Coumarins The coagulation factors II, VII, IX and X, as well as the natu- rally occurring a nticoagulants protein C and S, are depend- ent upon vitamin K. In each case, synthesis of t he functional protein requires the post-translational -carboxylation of N-terminal glutam ine residues, and warfarin antagonizes the effect of vitamin K. Peak serum concentrations a re reached at 3h of oral administration, and the half-life is 36 \200\22342h. Warfarin is highly protein bound, mainly to albumin. Despite rapid absorp- tion of warfarin and other c oumarins, the onset of the anti- coagulant effect is delayed as it requires the gradual dep letion of functional coagulation factors. Metabolism is hepatic, requiring the cytochrome P 450-2C9 hepatic microsomal enzyme. A number of genetic and environmental factors affect the absorption, pharmacokinetics and pharmacodynamics of coumarins. Genetic polymorphisms of t he CYP2C9 enzyme are primarily responsible for differences in warfarin metab- olism. The mo st common polymorphisms, CYP2C9*2 and CYP2C9*3, are each seen in 10% of Caucasians, and ar e associated with a reduced warfarin requirement. A small proportion of individuals (<1%) h ave a hereditary resist- ance to coumarins mediated by reduced af \201 nity of the cou- ma rin receptor and require very large doses of coumarins (e.g. \211 30mg warfarin daily) to achieve an anticoagulant effect. Dosage and monitoring LMWHs should be dosed according to the manufacturer \200\231s instruc tions. Given the renal clearance of LMWHs, bleeding complica- tions are more common; with r enal failure, dose adjust- ment is necessary and should be guided by monitoring of the anti -Xa level or UFH should be used. One of the advantages of LMWHs is that routine monitor- in g is not necessary unless there is renal failure or in mor- bidly obese patients. If monito ring is required, the aPTT is not suf \201 ciently sensi- tive to anti-Xa activity so dire ct measurement of plasma anti-Xa activity is required. As anti-Xa activity declines rap- id ly in vitro, analytic samples must be rapidly transported to the laboratory on ice, centrif uged at 4 C, separated and either assayed immediately or frozen at \200\22370 C for subs e- quent analysis. Target anti-Xa ranges vary by LMWH prod- uct and indication; manufacture rs \200\231 data should be consulted. Because of the risk of HIT, patients receiving LMWHs should have a baseline platelet count on the day of starting treatment, and platelet counts every 2 \200\2234 days between days 4 and 14 of treatment. Interactions Foods rich in vitamin K1 (phytonadione) reduce the ef \201 - cacy of coumarin s by overcoming its inhibition of vitamin K recycling. Numerous drugs and herbal remedies a re known to interact with coumarins and alter the anticoagulant effect. In addition, antipl atelet agents, including NSAIDs, can lead to an increase in bleeding risk. Reversal Most bleeding complications can be managed by dose reduction or cessation of LMWH. For severe bleeding, par- tial reversal of the anticoagulant activity of LMWH can be achie ved with 1mg protamine for every 100IU of LMWH given within the previous 8h (maximum 40 \200\22350mg pro- tamine); this can reverse up to 90% of anti-IIa and 60% of anti-Xa activi ty. A partial return of LMWH anticoagulant activity may be seen 3h after reversal due to co ntinued LMWH absorption from the SC injection site. Protamine can be re-administered if nec essary. Monitoring Because of the considerable interindividual variability in dose requirements, an d the myriad food and drug interac- tions, coumarins require routine therapeutic monitoring of the INR. Reversal Administration of vitamin K1 can reverse the anticoagulant effects of coumarins, b ut takes at least 6h, as it necessitates the de novo production of active -carboxylated c oagula- tion factors by the liver. 222 B HUNT sites of the thrombin molecule. Hirudin is given either as an IV infusion or by twice-daily SC injection. It is not active orally. As the clearance of hirudin is exclusively renal, t he half-life is highly dependent on renal function. With normal renal function, hirudin has a half-life of 60min after IV administra- tion, but in those with end-stage renal failure the half-life can be as long as 300h. Hirudin requires therapeutic monitoring. The aPTT is usu- ally used, with a typical target aPTT-R of 2.0 \200\2232.5. The ecarin clotting time m ay be a better alternative for hirudin moni- toring, but is less widely available. Hirudin is licensed for the treatment of thrombosis associ- ated with HIT. Its major adverse effect is bleeding. 