REVIEW ARTICLE

Year : 2023  |  Volume : 2  |  Issue : 1  |  Page : 7-17

Antibiotic challenges and review of appropriate uses in intensive care unit

Lalit Gupta, Kirti N Saxena, Ruchi Goyal
Department of Anaesthesiology and Critical Care, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India

Correspondence Address:
Dr. Ruchi Goyal
Department of Anaesthesia and Critical Care, Maulana Azad Medical College, Lok Nayak Hospital, New Delhi - 110 002
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jica.jica_1_23

Antibiotic use in the intensive care unit (ICU) presents unique challenges due to the high acuity and complexity of critically ill patients. Inappropriate use of antibiotics can contribute to the emergence of multidrug-resistant organisms, while underuse can lead to poor outcomes. Antimicrobial stewardship programs can assist in optimizing antibiotic use in the ICU, but implementation can be challenging. One approach to improving appropriate antibiotic use in the ICU is through prolonged infusions, which can be beneficial in populations with altered pharmacokinetics. Other strategies include de-escalation and targeted therapy based on culture results. This review highlights the current literature on antibiotic use in the ICU, including the challenges and opportunities for effective antimicrobial stewardship. Key considerations for appropriate use of antibiotics in the ICU include patient factors, pathogen susceptibility, and local resistance patterns. Ongoing efforts are needed to improve antibiotic prescribing practices in the ICU, with the goal of achieving optimal patient outcomes while minimizing the risk of antibiotic resistance.

Keywords: Antibiotics, intensive care unit, antimicrobial stewardship, prolonged infusions, de-escalation, targeted therapy

Introduction

Classification of Antibiotics

Figure 1: Mechanism of action of antibiotics Click here to view

Table 1: Basis of antibiotic classification Click here to view

• Beta-lactams^[3],[4] = Penicillins (PCNs), cephalosporins, carbapenems, and monobactam.



• Significant side effects: Anaphylaxis, rashes, gastrointestinal (GI) symptoms (nausea, diarrhea, and Clostridioides difficile), bone marrow suppression, and interstitial nephritis.

• 1^st generation = Penicillin G (IV) or V (PO), used for Group A Strep (for example, Strep throat), syphilis, and PCN-sensitive Streptococcus, also gets most oral anaerobes
• 2^nd generation = Ampicillin (IV), Amoxicillin (PO) covers some Gram (+) and Gram (−), but not Pseudomonas. Best indicated and prescribed for upper respiratory infections
• 3^rd generation = Anti-Staph PCNs: Methicillin/nafcillin/oxacillin (IV). Nafcillin is a drug of choice for methicillin-susceptible Staphylococcus aureus (MSSA). Good for cellulitis, osteomyelitis, and endocarditis (IV only)
• 4^th generation = Antipseudomonal PCNs – piperacillin, ticarcillin – usually combined with beta-lactamase inhibitors (see below).

• Tazobactam is added to the extended-spectrum beta-lactam antibiotic piperacillin. By enabling piperacillin to be effective against organisms that produce β-lactamase, it broadens the spectrum of piperacillin. Piperacillin has antimicrobial activity against a wide range of Gram (−) organisms, including Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacteriaceae, Haemophilus influenzae, and bacteroids and against Gram (+) organisms, for example, S. aureus (except MRSA), Enterococcus faecalis, and Bacteroides fragilis.



1. Dose: IV – The therapeutic dose is 3.375 mg four times a day, for 7–10 days. A higher initial dose of 4.5 mg four times a day may be used for more severe infections. Start with 4.5 g every 8 h plus an aminoglycoside. The recommended duration of treatment is 7–14 days
2. Indicated for the treatment of moderate-to-severe infections
3. Appendicitis (complicated by rupture or abscess) and peritonitis: The Bacteroides group: B. fragilis, etc.
4. Skin infections such as cellulitis, cutaneous abscesses, and ischemic/diabetic foot infections
5. Postpartum endometritis or pelvic inflammatory disease
6. Community-acquired pneumonia (moderate severity only)
7. Nosocomial pneumonia (moderate to severe).

1. Augmentin (amoxicillin/clavulanate = PO), Unasyn (ampicillin/sulbactam = IV) Gram (+), Gram (−), anaerobes, but no Pseudomonas. Used for a variety of infections, including respiratory infections, some skin/soft-tissue infections, some intra-abdominal infections, and more
2. Zosyn (piperacillin/tazobactam), Timentin (ticarcillin/clavulanate) – as above, but also covers Pseudomonas. Many uses: Hospital-acquired Pseudomonas, complicated skin infections such as cellulitis, cutaneous abscesses, empiric sepsis, and intra-abdominal infections.



