been occasionally described in association with Coxsackievirus in children and has been labelled eczema coxsackium. Other atypical dermatological manifestations of Coxsackievirus A6 have been described, including a 2-yearold child with lesions mimicking disseminated herpes zoster. Hand, foot, and mouth disease is common in children and has resulted in large outbreaks in several parts of the world. The disease can also occur in adults, but to our knowledge only one previous report exists of eczema coxsackium, in an adult with HIV infection. With the emergence of the previously obscure Coxsackievirus A6 as a notable cause of hand, foot, and mouth disease, this virus should be considered in patients with atypical cutaneous lesions in addition to typical symptoms of hand, foot, and mouth disease — especially those with a background presence of eczema. As shown by Feder and colleagues, Coxsackievirus A6 seems to be associated with atypical skin presentations and a benign outcome. Our case also shows that this phenomenon is not limited to infants or young children.