Chapter 43: Antimicrobials in the ICU

The principles used to guide antimicrobial therapy in all patients can be applied to the critically ill patients, with some modification. Patient characteristics including environmental history, immune status, prior antimicrobial exposure, and prior culture results are essential in determining likely organisms and appropriate empiric therapy. In patients who develop infection after hospital admission, knowledge of common local institutional pathogens and their sensitivity patterns is important. Source identification and control are crucial, although imaging tests may be limited by patient instability and organ failure. As discussed further in the Chapter “Pharmacology in Critical Illness,” the efficacy and toxicity of antimicrobial agents can be profoundly affected by the alterations in tissue perfusion, volume of distribution, serum protein levels, and renal and hepatic function that occur in the critically ill patients.

In ICU patients with new onset of shock and organ dysfunction thought secondary to infection, prompt empiric broad-spectrum antimicrobial therapy is crucial. Each hour of delay in adequate antimicrobial therapy after the onset of hypotension has been associated with a mean decrease in survival of 7.6%.¹ Although the common infectious syndromes encountered in the ICU are discussed elsewhere, suggested empiric antimicrobial therapy for nonimmunocompromised patients based on suspected source is provided in Table 43–1.

Unfortunately, antimicrobials are also the most unnecessarily prescribed medications in the ICU. Antimicrobial overuse has numerous deleterious effects. Allergic reactions, drug fever, and nephrotoxicity are common. In additon, antibiotic overuse has been clearly linked to the development and transmission of multidrug resistant (MDR) organisms.² Finally, the development of antibiotic-associated C. difficile colitis is a particular danger to ICU patients that has been worsened by the recent emergence of hypervirulent strains.³

A few strategies may help to strike a balance between the seemingly opposing recommendations to provide broad antimicrobial coverage for septic critically ill patients and to avoid antimicrobial overuse in the ICU. While it is important to provide empiric therapy that covers all likely pathogens in the critically ill patient, it is also imperative to step down the antimicrobial regimen as much as possible once culture results are available. Because standard culture techniques have limited sensitivity, it is sometimes necessary to continue broad empiric therapy even in the face of negative cultures. Biomarkers such as procalcitonin tend to become markedly elevated in the face of serious bacterial infections, and normal levels may be useful in rapidly ruling out such a process.⁴ Unfortunately, a myriad of noninfectious critical illnesses cause these nonspecific biomarkers to rise as well. Because of this, they are usually unable to safely rule out bacterial infections in the acutely critically ill patients and may actually increase the use of antibiotics when they are used to drive antimicrobial initiation.⁵ Molecular tests to detect the presence of invasive pathogens are just beginning to show clinical utility, and in the future may greatly increase our ability to rapidly and safely narrow antimicrobial therapy.

When narrowing antimicrobial coverage it is important to understand that antibiotic spectrum and antibiotic potency are distinct concepts, and that many of the antimicrobials that are reserved to treat MDR infections have both suboptimal efficacy and increased toxicity. For health-care–associated pneumonia (HCAP) caused by pathogens other than methicillin-resistant Staphylococcus aureus (MRSA) and nonlactose fermenting gram-negative rods, there is now adequate evidence that antibacterials may be stopped after 8 days, thus decreasing overall antibiotic exposure.⁶ Properly organized antibiotic stewardship programs can help clinicians to rationally utilize antimicrobials and have been shown to safely reduce antimicrobial overuse in the ICU.⁷

Due to space limitations several agents that are significant but infrequently used will not be discussed here. These include the antibacterial agents quinupristin/dalfopristin and telavancin, the antiviral agents cidofovir and ribavirin, the antifungal agents itraconazole and pentamidine, and the antiparasitic agents albendazole, ivermectin, artesunate, and quinine.

Antibacterials

β-Lactams

The β-lactam group includes the penicillins, cephalosporins, carbapenems, and monobactams. All β-lactams share a common mechanism of action: inhibition of synthesis of the bacterial peptidoglycan cell wall by binding to variety of penicillin-binding proteins (PBPs). All β-lactams are bactericidal and demonstrate time-dependent killing; time for which drug levels exceed the minimum inhibitory concentration (MIC) correlates best with bacterial eradication. β-lactams can be inactivated by bacterial β-lactamases, a process that can be prevented by combining them with β-lactamase inhibitors such as sulbactam, clavulanate, and tazobactam. Bacterial resistance against the β-lactam antibiotics continues to increase at a dramatic rate. Mechanisms of resistance include not only production of β-lactamases but also alterations that cause decreased entry or active efflux of antibiotic and acquisition of novel PBPs.