• Does NOT cover: MRSA, VRE, atypicals (Chlamydia, Mycoplasma, and Legionella), and ESBLs
• Higher dosing for Pseudomonas coverage: 4.5 g q6 h (vs. 3.375 q6 for others)
• ”Extended Infusion” strategy– 3.375 g over 4 h, q8 h (maximize above minimal inhibitory concentration).

• Main indication is resistant Gram (−) bacteria, particularly P. aeruginosa and Proteus vulgaris
• Indicated for septicemia caused by beta-lactamase-producing isolates of Klebsiella species, Escherichia coli, S. aureus, or P. aeruginosa
• Dose: 3.1 g IV q4-6 h.

• 1^st generation: Cefazolin (Ancef or Kefzol) - IV, cephalexin (Keflex) - PO - excellent Gram (+) (MSSA and Strep), minor Gram (−) = Proteus, E. coli, and Klebsiella. Good drug for cellulitis (unless suspect MRSA), also cefazolin is used for prophylaxis during surgery. Sometimes used for UTIs as well
• 2^nd generation: (a) Cefuroxime: Gram (+) and more Gram (−); more specific for respiratory infections. (b) Cephamycins-cefoxitin and cefotetan: Anaerobes (especially Bacteroides) and Gram (−), not Pseudomonas or Gram (+). Used for intra-abdominal infections, like cholecystitis. Cefotetan can cause elevated INR
• 3^rd generation: (a) Ceftriaxone (Monocef), cefotaxime = IV, cefpodoxime = PO: Good Gram (+) and Gram (−) coverage, but not Pseudomonas or anaerobes. Used for community-acquired Pseudomonas (with azithromycin), meningitis (ceftriaxone – best for intracranial pathology due to excellent cerebrospinal fluid [CSF] penetration), spontaneous bacterial peritonitis, skin/soft-tissue infections, bacteremia/endocarditis from susceptible Strep and Enterococcus, and more. (b) Ceftazidime (IV) has coverage limited to only Gram (−), including Pseudomonas with no Gram (+) coverage. Apart from pseudomonal infections, also antibiotic of choice for neutropenic fever (but beware no Staph/Strep coverage)
• 4^th generation: Cefepime (IV)-broad spectrum: Gram (+) and Gram (−) including Pseudomonas, but weak anaerobes. Used for empiric neutropenic fever, hospital-acquired PNA, meningitis if suspect Gram-negatives, and more
• 5^th generation: Ceftobiprole (IV) – broadest spectrum – Gram (+) including MRSA and Enterococcus, Gram (−) including Pseudomonas. Still awaiting approval in the U. S.
• (Note: No cephalosporin covers Enterococcus or atypicals. Only ceftazidime/cefepime covers Pseudomonas. Only cefoxitin and cefotetan have anaerobic coverage.)

Clinically Used Cephalosporins

1. Lower respiratory tract infections, including pneumonia, caused by Streptococcus pneumoniae, H. influenzae (including ampicillin-resistant strains), Klebsiella spp., S. aureus, Streptococcus pyogenes, and E. coli
2. Urinary tract infections caused by E. coli and Klebsiella spp.
3. Skin and bone and joint infections caused by S. aureus (penicillinase- and nonpenicillinase-producing strains), S. pyogenes, Klebsiella, Enterobacter, and E. coli
4. Septicemia caused by S. aureus (penicillinase- and nonpenicillinase-producing strains), S. pneumoniae, H. influenzae (ampicillin-resistant strains), Klebsiella, and E. coli
5. Meningitis caused by S. pneumoniae, H. influenzae, Neisseria meningitidis, and S. aureus (its distinctive feature is that it can cross the blood–brain barrier)
6. Gonorrhea: Neisseria gonorrhoeae (penicillinase- and nonpenicillinase-producing strains).

1. Cefepime is a reserved drug for infections caused by multidrug-resistant bacteria (for example, P. aeruginosa), nosocomial pneumonia, and empirical treatment of febrile neutropenia
2. Cefepime has good activity against important pathogens including P. aeruginosa, S. aureus, and multidrug-resistant S. pneumoniae. Its main strength is its activity against Enterobacteriaceae. Unlike other cephalosporins, which are degraded by many plasmid- and chromosome-mediated beta-lactamases, cefepime is stable and is used as a first-line therapy against Enterobacteriaceae
3. Dosage: Adults: 1–2 g every 12 h. for 10 days.

1. It has broad-spectrum activity against Gram (+) and Gram (−) bacteria. Unlike most third-generation agents, it is also active against P. aeruginosa; however, it has weaker activity against Gram (+) microorganisms and is not used for such infections
2. Indications: Lower respiratory tract infections, skin and skin structure infections, urinary tract infections, pelvic inflammatory disease, bacterial septicemia, bone and joint infections, intra-abdominal infections, and central nervous system (CNS) infections.