40 \200\22370% of patients develop hirudin antibodies after a week of treatme nt. The antibodies are rarely inhibitory, but may bind to hirudin and reduce renal clearanc e, resulting in a prolongation of half-life. There is no speci \201 c reversal agent for h irudin. Options in bleeding patients include blood product support, activated prothrombin c omplex concentrates or recombinant acti- vated factor VII. Hirudin is not cleared by haemod ialysis. A dose of 10mg vitamin K will make anticoagulation with coumarins dif \201 cult during the following 2 weeks, so 1mg vitamin K may therefore be preferable in patients without life-t hreatening bleeding. FFP contains all the vitamin K-dependent coagulation fac- tors, and ca n reverse warfarin when given at a dose of 15 \200\223 20ml/kg. As the half-life of factor VII is short, vitamin K replacement should be given concomitantly. Prothrombin complex conc entrates (PCCs) are plasma- derived products containing the vitamin K-dependent coagulation factors in a concentrated form. The activity of PCCs is usually expressed in terms of unit s of factor IX, the typical dose required for warfarin reversal being 20IU/kg in a slow IV push over several minutes. Although more expen- sive than FFP, PCCs have the advantage of a small volume of administration, rapid preparation (no thawing required) and more complete reversal of warfarin activity. They are the treatment of choice when fast reversal is requi red. As with FFP, vitamin K replacement should be given in con- junction with PCCs. Adverse effects The principal adverse effect of coumarins is bleeding, with a risk of fatal hemorrhage of 0.25%/yr in unselected patients, the risk being much higer in critical care patients. In individuals with hereditary protein C de \201 ciency, cou- marin-induced skin necrosis due to microvascular throm- bosis can occur. This complication can be avoided by using an alternative anticoagulant (e.g. a LMWH) during cou- marin loading. Bivalirudin Bivalirudin is a recombinant 20 amino acid polypeptide analog of hirudin. It bi nds to the substrate-binding site of thrombin, but, unlike hirudin, can be cleaved by throm bin itself, making bivalirudin a reversible thrombin inhibitor. Bivalirudin has a half-life of 25min following IV injection. Because only a proportion of excretion is renal, clearanc e is less dependent upon renal function than for hirudin. Bivalirudin is monitored using th e aPTT or ecarin clotting time. Because of its short half-life, the clini- cal use of bival irudin is usually restricted to the manage- ment of acute coronary symptoms and to anticoag ulation during PCI. There is no speci \201 c reversal agent for bivalirudin. Because of th e short half-life, bleeding can be managed with blood product support alone until the antic oagulant activity declines. Synthetic pentasaccharides Fondaparinux Fondaparinux is a synthetic pentasaccharide \200 \224consisting of the antithrombin-binding pentasaccharide sequence found in the heparin mo lecule. Like LMWHs, fondaparinux binds the antithrombin molecule causing a conformational c hange, which enhances its activity against factor Xa. Because there are no additional sacch arides to provide the necessary bridging function for thrombin binding, fonda- parinux has no anti-thrombin activity. Fondaparinux is given as an SC injection and has a half-life of 17h, making it suitable for once-daily dosing. Clearance is exclusively renal, so it is not recommended in those with a creatinine clearance of <30ml/min. Fondaparinux does not bind to platelet factor 4, so has no capacity to cause HIT. The dose is 2.5mg SC once daily for thromboprophylaxis and acute coronary syndrome, or 7.5mg SC once daily for treatment of ven ous thromboem- bolism. There is no speci \201 c reversal agent for fondaparinux \200\224pr o- tamine sulfate is ineffective. Experimental data indicate that recombinant activated fac tor VII may partially reverse the anticoagulant effect of fondaparinux. Argatroban Argatroban is a small molecule reversible thrombin inhibi- tor derived from the amino acid arginine. It is only active parenterally. The half-life is 40min, and clearance is prima- rily hepatic. Dose adjustment is recommended in those with moderate liver failur e. Argatroban is monitored using the aPTT. As with hirudin and bivalirudin, there is no spe - ci \201 c reversal agent. Argatroban has been used principally in the management of HIT and during percutaneous coro- nary procedures in patients at risk of HIT. Thromboprophylaxis in critical care patients Such is the risk of venous thromboembolism in patients admitted for critical care, that thromboprophylaxis should be administered unless there is a bleeding risk. Each ICU should have a policy for using thromboprophylaxis. The r eader is referred to the gold standard of thrombo- prophylaxis, the American College of Che st Physicians guidelines. Parenteral direct thrombin inhibitors Unlike heparins, direct thrombin inhibitors are not d epend- ent on endogenous antithrombin for their anticoagulant effects. Hirudin Hirudin is a 65 amino acid polypeptide, originally discov- ered in the saliva of th e medicinal leech, Hirudo medicinalis. Two recombinant derivatives are available: lepirudin and desirudin. Hirudin is an irreversible direct thrombin inhibi- tor, binding to both the active and substrate recognition Further reading Avling BM. How I treat heparin-induced thrombocytopenia and thrombosis. Blood 2003; 31: 31 \200\2237. Baglin T, Barrowcliffe TW, Cohen A, et al. Guidelines on the use and monitoring of heparin. Br J Haematol 2006; 133: 19 \200\22334. 