Penicillins

Natural penicillins (penicillin G)—The use of penicillin G in the ICU is limited to treatment of proven infection due to sensitive organisms. It is active against most streptococci but penicillin-resistant S. viridans and S. pneumonia are becoming more common. It is not active against staphylococci. It continues to be highly active against Neisseria, Clostridia, Corynebacterium, Treponema, Leptospira, and Actinomyces species as well as Treponema pallidum and Borrelia burgdorferi.

Antistaphylococcal penicillins (methicillin, oxacillin, and nafcillin)—The antistaphylococcal penicillins were specifically developed to treat infections due to S. aureus. They are the preferred drugs for infections with methicillin-sensitive strains (MSSA) because their use has been associated with decrease mortality compared to vancomycin.⁸ However, in areas where MRSA is broadly prevalent these agents should not be used alone for empiric treatment of suspected S. aureus infections.⁹

Aminopenicillins (ampicillin and ampicillin/sulbactam)—Ampicillin is the drug of choice for infections due to Listeria monocytogenes and those caused by sensitive strains of Enterococcus. Although it has activity against some community-acquired gram-negative organisms, many strains of H. influenza, E. coli, Enterobacter, and Klebsiella species are resistant, as are Serratia, Pseudomonas, and Acinetobacter species. Ampicillin–sulbactam has a wide range of antibacterial activity that includes gram-positive and gram-negative aerobic and anaerobic bacteria. However, the drug is not active against Pseudomonas and pathogens producing ESBLs. In addition, it is no longer recommended as an empiric treatment for community-acquired intra-abdominal infections due to a high prevalence of resistant E. coli.¹⁰ One of the specific advantages of this agent is the inherent activity of sulbactam against Acinetobacter baumannii, making it a valuable option against MDR isolates.¹¹

Extended spectrum penicillins (piperacillin–tazobactam and ticarcillin–clavulanate)—Piperacillin–tazobactam and ticarcillin–clavulanate are β-lactam/β-lactamase combinations with a broad spectrum of antibacterial activity. Their gram-positive activity includes MSSA and some strains of Enterococcus. They have good activity against many nosocomial gram-negative organisms including most strains of Pseudomonas, but are not effective against ESBL-producing E. coli and Klebsiella species. Resistance may develop during therapy for Enterobacter and other organisms that produce inducible β-lactamases, so they are not the preferred drugs for serious infections due to these organisms. They are frequently included as part of an empiric regimen for critically ill patients with new-onset sepsis. Piperacillin–tazobactam, in particular, has been shown to be effective in the treatment of patients with intra-abdominal infections, HCAP, complex skin and soft tissue infections (cSSTIs), and febrile neutropenia.¹²

Cephalosporins

The cephalosporins are commonly used in the ICU. They are classified into generations, each having been developed to combat specific groups of resistant organisms.

First-generation cephalosporins (cefazolin)—Cefazolin has good activity against β-hemolytic streptococci, MSSA, and many community-acquired gram-negatives. It is no longer a preferred drug for empiric treatment of skin and soft tissue infections due to the increased prevalence of community- and hospital-acquired MRSA.

Second-generation cephalosporins (cefoxitin, cefotetan, and cefuroxime)—These have broader spectra than the first-generation agents, covering most strains of E. coli, Enterobacter, Proteus, and Klebsiella species. They are less active than the first-generation agents against gram-positives, but both cefoxitin and cefotetan have good anaerobic activity. The use of these agents in the ICU is generally limited to community-acquired intra-abdominal infections. Like nearly all cephalosporins, they are not active against Enterococcus species.