1. Sulbactam/cefoperazone is a broad-spectrum antimicrobial agent that has activity against most Gram-negative organisms, including P. aeruginosa and Acinetobacter baumannii, Gram-positive organisms such as Streptococcus and MSSA, and anaerobes. However, its spectrum is still narrower than imipenem/cilastatin plus vancomycin. Sulbactam/cefoperazone does not have activities to MRSA and enterococci and it has a limited activity to ESBL-producing Gram-negative bacilli
2. It has at least four times the activity of cefotaxime or moxalactam against P. aeruginosa, A. baumannii, Enterobacteriaceae, and anaerobes, including Peptostreptococcus and is roughly as active as piperacillin. Cefoperazone is also highly active against Haemophilus and Neisseria species. If aminoglycoside is used as a second antibiotic, renal function should be monitored during the course of the therapy.

1. Broadest spectrum antibiotics cover Gram (+), Gram (−), including Pseudomonas (except ertapenem) and ESBL (extended-spectrum beta-lactamase producers) and also anaerobes. Great penetration virtually everywhere, including CSF. Only class that reliably covers ESBL-producing organisms
2. Very broad – easier to remember what it does not cover: MRSA, VRE, atypicals, and Stenotrophomonas
3. Note that ertapenem does NOT cover Pseudomonas, but does still cover ESBL (the main advantage is once/day dosing-great outpatient IV drug)
4. Doripenem – newest carbapenem, main advantage = increased in vitro potency against Pseudomonas
5. Cross-reactivity with PCNs – previously thought to be fairly high (up to 40%), but the latest literature suggests that vast majority with PCN allergies will tolerate carbapenems
6. Main additional side effect is lowering seizure threshold (imipenem > meropenem).

1. It has a very wide spectrum of activity against many Gram (+) and Gram (−) bacteria (including Pseudomonas) and anaerobic bacteria. It is stable to dehydropeptidase-1, unlike imipenem, hence it can be administered without cilastatin. Meropenem is often more effective against Gram (−) bacilli, while imipenem is more effective against Gram (+) cocci
2. Meropenem is 4–16 times more active against Enterobacteriaceae and almost eight times more effective N. gonorrhoeae and H. influenzae than imipenem
3. Meropenem is one of the primary indications for febrile neutropenia due to hematological malignancies
4. Meropenem has high comparatively higher penetration in gynecological tissues, respiratory tract tissues, urinary tract tissues, bile, blister fluid, inflammatory exudate, CSF (in the presence of inflammation), and abdominal tissues
5. It has primarily renal excretion and hence reduction is required in patients with reduced renal function; no dosage adjustment is required for patients with hepatic impairment.

1. Only has activity against aerobic Gram (−), very similar coverage as aminoglycosides
2. Almost no significant toxicity
3. Main advantages: (1) No cross-reactivity with penicillins, and (2) does not cause renal failure
4. Has a similar side chain as ceftazidime – if ceftazidime allergy, avoid aztreonam!

1. Azithromycin is a drug of choice for atypical coverage (Chlamydia, Mycoplasma, and Legionella), with some activity against Gram (+) cocci and some Gram (−). Commonly used for low-risk bronchitis or community-acquired Pseudomonas infections, sinusitis, and others
2. Used in conjunction with ceftriaxone for community-acquired pneumonia that requires hospitalization. Dose: 500 mg as a single daily dose by the intravenous route for at least 2 days, followed by 500 mg PO × 1 dose on day 1, followed by 250 mg PO qDay (every day) on days 2–5
3. Used for Mycobacterium avium complex (MAC) primary prophylaxis in HIV/AIDS patients. Also used for STD Chlamydia
4. Erythromycin use is now limited to GI motility agent – before endoscopy, or to advance feeding tubes
5. Clarithromycin is bactericidal and primarily indicated for MAC treatment (in combination with other drugs). Other indications are acute otitis media (H. influenzae and S. pneumoniae) and respiratory (S. pyogenes) tract infections. Side effects: QT prolongation, GI side effects, Rash. Dose: 250–500 mgs qBD for 7–14 days.

1. Great for atypicals, pathogens such as Rickettsia, Lyme disease, tularemia, Vibrio, Brucella, and also acne and rosacea
2. Weakly broad-spectrum versus Gram (+) and some Gram (−): Reasonable choice for low-risk outpatient respiratory infections. Furthemore, for some community-acquired MRSA skin infections
3. Resistance to tetracycline is common among the Enterobacteriaceae, staphylococci, streptococci, and Bacteroides
4. Side effects: Discoloration of teeth, inhibits bone growth in children, teratogenic, photosensitivity, and GI discomfort
5. Not in much use except doxycycline that has shown some positive results in COVID patients and in patients of pelvic inflammatory diseases
6. New tetracycline derivatives, such as glycylcyclines and dactylocyclines, are all being studied for potential use as clinical agents to circumvent existing tetracycline resistance mechanisms.

1. