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INTENSIVE CARE

Nosocomial infections in the intensive care unit

Learning objectives After reading this article, you should be able to: C list the common pathogens that cause infections in the ICU C discuss strategies used to prevent antimicrobial resistance in the ICU C name the steps in the WHO ‘5 moments of hand hygiene’ campaign C discuss the risk factors for VAP, CLASBI and UTI in the ICU C list the components of the care bundles for VAP and CLASBI

Jason A Trubiano Alexander A Padiglione

Abstract Nosocomial infection in the intensive care unit (ICU) is associated with increased mortality, morbidity and length of stay. It is defined as infection that begins 48 hours after admission to hospital. The most common types are ventilator-associated pneumonia (VAP), central line-associated bloodstream infection (CLABSI), urinary catheter-related infection and surgical site infection. The common pathogens include Staphylococcus aureus, Pseudomonas aeruginosa, Candida spp., Escherichia coli and Klebsiella spp. Antimicrobial resistance is generally increasing, and has emerged from selective pressure from antibiotic use and transmission via health workers. Prevention of infection can be achieved through good antimicrobial use and infection control, including hand hygiene. Grouped, easy to follow best practice activities called ‘care bundles’ have been developed to prevent VAP and CLABSI. Microbiological cultures are central to a rapid and accurate diagnosis, which improves outcomes and reduces resistance. The principles of treatment include early antimicrobial therapy (after appropriate specimens are taken) targeted to the local microbes, then de-escalation according to culture and susceptibility results. This article summarizes the pathogenesis, risk factors, microbiology, diagnosis, prevention and treatment of VAP, CLASI and nosocomial UTI in the adult ICU.

related infection and surgical site infection. Other types of nosocomial infection are also important, such as those in immunocompromised hosts and neonates, but beyond the scope of this article.

Microbiology and resistance Colonization of critically ill patients with nosocomial organisms usually occurs after 48e72 hours of admission; the most important pathogens are displayed in Table 1. The spectrum of nosocomial microorganisms is different from those in the community, with higher rates of resistant organisms. Antimicrobial resistance emerges in ICU because of:  evolution of resistance in existing bacteria, through selective pressure from antibiotic use  nosocomial transmission especially through contact with healthcare workers or via procedures. Increasing incidence of resistant bacteria in ICUs is associated with poorer outcomes. These include: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) and multi-drug resistant (MDR) Gram negatives. There is a longer time to receipt of effective therapy; and the agents used for treatment often have inferior efficacy, poor pharmacokinetics/pharmacodynamics or increased toxicity (e.g. vancomycin, linezolid, daptomycin, amikacin, colistin). More recently, studies describe success in controlling some types of resistant organisms (most notably reductions in MRSA, particularly attributed to better hand hygiene practices), but little impact on MDR Gram negative and fungal resistance. Inappropriate broad-spectrum antibiotic therapy increases the incidence of MDR organisms, and is also an independent risk factor for mortality.1 The emergence of resistant organisms tends to add to the total burden of infections, rather than substituting for the more sensitive organisms previously present. For example, as MRSA becomes endemic in a unit, the total number of staphylococcal infections increases; when MRSA is eliminated, the total number of staphylococcal infections reduces.

Keywords Catheter related infections; cross infection; intensive care; nosocomial infections; urinary tract infections; ventilator-associated pneumonia Royal College of Anaesthetists CPD Matrix: 2C00, 2C03

Introduction Nosocomial infection (defined as onset more than 48 hours after hospital admission) in the intensive care unit (ICU) is associated with increased mortality, morbidity and length of stay. Prevalence rates of infection acquired in ICUs vary from 9% to 37% when assessed in Europe and the USA. Timely diagnosis, appropriate management and prevention improve patient outcomes and reduce antimicrobial resistance. The most common types are ventilator-associated pneumonia (VAP), central lineassociated bloodstream infection (CLABSI), urinary catheter-

Jason A Trubiano BBiomedSci MBBS(Hons) FRACP is an Infectious Diseases Physician at The Alfred Hospital, Austin Health and Peter MacCallum Cancer Centre, Melbourne, Australia. Conflicts of interest: none declared.

Diagnosis of nosocomial infection Rapid and accurate diagnosis of nosocomial infection both improves patient outcomes and decreases selection pressure for resistance. It ‘streamlines’ patients into the most effective treatment, allowing rapid cessation of unnecessary antibiotics and minimizing unnecessary side effects. Correct timing is vital with

Alexander A Padiglione MBBS(Hons) FRACP PhD is an Infectious Diseases Physician at The Alfred Hospital and Monash Medical Centre, Melbourne, Australia. Conflicts of interest: none declared.

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stewardship services can reduce broad-spectrum antibiotic usage, adverse antimicrobial events and MDR bacteria resistance rates, whilst improving antibiotic treatment in life-threatening bacterial infections, improve antibiotic dosing and shorten antibiotic durations without effecting patient outcome.2 Elements of good antibiotic use in ICU are given in Box 2. The role of combination antibiotics in preventing resistance is controversial. It is usually necessary to use combination empiric therapy for sepsis to ensure adequate coverage of potential pathogens, but de-escalating to narrower cover once cultures results are known or the patient improves. Even pseudomonal infections do not require combination therapy once sensitivities are known, though some multidrug resistant organisms may have few alternatives to combination therapy. ‘Cycling’ antibiotic use is poorly studied, and not recommended. Infection control minimizes cross transmission and prevents colonizing bacteria from causing infection. One of the key elements is hand hygiene, which prevents cross transmission of pathogens between patients by the hands of healthcare workers. It is estimated that over 30% of healthcare associated infections are preventable by hand hygiene. Multiple studies have shown a reduction in healthcare-associated infection rates, specifically reductions in MRSA and even elimination in some centres. The WHO has recommended ‘5 moments for hand hygiene’ in healthcare settings, both resource rich and poor.3 Alcohol-based hand-rubs should be used before touching a patient, before a procedure, after body fluid exposure, after touching a patient and after touching patient surroundings. Other aspects of infection control include surveillance for, and isolation of, patients with multi-resistant organisms. Alternative infection control measures such as chlorhexidine bathing and washcloths have in some cohorts demonstrated reductions in MDR bacteria colonization/ infection and overall bacteraemia rates.4,5 Recent years have seen the widespread promotion of infection control ‘care bundles’. These are groupings of ‘best practices’ that when applied together appear to result in greater improvement in outcomes, based on the philosophy that the ‘total may be greater than the sum of the parts’. They are simple, logical (mostly, but evidence base can be variable) and easily evaluable (compliance

Common ICU nosocomial pathogens (EPIC II study) Staphylococcus aureus 20% Includes MRSAa (10%) Pseudomonas aeruginosa 20% Candida 17% Escherichia coli 16% Klebsiella species 13% Enterococcus 11% Includes VREb (4%) Staphylococcus epidermidis 10% Acinetobacter 9% Enterobacter 7% Important Gram negative resistance mechanisms include: Extended-spectrum beta-lactamases (ESBLs): plasmid encoded genes that confer resistance to penicillins and extended-spectrum cephalosporins. Carbapenems are the treatment of choice. AmpC-type beta-lactamases: Chromosomal or plasmid genes that are similar to ESBLs. Metallo-beta-lactamases (MBLs): Confer resistance to carbapenems, inherent chromosomal (e.g Stenotrophomonas maltophilia) versus plasmid acquired (e.g. New Delhi metallo-beta-lactamases (NDM)). May be susceptible to colistin, tigecycline or fosfomycin. Combination therapy including a carbapenems (even if resistant) improves outcomes. a b

Methicillin-resistant Staphylococcus aureus. Vancomycin-resistant Enterococcus faecium.

Table 1

all microbiologic tests: samples taken after new antibiotics are started rapidly lose sensitivity. The single most useful microbiologic test in ICU is correctly performed blood cultures. A simple protocol is shown in Box 1.

General prevention measures Nosocomial infections are reduced by good antibiotic use and strict infection control. Ongoing liaison between ICU, infectious diseases (or clinical microbiology) and pharmacy personnel is essential. This multidisciplinary approach is needed to develop local guidelines (preferably guided by local microbiology data), provide day-to-day advice, monitor usage and oversee control measures for broad-spectrum antimicrobials, and provide feedback to the ICU staff in a useful manner. Antimicrobial

Good antibiotic use in ICU to reduce selection pressure for resistance C

Effective diagnosis of nosocomial infection: taking blood cultures

C

C C C

C

C C

Take three sets before starting or changing antibiotics Fresh venepuncture, sterile technique (or from a new line inserted in an aseptic manner) Swab skin (70% alcohol with chlorhexidine), allow 30 seconds before venepuncture 10 ml per blood culture bottle No further BCs need be taken for 2e3 days unless clinical situation changes, or to demonstrate clearance of proven bacteraemia

C

C

C

Box 1

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Knowledge of local microbiological epidemiology to guide empiric therapy Prompt appropriate therapy for sepsis, including antifungals in higher risk patients Early source control, including changing of lines in a septic patient De-escalating broad-spectrum antibiotics early according to cultures and patient condition Using shorter duration of antibiotics overall, e.g. 5e7 days is adequate for most cases of VAP Appropriate dosing will both maximize cure rates and minimize selection of resistance. Unfortunately both under and over-dosing are common in the ICU setting

Box 2

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with each element in the bundle can be measured as a simple ‘yes/no’). Not all possible proven therapies are included in the bundle, as factors such as ease of implementation, adherence and cost are considered. Examples of care bundles are given in Box 3.

consciousness and aspiration. The key modifiable factors increasing risk of VAP are anti-acid therapy, previous antibiotic exposure (particularly 3rd generation cephalosporins), use of paralytic agents, re-intubation or prolonged intubation, frequent/ routine ventilator circuit changes, presence of a nasogastric tube or intracranial pressure monitor.

Specific conditions Ventilator-associated pneumonia Hospital-acquired pneumonia (i.e. pneumonia that begins 48 hours or more after admission) is a leading cause of hospital acquired infection leading to mortality.6 Ventilator-associated pneumonia (VAP) is a subset of HAP, occurring 48 hours or more after endotracheal intubation. Clinically diagnosed VAP has a prevalence of 13e16%, though rates using stricter surveillance definitions are much lower. Whilst crude mortality rates of 20 e30% are typically reported,7 most of these patients die not because of their VAP but because of the underlying severity of illness. The attributable mortality of treated VAP is commonly said to be 10%, but may in fact be as low as 1% at day 30 if careful adjustment for other patient factors in the course of their ICU stay are taken into account.8 Some authors also describe ventilator-associated tracheobronchitis (VAT) as a precursor condition, differentiated from VAP by the absence of chest X-ray infiltrates. It is unclear if VAT requires treatment; with studies showing it increases duration of ventilation, length of ICU stay, but not mortality rate. The pathogenesis is thought to involve microaspiration of oropharyngeal microorganisms, which enter into the lower respiratory tract via leakage around the endotracheal tube cuff or directly through the tube. Aspiration of gastrointestinal microorganisms contributes to a lesser extent. Microbial virulence factors and host defence factors then determine if pneumonia occurs.

Microbiology: a wide spectrum of organisms causes VAP, including aerobic Gram negatives (Escherichia coli, Klebsiella, Enterobacter etc), Gram positive cocci (Streptococci, Enterococci etc), and oropharyngeal flora; some of these may be multiresistant. However the local epidemiology is important. Diagnosis: the optimal diagnostic algorithm for VAP remains unclear. Clinical plus radiological features only have moderate sensitivity (69%) and specificity (75%). Positive microbiological sampling alone cannot differentiate between colonization, VAT or VAP; however negative cultures from good quality specimens (before receipt of antibiotics) reasonably excludes VAP. Microbiology results need to be interpreted, especially in poorer quality samples: isolation in sputum of Pseudomonas is usually significant, Staphylococci may not always be, Acinetobacter and Stenotrophomonas are most commonly just colonizers, and Candida pneumonia probably does not exist. A combination of clinical, microbiological and radiological criteria is required. Clinical risk rules have shown promise in trials but have proved cumbersome to implement in clinical practice. Biomarkers such as procalcitonin seem to be of most value in less sick patients, and only some studies show benefit. More reliable microbiology results translate into improved outcomes in a number of studies, with less antibiotic use, less development of resistance, better patient outcomes and increased clinician confidence. Quantitative culture of good quality bronchoscopy specimens yields the most reliable microbiologic result, but has variable application within units due to concerns around cost, logistics and side effects. Invasive specimens may be risky to obtain, whilst quantitative cultures did not reduce mortality, time in ICU, time on mechanical ventilation or antibiotic usage.9 The most important factor is that a good quality specimen should be collected before starting or changing antibiotics. Rapid pathogen detection technologies (for example nucleic acid amplification combined with mass spectrometry) are in late stage development but clinical correlation and impact on management will take longer to determine.

Risk factors: mechanical ventilation increases the risk of pneumonia 6e20 times. The most significant risk factors for VAP include age >70 years, chronic lung disease, depressed

Care bundles in the ICU VAP care bundle C C

C C

Elevate the head of the bed 30e45 degrees Daily sedative interruption and assessment of readiness to extubate Peptic ulcer disease prophylaxisa Venous thromboembolism prophylaxisa

Management: the principles of treating VAP include early antimicrobial therapy (after appropriate specimens are taken) guided by the local microbiology, then de-escalation according to culture and sensitivity results. In many units this will result in empiric combination therapy to cover multi-resistant organisms (MROs). Aerosolized agents are not proven for routine use; this may change with trials underway of newer technologies better able to deliver the right droplet size to the site of infection. ‘Streamlining’ treatment to the most effective narrow-spectrum agent should occur once an organism is isolated, with a total duration of 5e7 days of effective therapy adequate for most pathogens, though most physicians would treat for 10e14 days for Pseudomonas spp., MDR Gram negatives or S. aureus pneumonia.

CLABSI care bundle C C C C C C

Hand hygiene Avoid femoral insertion site in adults Maximum barrier precautions Alcoholic chlorhexadine skin antisepsis Optimal catheter site selection Daily review of line necessity & prompt removal

a

Not supported by good evidence, but commonly included in bundle.

Box 3

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Prevention: strategies to prevent VAP include reducing need for ventilation, reducing colonization and reducing aspiration. Sedation should be avoided or minimized, and interrupted daily if possible, together with daily assessment of readiness to extubate. Non-invasive ventilation is preferred where possible. Early mobilization is encouraged. Methods to reduce aspiration include the use of semirecumbent patient positioning, subglottic drainage techniques and ventilator circuits should not be routinely changed. Although they may lower VAP rates, there is little evidence for improved patient outcomes from acid-suppressants, early tracheostomy, early TPN, prone positioning or antiseptic impregnated ETTs.10 Selective digestive decontamination (SDD) involves the application of topical antimicrobials to the oropharynx and/or oral antibiotics to the digestive system via nasogastric tube, with or without systemic antibiotics. SDD has been shown in three meta-analyses to reduce the rates of VAP, bacteraemia, MDR bacteria colonization (e.g. MRSA, VRE) and mortality in certain subgroups, though the most significant effect is seen in the groups receiving systemic therapy. It is not accepted widely into practice, due in part to concerns of selection of antimicrobial resistance (e.g. colistin and aminoglycoside resistance increased following one SDD program).11 It is probably most effective where VAP rates are high but background resistance rates low. Topical chlorhexidine along with good oral hygiene, such as tooth brushing, may be a more acceptable way to stop microaspiration of oral flora into the respiratory tree, however further studies are required.

as well as therapeutic. Culture of a catheter tip is only useful if the catheter is thought to be infected. There is little evidence for drawing cultures from every lumen of a central line. Newer diagnostic methods such as direct nucleic acid amplification on blood, or markers of fungal infection such as 1e3 beta-D-glucan, show promise for earlier detection of bloodstream infection, but low specificity, false positivity and cost currently limit their widespread implementation. Management: if CLABSI is suspected, the catheter should be removed, cultures taken (peripheral, tip of CVC) and antimicrobial therapy initiated, most commonly a broad-spectrum betalactam antibiotic though extra gram negative (e.g. aminoglycoside) and/or Gram positive (e.g. glycopeptide) may be added depending on the local microbiology. In patients at higher risk of candidaemia (multi site colonization, immunosuppression, recent abdominal surgery, recent receipt of broad-spectrum antibiotics, TPN) empiric fluconazole is also appropriate whilst awaiting culture results. Unfortunately most patients have at least some of these risk factors and clinical prediction tools for candidaemia are too imprecise for widespread implementation. Empiric use of an echinocandin (e.g. micafungin, caspofungin, anidulafungin) over fluconazole is preferred in patients with septic shock, prior azole exposure or underlying immunosuppression. Empirical therapy for S. aureus bacteraemia usually requires the addition of a glycopeptide to an anti-staphylococcal beta-lactam (flucloxacillin, cephazolin, cephalothin) until the isolate is confirmed as methicillin sensitive. Newer agents such as linezolid, ceftaroline or daptomycin have no clear benefits over existing agents. Staphylococcus aureus CLABSI requires a minimum of 14 days of intravenous therapy. Echocardiography is indicated in all S. aureus bacteraemia, as endocarditis (or metastatic infection such as endophthalmitis, osteomyelitis, septic thrombosis) or tunnelled line infection requires prolonged therapy (4e6 weeks). Coagulase-negative Staphylococcus can be treated for 3e5 days, Gram negatives for 10e14 days, and Candida for 14 days, if metastatic foci are not identified. Ophthalmology review in candidaemia is mandatory to exclude endophthalmitis.

Central line-associated bloodstream infection Intravascular catheter-related infections are a major cause of morbidity and mortality in the ICU. A meta-analysis showed a case fatality rate of 19% of catheter related bloodstream infections.12 We will focus on central line associated bloodstream infection (CLABSI). Risk factors: host predisposing factors include immunosuppression, burns, malnutrition, use of TPN and extremes of age; however these are not modifiable. The risk of infection increases after day 3. In adults higher rates of infection are seen with femoral vein insertion sites, then jugular, and lowest with subclavian.

Prevention: simple practices to modify risk factors can eliminate most CLABSI. Local protocols should reinforce: hand hygiene practice and auditing, strict aseptic technique by an appropriately qualified person, full barrier precautions, avoidance of femoral placement, and use of 2% chlorhexidine for skin disinfection. Vigilant catheter care is essential: all lines should be assessed daily for infection, and unnecessary catheters removed. If inserted under emergency conditions they should be removed/ replaced within 48 hours. Guide-wire exchange techniques result in higher rates of associated bacteraemia and should be avoided. Multi-modal strategies combining these strategies can virtually eliminate CLABSI in large tertiary referral ICUs. Antibiotic impregnated CVCs (e.g. minocycline/rifampicin) may be of benefit in units with high rates of CLABSI, or selected patients at high risk, whilst antiseptic coated CVCs appear less effective, but have fewer concerns around selection pressure for resistance.

Microbiology: the pathogenesis of infection involves skin flora colonizing the device. Infections in the first week after placement are typically due to poor insertion technique, with skin organisms travelling along the external surface of the catheter; infections occurring later than 1 week after insertion are more typically caused by intraluminal spread following contamination during handling of the catheter. The pathogens involved are Staphylococci (coagulase-negative and aureus; 50%), Gram negative bacilli (30%), Enterococci (10%) and Candida species (10%). Staphylococcus aureus has a significantly higher attributable mortality rate than the other pathogens. Host factors play a role: for example, gram negatives predominate in burns patients. Diagnosis: this involves establishing bloodstream infection and showing that the source is the catheter. Rapid removal or replacement of all existing lines is necessary in undifferentiated sepsis, and rapid response to removal of lines may be diagnostic

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Nosocomial urinary tract infections Catheter-associated urinary tract infection (CA-UTI) refers to infection occurring in a person whose urinary tract is currently

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REFERENCES 1 Zilberberg MD, Shorr AF, Micek ST, Vazquez-Guillamet C, Kollef M. Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic shock: a retrospective cohort study. Crit Care 2014; 18: 596. 2 Kaki R, Elligsen M, Walker S, Simor A, Palmay L, Daneman N. Impact of antimicrobial stewardship in critical care: a systematic review. J Antimicrob Chemother 2011; 66: 1223e30. 3 Pittet D, Allegranzi B, Boyce J, for the World Health Organization, World Alliance for Patient Safety First Global Patient Safety Challenge Core Group of Experts. The World Health Organization guidelines on hand hygiene in health care and their consensus recommendations. Infect Control Hosp Epidemiol 2009; 30: 611e22. 4 Septimus EJ, Hayden MK, Kleinman K, et al. Does chlorhexidine bathing in adult intensive care units reduce blood culture contamination? A pragmatic cluster-randomized trial. Infect Control Hosp Epidemiol 2014; 35(suppl 3): S17e22. 5 Climo MW, Yokoe DS, Warren DK, et al. Effect of daily chlorhexidine bathing on hospital-acquired infection. N Engl J Med 2013; 368: 533e42. 6 American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171: 388e416. 7 Craven DE, Hjalmarson KI. Ventilator-associated tracheobronchitis and pneumonia: thinking outside the box. Clin Infect Dis 2010; 51(suppl 1): S59e66. 8 Bekaert M, Timsit JF, Vansteelandt S, et al. Attributable mortality of ventilator-associated pneumonia: a reappraisal using causal analysis. Am J Respir Crit Care Med 2011; 184: 1133e9. 9 Berton DC, Kalil AC, Teixeira PJ. Quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia. Cochrane Database Syst Rev 2014. Issue 10. Art. No.:CD006482. 10 Klompas M, Branson R, Eichenwald EC, et al. Strategies to prevent ventilator-associated pneumonia in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014; 35: 915e36. 11 Halaby T, Al Naiemi N, Kluytmans J, van der Palen J, VandenbrouckeGrauls CM. Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. Antimicrob Agents Chemother 2013; 57: 3224e9. 12 Mermel LA, Allon M, Bouzaet E, et al. Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis 2009; 49: 1e45.

catheterized (or catheterized within the previous 48 hours). Catheter-associated asymptomatic bacteruria (CA-ASB) may also occur in a patient without symptoms or signs attributable to the urinary tract. Rates of CA-UTI and CA-ASB have declined significantly in hospitals with active prevention programs. Pathogens usually ascend from the urethral meatus on the external surface of the tube. However, one-third ascend intraluminally (e.g. from a contaminated bag). Microbiology: CA-UTI in the ICU may be caused by Staphylococci and Pseudomonas, in addition to the usual community acquired pathogens (Gram negatives, Enterococci). The presence of Candida species is a common finding which normally represents colonization in patients who have received broad-spectrum antibiotics, even in immunocompromised hosts. Rarely, it reflects the presence of candidaemia (1.3% in one study). Risk factors include prolonged catheterization and bacterial colonization of the drainage bag. Diagnosis: it can be difficult to distinguish true pathogens from colonizing organisms, but presence of neutrophils, absence of squamous epithelial cells and presence of organisms on Gram stain all support true infection. Urine cultures should be obtained prior to antibiotic administration and not from the drainage bag. A catheter change prior to sampling avoids culturing colonizers. Management: it is essential that a urine culture must be obtained prior to the initiation of treatment. Treatment duration for patients who respond promptly to antibiotics is 7 days and 10e14 days for a delayed response or infection occurring in a male. Asymptomatic candiduria usually resolves with catheter change. Prevention: the principles of prevention are avoiding catheterization where possible, aseptic technique and catheter care, early removal and considering intermittent catheterization. Antibiotic-impregnated catheters are proven to be effective and likely to be cost effective. It is unclear if they select for resistant organisms. There is no evidence to support the use of prophylactic antibiotics during catheter insertion and removal. A

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