Third-generation cephalosporins (ceftriaxone and ceftazidime)—Ceftriaxone has good activity against Pneumococcus, β-hemolytic streptococci, and MSSA. Its activity is more variable against S. viridans and it has no activity against MRSA. It is highly active against Haemophilus, Moraxella, Neisseria, Salmonella, and Shigella species. However, like other third-generation cephalosporins, it has variable activity against most Enterobacteriaceae. It is not active against Acinetobacter, Pseudomonas, or Stenotrophomonas maltophilia. Extensive data from randomized clinical trials confirm the efficacy of ceftriaxone in treatment of serious and difficult to treat community-acquired infections including pneumonia, pyelonephritis, and (at high dose) meningitis. Ceftriaxone is currently recommended as a first-line empirical treatment option (with the addition of a macrolide) for community-acquired pneumonia (CAP) in both Europe and the United States. Ceftazidime has good coverage against gram-negatives including Pseudomonas. However, its gram-positive activity is poor. In the past it was used extensively for neutropenic fever and for meningitis related to neurosurgical procedures, but its clinical niche has been greatly diminished by the development of cefepime.

Fourth-generation cephalosporins (cefepime)—Cefepime is a broad-spectrum agent with activity against gram-positive organisms such as Streptococcus pyogenes, Streptococcus pneumoniae, and MSSA. It also has good activity against nosocomial gram-negative bacteria including many strains of Pseudomonas, E. coli, and Klebsiella. It has poor activity against agents such as Stenotrophomonas maltophilia, Acinetobacter, and gram-negative anaerobes. Although ESBL-producing organisms are frequently sensitive to this agent in vitro, the clinical efficacy of cefepime in treating serious infections due to these organisms may be inferior to that of the carbapenems. Cefepime is a recommended agent for empiric treatment of HCAP, neutropenic fever, and central nervous system (CNS) infections associated with neurosurgical procedures.

Fifth-generation cephalosporins (ceftaroline)—Ceftaroline, unlike other cephalosporins, possesses bactericidal activity against resistant gram-positive pathogens including MRSA and resistant pneumococci. It also covers many gram-negative pathogens. However, it has poor activity against Pseudomonas, Acinetobacter, and ESBL-producing organisms. Approved indications for ceftaroline include cSSTIs and CAP.

Carbapenems (Imipenem/Cilastatin, Meropenem, Doripenem, and Ertapenem)

Carbapenems are broad-spectrum agents that are frequently reserved for critically ill patients with suspected or proven infection due to resistant nosocomial organisms. They are active against organisms that produce inducible amp-C β-lactamases as well as those that produce ESBLs. With the exception of ertapenem, they are useful in the treatment of Pseudomonas and Acinetobacter infections. However, they are not active against MRSA, Enterococcus faecium, Stenotrophomonas maltophilia, and Burkholderia cepacia. Because of their broad range of activity, imipenem–cilastatin, meropenem, and doripenem are indicated for complicated intra-abdominal infections, HCAP, neutropenic sepsis, and CNS infections related to neurosurgical procedures. Ertapenem is a newer analogue and has a prolonged half-life. It has a narrower spectrum than the other carbapenems and is not active against Pseudomonas or Acinetobacter species. It is indicated for CAP, urinary tract infections (UTIs), and intra-abdominal infections.

Monobactams (Aztreonam)

Aztreonam has broad aerobic gram-negative activity but lacks gram-positive and anaerobic activity. Its spectrum includes Pseudomonas but it is ineffective against ESBL-producing organisms. The majority of Acinetobacter and S. maltophilia strains are resistant. Resistant strains of P. aeruginosa frequently emerge during aztreonam monotherapy. Aztreonam has minimal cross-allergenicity with the other β-lactams, with the exception of ceftazidime due to structural similarity. Aztreonam is frequently used in treating patients with severe β-lactam allergy, usually in combination with other agents such as vancomycin or an aminoglycoside.

Adverse Effects of β-Lactams

Allergic reactions are the most common serious adverse effects noted with the β-lactams. These may manifest as maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens–Johnson syndrome, and anaphylaxis. The reported overall incidence of such reactions to the penicillins is 0.7% to 10%. Historical reports of penicillin allergy may be inaccurate; only about 20% of patients with a reported penicillin allergy have such an allergy confirmed on skin testing.¹³ There is cross-allergenicity between all the forms of penicillin. Studies have reported 1% to 20% cross-allergenicity between penicillins, cephalosporins, and carbapene-ms. Persons who have had a non-life–threatening reaction to one class of β-lactam may receive a trial agent of a different class for appropriate empiric or definitive therapy. For patients with a history of life-threatening allergy, in whom a β-lactam agent is necessary, desensitization may be required. Other serious adverse effects of the β-lactams include interstitial nephritis, transaminitis, bone marrow suppression, and lowering of the seizure threshold.

Aminoglycosides (Gentamicin, Amikacin, and Tobramycin)

Aminoglycosides are bactericidal agents which bind irreversibly to the 30S subunit of the bacterial ribosome. They have excellent activity against gram-negative aerobic bacteria. They are ineffective against gram-positive and anaerobic bacteria. However, in the presence of a cell-wall active antibiotic, they may have a synergistic effect against aerobic gram-positive organisms. These agents exhibit concentration-dependent killing; bactericidal activity is maximized when the peak serum concentration is 8 to 10 times above the MIC. They also have a significant postantibiotic effect. These two pharmacodynamic properties provide the rationale for high-dose, extended-interval dosing of aminoglycosides.¹⁴ High dosing (5-7 mg/kg for gentamicin or tobramycin and 15-20 mg/kg for amikacin) assures adequate peak concentrations; this eliminates the need to check peak serum levels. Extended dosing intervals may also limit nephrotoxicity by allowing time for renal recovery. Trough concentrations should be confirmed to be essentially zero when this strategy is used.

The most common indications for the primary use of aminoglycosides in the critically ill patient are complicated UTIs, complicated intra-abdominal infections (in addition to an agent with anaerobic activity), and gram-negative bacteremia. These agents are also recommended in combination with an antipseudomonal β-lactam as empiric therapy for patients with HCAP and as definitive therapy for patients with confirmed pseudomonal bacteremia. Synergistic doses of gentamicin (1-1.5 mg/kg every 8-12 hours for patients with normal renal function) are recommended for combination therapy for enterococcal endocarditis, staphylococcal or streptococcal endocarditis in the presence of a prosthetic valve, and streptococcal endocarditis in the presence of intermediate penicillin resistance.

Aminoglycosides are inactivated in acidic, anaerobic environments such as abscesses and have poor lung tissue penetration. Inhaled aminoglycosides may overcome this latter limitation, although clinical data to support this mode of administration are limited.

The primary toxicities of aminoglycosides are dose-related nephrotoxicity, ototoxicity, and neuromuscular paralysis. With the exception of the ototoxicity, these adverse reactions may be reversible after drug discontinuation. Elevated serum trough levels, hypotension, concurrent nephrotoxic drugs, female sex, and liver disease have been shown to increase the risk of aminoglycoside-induced nephrotoxicity. These agents should be used with caution in patients receiving neuromuscular blocking agents and in patients with neuromuscular disease.

Fluoroquinolones (Ciprofloxacin, Levofloxacin, and Moxifloxacin)

These bactericidal agents act by inhibiting bacterial DNA gyrase and/or topoisomerase-IV, resulting in damage to bacterial DNA and cell death. Quinolones exhibit concentration-dependent killing. Bactericidal activity becomes more pronounced as the serum drug concentration increases to roughly 30 times the MIC. Ciprofloxacin, a second generation quinolone, has expanded gram-negative activity and atypical pathogen coverage. It is distinguished by its potency against Pseudomonas, for which it is the most useful fluoroquinolone for systemic therapy. It is a valuable agent for treatment of complicated UTIs, prostatitis, and as part of combination therapy for HCAP. However, it is not a preferred agent for CAP because of poor pneumococcal susceptibility. Levofloxacin and moxifloxacin, the third generation quinolones, are characterized by clinically useful antibacterial activity against Chlamydia, Legionella, Mycoplasma, and streptococci including penicillin-resistant pneumococci. They are recommended first-line agents for treatment of CAP, either alone or in combination with extended-spectrum cephalosporin. Moxifloxacin does not concentrate in the urine and thus should not be used for UTIs. Fluoroquinolones are generally well tolerated. Adverse effects include gastrointestinal and CNS symptoms as well as dysglycemia and QT-interval prolongation. Achilles tendon rupture is a rare adverse effect of fluoroquinolones.

Miscellaneous Antibacterials

Vancomycin—The glycopeptide antibiotic vancomycin acts by disrupting the biosynthesis of peptidoglycan, the primary structural polymer of gram-positive cell walls. Vancomycin exhibits time-dependent bactericidal activity. It is active against number of aerobic and anaerobic gram-positive bacteria. Vancomycin is a first-line agent for suspected or proven methicillin-resistant strains of coagulase-negative and coagulase-positive staphylococcal infections, including bacteremia, endocarditis, pneumonia, cSSTI, osteomyelitis, septic arthritis, and CNS infections. It should not be used to treat MSSA infections because it is inferior to β-lactams for these infections. Vancomycin is a drug of choice for infections caused by penicillin-resistant streptococci and enterococci. It is recommended as initial therapy for cases of proved, suspected, or possible pneumococcal meningitis, in combination with a third-generation cephalosporin. Oral vancomycin is the drug of choice for the treatment of severe C. difficile enterocolitis.

Unfortunately, the prevalence of vancomycin resistance is on the rise among Enterococcus species and S. aureus. Although plasmid-mediated vancomycin resistance remains rare among S. aureus, intermediate sensitivity due to the production of a thickened cell wall is an increasing problem. Intermediate resistance may develop during therapy, so MICs should be rechecked whenever cultures remain persistently positive. S. aureus strains with MICs more than 1.5 mcg/mL have been associated with poorer response rates. In addition, strains that display variable sensitivity to vancomycin (heteroresistance) have been reported and associated with treatment failure.¹⁵

Rapid infusion of vancomycin can lead to histamine-release-induced “red man” syndrome. Clinical signs and symptoms include pruritus, erythema and flushing of the upper torso, angioedema, and (occasionally) hypotension. Slow infusion (over at least 2 hours) and prophylactic antihistamines may prevent this syndrome. Nephrotoxicity is much less common with modern formulations of the drug but may occur with persistently elevated trough levels (>20 mcg/mL) or with concurrent aminoglycoside therapy. These are also the primary risk factors for ototoxicity, which may be irreversible. Vancomycin-induced neutropenia is rare.

Linezolid—Linezolid is an oxazolidinone antibiotic which acts in a bacteriostatic manner by blocking protein synthesis via the 50S ribosomal subunit. It is active against gram-positive aerobes including S. aureus (MSSA, MRSA, VISA, and VRSA), streptococci, and enterococci including vancomycin-resistant strains (VRE). Linezolid is recommended as an initial or alternative therapy for patients with cSSTIs, osteomyelitis, septic arthritis, meningitis, and brain abscesses. In one clinical trial, patients with confirmed MRSA pneumonia treated with linezolid had higher clinical response rates than those who received vancomycin (57% vs 46%).¹⁶ Thus it is a reasonable choice for initial empiric MRSA coverage in patients with HCAP. However, because linezolid is a bacteriostatic agent, it is generally not recommended as first-line therapy for endovascular infections. Some gram-positive organisms have developed resistance to linezolid, but fortunately this is currently at low prevalence (<1%). Irreversible peripheral neuropathy and optic neuritis have been described with prolonged use. Other adverse effects with extended use include thrombocytopenia and lactic acidosis. Linezolid is a weak monoamine oxidase inhibitor. Concurrent serotoninergic medications are contraindicated.

Daptomycin—Daptomycin, a cyclic lipopeptide antibiotic, exerts its bactericidal effects by binding to, damaging, and causing depolarization of the cell membrane of gram-positive bacteria. Its antibacterial spectrum covers staphylococci (MSSA, MRSA, VISA, and VRSA), streptococci, and enterococci including VRE. Daptomycin is indicated for bacteremia and endocarditis caused by these organisms, either as initial therapy or in cases of reduced vancomycin sensitivity or clinical failure. It is also recommended as an initial or alternative therapy for cSSTIs. Its antibacterial activity is inhibited by pulmonary surfactant, and it should not be used for treatment of pneumonia. The prevalence of daptomycin resistance in clinical isolates of S. aureus appears to be low (0.3%). Unfortunately, the prevalence of daptomycin resistance appears to be increased in those MRSA isolates with reduced vancomycin sensitivity. Rhabdomyolysis is the primary toxicity of the drug. Concurrent use of statins may increase the risk of this toxicity.

Tigecycline—Tigecycline, a glycylcycline antibiotic closely related to the tetracyclines, has a broad spectrum of activity. It is a bacteriostatic agent that binds to the bacterial 30S ribosomal subunit. Tigecycline covers gram-positive and gram-negative aerobes and anaerobes as well as atypical species. It is active against MRSA, VRE, ESBL-producing organisms, inducible ampC producing organisms, KPC organisms, Stenotrophomonas, and C. difficile. However, it is inherently inactive against Pseudomonas species and is less effective against Proteus and Providencia species. Although it is effective in vitro against Acinetobacter isolates, there is increasing concern with clinical-treatment failures. It is FDA approved for the treatment of CAP.

Tigecycline is a bacteriostatic agent and does not maintain adequate serum concentrations for the treatment of bloodstream infections. In addition, in 2013 the FDA issued a black box warning based on postmarketing analyses suggesting an increased risk of death in patients with pneumonia who receive tigecycline as compared with other antimicrobials.¹⁷ Thus, this agent should only be used when no other antimicrobial options are available. The most frequent side effects associated with the use of tigecycline are gastrointestinal.

Azithromycin—Azithromycin belongs to the macrolide class of antibiotics, which inhibit protein synthesis by binding to the 50S subunits of bacterial ribosomes. It is active against S. pneumonia and Hemophilus as well as atypical pneumonia pathogens including Legionella, Chlamydia, and Mycoplasma. It is recommended in combination with ceftriaxone for the empiric treatment of CAP. Major toxicities of azithromycin include hepatic injury and QT-interval prolongation.

Doxycycline—Doxycycline is the most commonly used tetracyclines which function by binding to the 30S ribosomal subunit. It is a bacteriostatic agent that is active against many aerobic and atypical pathogens including Rickettsia, Borrelia Chlamydia, and Mycoplasma. Due to high rates of pneumococcal resistance in the United States it is not a drug of choice for CAP.

Clindamycin—Clindamycin works primarily by binding to the 50S ribosomal subunit of bacteria and disrupting protein synthesis. It is active against gram-positive organisms including streptococci and S. aureus including some strains of community-acquired MRSA. It has excellent anaerobic activity, although some gram-negative anaerobes such as Bacteroides show resistance. It is also frequently used to decrease superantigen production in toxic shock syndromes due to β-hemolytic streptococci and S. aureus. Clindamycin use increases the risk of C. difficile colitis.

Metronidazole—Metronidazole is a bactericidal agent that acts by fatal destabilization of the DNA helix. It is active against most anaerobic gram-negative bacilli including Bacteroides, Prevotella, Fusobacterium, and Clostridium species but has minimal activity against many anaerobic gram-positive organisms. It is also active against some protozoa including Entamoeba and Giardia. Oral metronidazole is the drug of choice for treatment of mild to moderate C. difficile colitis. Because of good CNS penetration, it is empirically included to cover anaerobes in the setting of brain abscess. It is a preferred agent for intra-abdominal and genital infections. Taste disturbances and peripheral neuropathy are the major side effects of metronidazole.

Trimethoprim/sulfamethoxazole—Trimethoprim/sulfamethoxazole (TMP-SMX) is available in a fixed combination of 1:5 and works by sequential blockade of microbial folic acid synthesis. The use of TMP-SMX in the ICU is often limited to patients known to have susceptible organisms or to immunocompromised patients with suspected Pneumocystis jirovecii infections. TMP-SMX is also a first-line treatment for infections caused by the gram-negative bacilli Stenotrophomonas maltophilia and Burkholderia cepacia. Skin rashes, bone marrow suppression, interstitial nephritis, hyperkalemia, and aseptic meningitis are major side effects.

Polymyxin B and colistin (polymyxin E)—Polymyxins are cationic polypeptides which were originally discovered in 1950s. The use of polymixins decreased over the next few decades because of their toxicity profile and the development of newer, more tolerable agents. However, recently they have been reintroduced for the treatment of MDR gram-negative bacilli infections. These agents interact with the anionic lipopolysaccharide molecules in the outer membrane of gram-negative bacteria, ultimately resulting in loss of membrane integrity and cell death. Polymyxin B and colistin have identical spectra, and are active against most aerobic gram-negative bacilli including MDR Pseudomonas aeruginosa, Acinetobacter species, Stenotrophomonas maltophilia, ESBL-producing organisms such as Klebsiella species and E. coli, and carbapenemase-producing Enterobacteriaceae. They are not active against Serratia and Proteus species. They are inherently inactive against gram-positive bacteria and anaerobes. Reasonable clinical cure rates (close to 70%) have been reported in critically ill patients treated with the polymyxins for pneumonia and bacteriemia caused by MDR strains of Pseudomonas and Acinetobacter.¹⁸ Although clinical data is limited, these agents may also be administered intrathecally for meningitis and in aerosolized form for pneumonia in cases of resistant or refractory disease. The most common toxicities of the polymyxins are dose-dependent nephrotoxicity and neurotoxicity. In the past, reported incidences of nephrotoxicity were as high as 58%. However, recent data suggest an incidence of 10%. Neurotoxicity occurs in about 5% of patients and includes perioral paresthesias, ataxia, visual disturbances, confusion, vasomotor instability, and neuromuscular blockade.

Antifungals

Polyenes (Amphotericin B Deoxycholate, Liposomal Amphotericin B, Amphotericin B Lipid complex, and Amphotericin B Colloidal Dispersion)

The polyenes act by binding to sterols in the fungal cell membrane, increasing permeability and precipitating cell death. The various formulations of amphotericin B have the broadest antifungal spectra, with resistance among only a few significant species including Aspergillus terreus and Candida lusitaniae. Amphotericin B in combination with flucytosine continues to be the mainstay of initial treatment of CNS or disseminated cryptococcosis. It has been replaced by voriconazole as the first-line agent for treatment of invasive aspergillosis. It is the mainstay of treatment against all forms of invasive mucormycosis as well as against life-threatening forms of histoplasmosis, blastomycosis, and coccidiomycosis. Infusion of amphotericin B is commonly associated with severe febrile reactions, generalized malaise, and gastrointestinal symptoms. These can be minimized by prophylactic antihistamines, antipyretics, and antiemetics. Rapid infusion of amphotericin B has been reported to precipitate life-threatening hyperkalemia and cardiac arrhythmias; therefore, the daily dose of amphotericin B should be infused over 2 to 6 hours. Dose-dependent nephrotoxicity is the major limitation of amphotericin B, and about 80% of the patients receiving the deoxycholate form of the drug show some degree of renal impairment. It manifests as azotemia, decreased urinary concentration ability and a distal renal tubular acidosis with profound potassium and magnesium wasting. The most effective preventative measure is preinfusion and postinfusion crystalloid administration. Although higher doses of the liposomal forms are necessary to achieve equivalent serum levels, they have been shown to be less nephrotoxic than amphotericin B deoxycholate. They are used routinely in critically ill patients despite their higher cost. Anemia is common with long-term amphotericin B therapy. Hepatotoxicity is rare but may be severe.

Azoles (Fluconazole, Voriconazole, and Posaconazole)

Azoles inhibit the enzyme lanosterol 14-alpha-demethylase, which converts lanosterol to ergosterol, a key component of cell membranes. In areas with a low prevalence of azole-resistance, fluconazole is a first-line empiric therapy for candidal infections in non-neutropenic, azole-naïve hemodynamically stable patients. It has no activity against Candida krusei and up to 30% of Candida glabrata; and therefore, should not be used as empiric therapy for invasive candida infections in hemodynamically unstable patients. It has good CNS penetration and may be used in stable patients with endophthalmitis and meningitis due to sensitive Candida species. It is effective in the primary treatment of coccidiomycosis and as maintenance therapy for disseminated cryptococcal infections. It is ineffective against the molds and is not reliable against Histoplasma or Blastomyces. Voriconazole is the first-line agent against invasive Aspergillus fumigatus infections and has been found to be superior to traditional amphotericin B against such infections.¹⁹ It is also active against Fusarium and Scedosporium species as well as some fluconazole resistant Candida species. It has no activity in mucormycosis. The intravenous form should be used with caution in patients with renal insufficiency due to potential accumulation of cyclodextrin, a vehicle used in the formulation. Posaconazole has expanded the spectrum of the triazole agents to include the Zygomycetes while maintaining against yeasts and molds covered by voriconazole. It may show activity against Candida species resistant to fluconazole and Aspergillus species resistant to amphotericin B and voriconazole. Posaconazole has shown promising results as a salvage therapy for the treatment of refractory fungal CNS, lung, oropharyngeal, and esophageal infections. Posaconazole is currently only available in the oral form. Absorption is improved when taken with high fat meals. Azoles are potent cytochrome P-450 enzyme inhibitors, leading to interactions with many drugs including cyclosporine, phenytoin, tacrolimus, and warfarin. The most common adverse effects of the azoles are gastrointestinal upset and reversible transaminitis. Voriconazole has been noted to cause transient visual disturbances.

Echinocandins (Caspofungin, Micafungin, and Anidulafungin)

The echinocandins act by inhibiting β-1,3 glucan synthase, thus disrupting cell wall synthesis. These agents are rapidly fungicidal against most Candida species and fungistatic against Aspergillus species. They are first-line agents for treatment of invasive Candida infections in critically ill patients, neutropenic patients, and those with prior azole exposure. At present, all 3 echinocandins should be viewed as equally effective for candidemia. In clinical trials, they have shown superior microbiologic and clinical cure rates to fluconazole when treating candidemia, including that caused by fluconazole-sensitive Candida albicans.²⁰ In addition, they may be used in combination with amphotericin B or voriconazole for treatment of invasive aspergillosis. They have no activity against mucormycosis and cryptococcal species. They are generally well tolerated with the most commonly reported side effects being headaches, chills, elevated liver enzymes, and phlebitis at the infusion site.

Antivirals

Nucleoside Analogues (Acyclovir, Valacyclovir, Ganciclovir, and Valganciclovir)

These drugs require phosphorylation in virally infected cells to become active. They then become competitive substrates for the viral DNA polymerase, causing chain termination. Acyclovir is the drug of choice for all forms of HSV-1 disease including encephalitis, pneumonia, and hepatitis as well as for genital disease due to HSV-2. It is also used for pneumonia or disseminated disease due to VZV. It is not effective for EBV or CMV disease. Valacyclovir is a prodrug which has enhanced oral bioavailability; it is converted to acyclovir after first-pass metabolism. Resistance to acyclovir most commonly develops from mutations in viral thymidine kinase. Ganciclovir is the mainstay of treatment and prophylaxis of CMV retinitis, pneumonitis, and gastrointestinal infections in immune-compromised (HIV, solid organ and bone marrow transplant) patients. Ganciclovir has activity against HSV and VZV, but its toxicity profile precludes its use in these infections. Resistance to ganciclovir results from either reduced phosphorylation because of mutations in viral phosphotransferase gene or secondary to mutations in the gene encoding viral DNA polymerases. Valganciclovir, a prodrug, is converted to ganciclovir providing a potent oral alternative to intravenous ganciclovir. The adverse effects of the nucleoside analogues are primarily seen when the drugs are given in high doses intravenously. Nephrotoxicity can occur with either drug. Acyclovir can precipitate in renal tubules; this can be prevented with adequate volume administration and slow infusion rates. Reversible myelosuppression (neutropenia, thrombocytopenia) is the most notable adverse effect of ganciclovir, occurring in 25% to 30% of recipients. Both drugs can cause CNS toxicity including confusion, seizures, extrapyramidal signs, and autonomic instability.

Pyrophosphate Analogues (Foscarnet)

Foscarnet acts by inhibiting DNA and RNA polymerases. It is active against CMV, HSV, and VZV. Foscarnet is the drug of choice for the treatment of CMV infections in individuals unable to tolerate ganciclovir, for patients with acyclovir-resistant HSV and VZV infection, and for those with ganciclovir-resistant CMV infections. Nephrotoxicity is a common adverse effect of foscarnet. Bone marrow suppression and transaminitis may also occur.

Neuraminidase Inhibitors (Oseltamivir and Zanamivir)

Oseltamivir and zanamivir are active against influenza A and influenza B. They are indicated for suspected or confirmed influenza infection in all critically ill patients. Oseltamivir is only available in oral formulation. Zanamivir can be delivered as an inhalational drug but this form cannot be given to patients on mechanical ventilation. An intravenous formulation of zanamivir exists, but currently can only be obtained from the manufacturer as compassionate release. The prompt receipt of these medications has been associated with improved outcomes in patients with pandemic H1N1 influenza. They are usually well tolerated, with the most common side effects being headache, dizziness, and vertigo. Inhaled zanamivir can cause bronchospasm and is contraindicated in patients with asthma and chronic obstructive pulmonary disease.