223 CHAPTER 14.1 Anticoagulants and heparin-induced thrombocytopenia Lo GK, Juhl D, Warkentin TE, et al. Evaluation of pretest clinical score (4 T \200\231s) fo r the diagnosis of heparin-induced thrombocy- topenia in two clinical settings. J Thromb Ha emostasis 2006; 4: 759 \200\22365. Baglin T, Keeling DM, Watson HG et al. Guidelines on oral antico- agulation (warfarin): thi rd edition \200\2242005 update. Br J Haematol 2005; 132: 277 \200\22385. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practi ce Guidelines (8th Edition). Chest. 2008; 133(6 Suppl):381S \200\223453S. Mueller RL, Scheidt S. History of drugs for thrombotic disease. Discovery, development, and directions for the future. Circulation 1994; 89: 432 \200\22349. Keeling D, Davidson S, Watson H, et al. The management of heparin- induced thrombocytopenia . Br J Haematol 2006; 133: 259 \200\22369. 224 B HUNT Thrombolysis The thrombotic and \201 brinolytic systems are exquisitely balanced. This ensures the rap id generation of thrombus and its localization at the site of vessel injury. Fibrinolysis p revents the excess deposition of \201 brin and enables its rapid removal. This minimizes the potential disruption to the blood supply. Fibrinolysis is a surface-bound phenome- non, with most of the events being catalyzed by \201 brin itself. It is frequently stated tha t \201 brin is the architect of its own destruction. Streptokinase Streptokinase is a produced by -haemolytic Streptococcus, and was the \201 rst agent to be used for thrombolysis on a large scale. The bene \201 ts of streptoki nase were con \201 rmed in the Second International Study of Infarct Survival. In this stu dy, the addition of streptokinase led to a signi \201 cant reduction in mortality in patie nts who had suffered an AMI. Streptokinase works by binding to and activating plasmino- gen . Streptokinase has a short half-life of 20min. Streptokinase stimulates an antibody respo nse. This limits the ability to give a repeat dose. When antibody titres to streptokinase a re high, treatment with streptokinase is unlikely to produce satisfactory thrombolysis. De \201 nition of thrombolysis Thrombolysis is the infusion of thrombolytic agents to dis- solve or directly destroy thrombi in blood vessels. Thrombolysis uses integral parts of th e \201 brinolytic path- way to achieve thrombus destruction. It is used in the man- ageme nt of AMI, acute ischaemic stroke, PE and aterial occlusion involving thrombus. The key to the successful use of thrombolysis is identifying those patients who are most likely to ben e \201 t from treatment and to initiate treatment as promptly as possible. Close observati on is required because of the inherent increased risk of bleeding associ- ated with these a gents. Urokinase Urokinase directly activates plasminogen; it is also known as urokinase-type plas minaogen activator (u-PA). It was ini- tially isolated from human urine. When compared with streptokinase, it does not induce an antigenic response. Urokinase is mainly used for clea ring thrombosed indwell- ing central venous catheters. Tissue plasminogen activator tPA plays a central role in limiting and localizing the normal haemostatic response. tPA is a serine protease and is pro- duced by the endothelium. It is the major naturally occur- ring physiological enzyme responsible for converting plasminoge n to plasmin. Recombinant tPA has now been synthesized. It does not produce an antigenic re sponse. It is also moderately more effective than streptokinase at clot lysis. It is curren tly the \201 rst-line choice in the UK for throm- bolysis when urgent percutaneous corona ry angiography is not available. tPA has a half-life of 5min and is rapidly cleared from p lasma by the liver. Physiology of \201 brinolyis The major components of the \201 brinolytic system are pla s- minogen, plasmin and tissue plasminogen activator (tPA). Plasminogen is produced in the liver and is incorporated into thromboses as they are formed. The generation of \201 brin and its binding to tPA leads to an increased af \201 nity of tPA for plasminogen. This le ads to the generation of plas- min at the site of the \201 brin clot. Plasmin proceeds to digest the \201 brin chains in an asymmetrical pattern, producing \201 brin degradatio n products and dissolving the thrombus. Fibrinolysis is inhibited by the actions of plasmin ogen activator 1 (PAI-1) and 2-antiplasmin ( 2-AP). PAI-1 acts directly on tPA to antago nize its action. This process is summariaed in Figure 14.2.1. The decreased level of \201 brin- ogen causes an increase in the INR and aPTT; the thrombin time is prolonged. Three a gents are used in clinical practice for thrombolysis: streptokinase, urokinase and alteplas e (recombinant tPA). Contraindications to thrombolysis The major contraindications to thrombolysis are a recent stroke, the presence of a cerebral malignancy or metas- tases, and pregnancy. The risk of h aemorrhagic complica- tions is significantly increased in patients who have undergone recen t surgery, or those with signi \201 cant retin- opathy or a profound coagulopathy. The cli nical decision to use it must be made after a careful assessment of the potential risks and bene \201 ts. Factors in \202 uencing a successful outcome The age and nature of the thrombus are key fa ctors in \202 u- encing the speed of lysis. The younger the thrombus, the greater the chan ce of success. Arterial thrombi tend to resolve more promptly than venous thrombi, and con- tinuous catheter-directed infusion is preferable to bolus infusion. PLASMINOGEN Tissue Plasminogen activator PLASMIN Tissue plasminogen activator inhibitor Myocardial infarction All the currently available trials show that thrombolytic agents redu ce the mortality in acute STEMI. The GUSTO-1 trial showed that recombinant tPA was superior to strep- tokinase. Thrombolysis has resulted in a 30% reduction in the mortality from MI. a 2 a 2 antimacroglobulin antiplasmin FDPs FDPs FDPs FDPs FIBRIN FDPs Acute limb ischaemia The most important treatment for acute limb ischaemia to try to preven t limb loss is the rapid initiation of anticoagu- lation with heparin. This prevents furthe r propagation of the thrombus and stimulates tPA release. Thrombolysis in FDPs FDPs FDPs FDPs FDPs Fig. 14.2.1 Overview of thrombolysis. 225 CHAPTER 14.2 Thrombolysis these patients can help to buy time before a de \201 nitive pro- cedure can be undertaken. It can open up vessels to allow a graft or enable a subsequent angioplasty. it can be life saving for individual patients. Doses vary con- siderably, but a dose of tPA of 100mg infused over 2h has been recommended in the ACCP guidelines. The patient should a lso receive anticoagulation with heparin. Pulmonary embolism Thrombolyis for PE remains a controversial issue. In view of the potenti ally life-threatening consequences of throm- bolytic therapy, it should be reserved only fo r cases where the diagnosis has been con \201 rmed and there is evidence that the PE is ca using haemodynamic compromise or RV failure (i.e. a massive PE). It is worth considering th at hypo- tension requiring vasopressor support is an independent risk factor for massive he morrhage post-thrombolysis. Studies suggest that thrombolysis produces a short-term improve ment in oxygenation and haemodynamic function. Speci \201 cally there is evidence to sugge st that it leads to a lower pulmonary artery pressure and PVR. However, there is no overall impact on mortality, even in those patients who have suffered a massive PE. It is reasonab le to con- tinue to have PE as a speci \201 c indication for thrombolysis as Further reading Buller HR, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thr omboembolic disease: the Seventh ACCP Conference on Antithrombotic therapy for venous throm boembolic disease. Chest 2004; 126: 401s. ISIS-2. ISIS-2 (Second International Study of Infarct Survival) ran- domised trial of intra venous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected myocard ial infarction: Lancet 1988; 2: 349 \200\22360. Thabut G, Thabut D, Myers RP, et al. Thrombolytic therapy of pulmonary embolism: ameta-anal ysis. J Am Coll Cardiol 2002: 40: 1660 \200\2237. The GUSTO Investigators. An international randomized trial com- paring four thrombolytic st rategies for acute myocardial infarc- tion. N Engl J Med 1993: 329: 673 \200\22382. 226 B HUNT Anti \201 brinolytics Tranexamic acid (trans-4-aminomethylcyclohexane-1- carboxylic acid) is a synthetic lysine a nalog that is a com- petitive inhibitor of plasmin and plasminogen. There is large variatio n in dose used. In vitro studies have suggested a dose of 10mcg/ml is required to inhibit f ibrininolysis. Tranexamic acid is distributed throughout all tissues, and the plasma half-l ife is 120min, with most of it being renally excreted. Studies of plasma levels con \201 r med that the Horrow regime, which has been shown to reduce blood loss in cardiac surgery, o f 10mcg/kg followed by 1mg/kg/h, attained theses levels. Other studies have used up to 5g p er patient with no ill-effect. A Cochrane review has shown no increased thrombotic risk wit h tranexamic acid or EACA. EACA ( -aminoncaproic acid) is also a synthetic lysine ana- log ue that has a potency that is 10 times weaker than tran- examic acid. It is therefore admin istered in a loading dose of 150mg/kg followed by a continuous infusion of 15mg/h. The init ial elimination half-life is 1 \200\2231.15h and therefore must be administered by continuo us infusion in order to maintain therapeutic drug levels. Aprotinin is a broad-spectrum ser ine protease inhibitor isolated from bovine lung, which forms irreversible inhibi- tory com plexes with a number of serine proteases. In par- ticular, it is a powerful antiplasmin age nt. The initial elimination of aprotinin is 1.5 \200\2232h and, like the synthetic anti \201 brinolytics, it is renally excreted. In cardiac surgery, the \200\230high-dose \200 \231 or Hammersmith regime, i.e. 2million KIU to the patient and cardiopulmonary bypass pri me, and an infusion of 500 000 KIU/h) has been shown to reduce peri- operative bleeding in open cardiac surgery. Lower doses do produce adequate antiplasmin effects. It is licensed i n a dose of 2million units to treat hyer \201 brinolysis. A recent Food and Drug Administration (FDA) warning was issued to cover the use of aprotini n. This was based on two studies in cardiac surgery. An open study by Manago et al. suggest ed that aprotinin usage in cardiac surgery was associated with an increased risk of MI, str oke and renal failure, and another study by Karkonti et al. cited an increased risk of rena l problems in those receiving apro- tinin when compared with tranexamic acid. However, Mana go \200\231s study was open and it remains unclear whether the perhaps sicker patients rece ived aprotinin. A ran- domized triple blinded study of aprotinin vs tranexamic acid vs EACA (BART), has shown that there is an increased morbidity & mortality in the aprotinin-treate d group. At the current time, due to the current FDA warning on aprotinin, its greater cost s and need to give a test dose, which is often impractical in an emergency situation, tran- examic acid and EACA are to be preferred. A dose of tranexamic acid 1 \200\2232gm is recom mended by the authors in emergency situations where hyper \201 brinolysis is suspected. Further Reading Fergussion DA, H bert PC, Mazer CD, et al. BART Investigators. A compariso n of aprotinin and lysine analogs in high-risk cardiac surgery. N Engl J Med. 2008;358(22): 2319 \200\22331. Epub 2008 May. Henry DA, Carless PA, Moxey AJ, et al. Anti \201 brinolyti c use for minimizing perioperative allogeneic blood transfusion. Cochrane Database Syst Rev . 2007 Oct 17;(4):CD001886. Review. 227 Chapter 15 Miscellaneous drugs Chapter contents Antibiotics 228 Antifungals 230 Antiviral agents 232 N-Acetylcysteine 234 Activated protein C 236 228 S IYER Antibiotics Introduction Infection is a common reason for admission to an ICU and a common complication of stay in an ICU. The presence of infection in patients in ICU is an important risk facto r for increased mortality and morbidity. Antimicrobial chemotherapy remains the cornerstone of therapy of patients with infection, and antibiotics are one of the most common therapie s administered in the inten- sive care setting. Often antibiotic use in ICUs is for (empir- ical) treatment of infections, for prophylaxis such as in selective digestive decontaminat ion of the digestive system (SDD), for prevention of ventilator-associated pneumonia (VAP) or for non-antimicrobial use such as the use of erythromycin as a prokinetic agent for gut motility. The effective management of infection in ICU requires an integrated multi-discipl inar y approach involving intensivist(s), infectious disease (ID) physician/microbiol- ogis t and pharmacists, systematic and comprehensive diag- nostic measures, use of appropriate a ntimicrobial therapy and supportive care. 2 The new treatment paradigm: \200\230getting therapy right \201 rst time \200\231. \200\230Appropriate (empirical) antimicrobial therapy \200\231 is comprises of 4 Rs: 1 Rig ht drug \200\223bug match; in other words, using the \200\230best guess antibiotic \200 \231 targeting the \200\230most likely pathogens \200\231. 2 Right regimen: Dose, route, frequency, duration. 3 Right tissue concentration for effecti ve eradication, 4 Right cost, i.e. cost-effectiveness. Factors in \202 uencing choice of initial (empirical) therapy Epidemiology of infection Ne arly half of the infections in ICU patients are acquired before admission to ICU and usuall y before admission to hospital, in the community (community-acquired); and, approximately h alf of infections are acquired following admission to ICU (hospital/ICU-acquired). The comm u- nity-acquired pneumonias and intra-abdominal sepsis are the most common community-acquir ed infections treated in ICU, and VAP and central intravascular catheter-related bacteraemi a are the most common nosocomial infections seen in the ICU. Important issues in antimicrobial management of infection in ICU patients Severity of infec tion ( \200\230Severe \200\231) sepsis is the most common reason for admission to ICU. The reported incidence of sepsis in ICU is as high as 35%, with mortality rates from 27 to 54% in sepsis and septic shock, respectively. Patients developing nosocomial sepsis in ICU gene rally have signi \201 cant co-morbidities and risk factors for complex, dif \201 cult to treat drug-resistant infections, associated with high mortality. Whist fever in an ICU pati ent is the most common trigger for treatment with broad-spectrum antibiotics, it is a non- speci \201 c sign of infection. At the same time, its importance as an important early war ning signal of sepsis must be appreciated. Antibiotic resistance ICUs are usually the \200\230hot zone \200\231 of antibiotic resista nce, and pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) have become e ndemic in many ICUs. There are several risk factors for emergence of antimicrobial resistan ce such as: \200 Selective pressure from use of broad-spectrum antibiot- ics for empirical therapy of septic patients. Crowding of patients with complex medical problems into a small area. Use of inv asive devices, e.g. central lines, catheters, etc., for monitoring or therapeutic purposes. Immunocompromised status of critically ill patients. High intensity of care required by IC U patients providing greater opportunities for cross-transmission of infection between pati ents and from the contaminated environ- ment by the healthcare workers from lapses in infec tion control. \200 Early appropriate antimicrobial therapy The key to ensuring survival in severe sepsis is the combi- nation of antibiotic therapy an d rapid removal of infected tissue or devices. Current challenges of antibiotic-resistant bacteria in ICU are: MRSA: MRSA strains are all resistant to: B-lactams; penicillins (oxacillin, \202 ucloxacillin, amoxicillin/co-amoxic lav, etc.), cephalosporins and carbapenems (meropenem/imi- penem/ertapenem). Hospital/healt hcare-acquired MRSA (HA/HACI MRSA) strains are multi-drug resistant (MDR), i.e. in addition to B-lactams, they are resistant to other multiple classes of antibiotic such as macrolide s (erythromycin, clarithromycin) and quinolones (cipro- \202 oxacin, moxi \202 oxacin, l evo \202 oxacin), and are distinct from community-associated MRSA (CA-MRSA) strains. CA- M RSA is an emerging pathogen in patients without tradi- tional risk factors for HA/HCAI MRSA (e.g. recent hospitalization, prior antibiotic therapy, recent surgery, nursing home resid ence, etc.), carries a distinctive viru- lence factor (the panton-valentine leucocidin, PVL ), causes mainly skin and soft tissue infection and, less frequently, necrotizing pneumonia , involves predominantly children and young adults and is usually susceptible to multiple c lasses of antimicrobials such as erythromycin, Two very important aspects of \200\230early appropriate antimicrobial therapy \200\231 are : 1 \200\230Time-to- \201 rst dose \200\231 of antibiotic \200\231: intensive monitoring, close supervision and expertise generally, of staff in the ICU, means that sepsis is more rapidly diagnosed com- pared with most emergency departments and, other hospital wards/unit s. Yet, sepsis in ICU carries a very high mortality. The international guidelines for the management of patients with severe sepsis; recommend i nitiation of anti- biotic therapy within 1h of presentation (recommenda- tion grade E, i.e. level of evidence IV or V). Rather alarmingly, only 50% of septic shock patients receive a nti- biotics within 6h of onset of hypotension! This necessitates a concerted effort in ICU and phar- macy staff to ensure that the \201 rst dose is ordered stat, it is readily available as a supply of pre-mixed antibiotics and is administered concomitantly with other resuscita- tive measures without waiting until aft er the blood pres- sure is normalized. 229 CHAPTER 15.1 Antibiotics cephalosporins, piperacillin \200\223tazobactam and cipro \202 oxacin, and have variable s usceptibility to aminoglycosides sensi- tive only to carbapenems. Carbapenemase-producing s trains of A. baumannii have been reported and are sensi- tive to only Colistin and Tigecycl ine. Other MDR pathogens in ICUs include MDR Pseudomonas aeruginosa, Stenotrophomonas malto philia treatment choice(s) should be based on antimicrobial susceptibility. co-trimoxazole, chloramphenicol and fluroquinolones. Anti-MRSA treatment options are mainly IV vancomy- cin and IV teicoplanin. Clinical isolates of vancomyin inter- mediate, and van comycin-resistant Staphylococcus aureus (VISA and VRSA) have also been reported. Newer agents include: Linezolid (IV/PO 600mg every 12h) is a member of a new class of antib iotics, the oxazolidinones, with a novel mecha- nism of inhibition of microbial protein syn thesis without risk of cross-resistance with other protein synthesis inhibi- tor antibiotic s such as macrolides, clindamycin, etc. It is 100% bioavailabile by the IV and oral route, is a suitable alternative to vancomycin, particularly in MRSA pneumo- nia, but can cause re versible myelosuppression and optic neuropathy on prolonged therapy. Daptomycin (IV 4 \200 \2236mg/kg once daily) is a cyclic lipopep- tide with a unique mechanism of action, its cli nical use is limited to skin infections, and possibly MRSA bacteraemia and/or endocarditis. Tigecycline (IV 100mg loading dose followed by 50mg twice daily) is a glycylcycline antibi otic with activity against MRSA and Gram-negative bacteria (except Pseudomonas aeruginosa) including MDR strains, and Acinetobacter bau- mannii. MDR Gram-negative bacteria: Extended- spectrum b-lactamase (ESBL)-positive Klebsiella pneumoniae, and other MDR Gram-negative bac illi with inducible B-lactamases such as Enterobacter, Citrobacter, Serratia spp. are resis tant to 2nd- and 3rd-gen- eration cephalosporins, i.e. cefuroxime, cefotaxime, ceftri- axon e, ceftazidime, gentamicin and quinolones, and usually cause urinary tract infections (UTIs ), respiratory tract infections or wounds. Localized lower UTIs may be treated with piperac illin \200\223tazobactam (Tazocin ) or ticarcillin \200\223cla- vulanate (Timentin) Severe systemic infections such as hospital-acquired pneu- monia/VAP, or urosepsis require treatm ent with carbapen- ems. Temocillin Negaban ) (IV 1 \200\2232g every 12h), a Ticarcillin de rivative; re-launched in the UK in 2006, is active against ESBL Klebsiella and Escherichia coli, and other MDR Enterbacter spp., and is a useful carbapenem-sparing (nar- row-spectrum ) antibiotic to treat these MDR Gram-nega- tive bacteria infections. MDR Acinetobacter baum annii can occasionally cause epidemics of infection in ICU patients. Epidemic strains are r esistant to many broad-spectrum antibiotics such as Other risks of antibiotic therapy \200\230Collateral damage \200\231 from antibiotic thera py refers to ecological adverse effects of antibiotic therapy, namely the selection of anti biotic-resistant organisms and the unwanted development of colonization or infection with s uch organisms, including Clostridium dif \201 cile. The following class(es) of antibiotics have been associated with risk of collateral damage: 3rd-generation cephalosporins: VRE, E SBL-producing Klebsiella, Enterobacter spp., MDR Acinetobacter spp., Clostridium dif \201 cile-associated disease (CDAD). Quinolones: MRSA, quinolone-resistant Gram-negative bacilli , ESBLs including P. aeruginosa, quinolone-resistant Acinetobacter species, CDAD. Carbapene ms: carbapenamase-producing K. pneumoniae, Enterobacter spp., MDR P. aeruginosa, Acinetobac ter bau- mannii, Stenotrophomonas maltophilia. While there is no one solution that can be a pplied to all ICUs, the use of prescribing guidelines which encourage the use of narrow-spe ctrum antibiotics and limit use of broad-spectrum antibiotics, and use of treatment algo- r ithms involving review of microbiological investigations to de-escalate therapy should be u sed to delay the emer- gence of drug resistance and prolong the utility of newer drugs. Further reading Cinel I, Dellinger RP. Current treatment of severe sepsis. Curr Infect Dis Rep 2006; 8: 358 \200\22365. Dellinger RP, Carlet JM, Masur H, et al. Surviving sepsis campaign guidelines for managemen t of severe sepsis and septic shock. Crit Care Med 2004; 32: 858 \200\22373. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit C are Med 2006; 34: 1589 \200\22396. Marik PE. Fever in the ICU. Chest 2000; 117: 855 \200\22369. McDonald LC. Trends in antimic robial resistance in health care \200\223 associated pathogens and effect on treatment. Cli n Infect Dis 2006; 42: S65 \200\22371. 230 S IYER Antifungals infusion-related reactions such as fever, chills and rigors that can be prevented or reduce d either by slowing the rate of infusion or by pre-medication with antihistamines/ hydrocor tisone and paracetamol. Dose-limiting nephro- toxity; usually reversible on discontinuation of therapy. Monitoring with estimated GFR (eGFR) is recommended. 6 Lipid-based formulation s due to their altered pharmaco- In a critical care setting, systemic antifungal agents may be prescribed to treat or preven t infections in two broad cat- egories of patients: those with classic risk factors such as prolonged neutropenia, haematopoietic stem cell trans- plantation (HSCT) or HIV infection/ AIDS, who may be admitted to ICU for advanced supportive care; and a broad group of less se verely immunocompromised critically ill patients; who may also be susceptible to these infe ctions. During the last decade, the landscape of invasive fungal infections has changed sig ni \201 cantly with regards to the epi- demiology, diagnosis and therapeutic options. Alth ough the incidence of invasive fungal infection has also increased in line with the broaden ing spectrum of the \200\230at-risk \200\231 popula- tion, parallel developments in antifu ngal chemotherapy have brought optimism of improved outcome for patients. Systemic antifung al agents used to treat invasive mycoses and mucocutaneous forms of candidiasis are describ ed in this chapter. Although Pneumocystis jirovecii (formerly Pneumocystis carinii) now is classi \201 ed among the fungi, tra- ditional therapy has been with trimethoprim \200\223s ulfameth- oxazole and hence is not described here. The echinocandin class of antifungal dru gs (described later) are active against the cyst form of P. jirovecii and offer a potential for prophy- lactic therapy, but they lack activity against the trophozoite form causing pn eumonia. There are three main families of systemic antifungal agents: 1 Polyenes, e.g. amph otericin B: conventional amphoter- icin B deoxycholate (cAMB (Fungizone)) and lipid-based p reparations such as liposomal amphotericin B (L-AMB (Ambisome)), amphotericin B lipid compl ex (ABLC (Abelcet)), amphotericin B colloidal dispersion (ABCD (Amphocil, Amphotec)) logical distributions are less toxic than cAMB. \200 These permit higher doses to be administered with- out dose-limiting side effects of cAMB. These can be used safely use in patients intolerant of cAMB, particulary those with renal i nsuf \201 ciency or at risk for developing nephrotoxity. None of the lipid fomulations has been proven supe- rior to cAMB in treatment of infections caused by Candida or Aspergillus spp. There is no difference in ef \201 cacy between the three lipid-based formulations, t hough infusion-related side effects such as fever, rigors and hypotension are more common w ith ABCD and the toxicity pro \201 le of L-AMB has been shown to be better than that of AB LC. However, there is a wide variation in the drug acquisi- tion costs. Lipid formulations are more expensive than cAMD, and L-AMB is the most expensive lipid formu- lation. The choi ce of formulation should be individual patient based. 7 Drug interactions. Amphotericin B can augment nephro- toxicity of gentamicin, cyclosporin and certain antican- cer drugs. Azoles The azoles are a large group of synthetic agents. Mechanism of action: fungal cell m embrane active agents that act by Inhibiting the cytochrome P450- (CYP-450) dependent funga l enzyme lanosterol demethylase, thereby inhibiting ergosterol synthesis and disrupting cel l mem- brane activity. 2 Azoles: 1st-generation triazoles: \202 uconazole (Di \202 ucan), itraco- nazole (Sporanox; Janssen-Cilag) Newer triazoles: voriconazole (Vfend, P \201 zer), posacona- zole (Noxa \201 l, Schering-Plow) Fluconazole \200 3 Echinocandins: caspofungin (Cancidas, MSD), micafun- gin (Mycamine, Astellas) and anidula fungin (Eraxis: P \201 zer) Spectrum of activity includes Candida albicans, C. parapsi- losis, C. tropicalis and Crypto coccus neoformans Blastomyces dermatidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides spp C. krusei and C. glabrata tend to be resistant. It has no activity against Aspergillus spp. Fluconazole has an excellent safety pro \201 le and is availa- bl e in oral and IV formulations; it is 100% bioavailable by the oral route and the generic dr ug is inexpensive com- pared with proprietary voriconazole and posaconazole. Itraconazole h as broader activity against yeasts and is also active against Aspergillus spp. Itraconazole has less reliable gastric absorption and greater potential for drug interactions. Voricona zole has a broader spectrum of activity against all species of Candida including C. krusei and C. glabrata, and is also active against \202 uconazole-resistant C. albicans. It is t he only antifungal drug approved for primary treat- ment of invasive aspergillosis. It is a vailable in oral and IV formulation. Blood concentrations are highly variable and require m onitoring when used to treat invasive mycoses, and has multiple drug interactions. 4 Miscellaneous: \202 ucytosine Amphotericin B 1 A polyene antibiotic derived from Streptomyces nodosus. 2 Introduced in 19 59 (without any randomized trials) for treatment of many invasive fungal infections, it has been the workhorse of antifungals. It is considered to be the \200\230gold standard \200 \231 for antifungal therapy and is the only anti- fungal with an indication for initial the rapy of many fungal infections. 3 Mechanism of action: it binds ergosterol in the fungal cell (absent in mammalian cells) w all rendering the cell leaky and resulting in cell death. 4 Broad spectrum of activity against most fungi that cause human disease. Aspergillus terre us, Scedosporium spp., Trichosporon spp. and Candida lusitaniae are resistant. Its spectrum is not in \202 uenced by the choice of formulation. 5 Adverse effects: parenteral administration of the conven- tional amphotericin B is often associated with unpleasant 231 CHAPTER 15.2 Antifungals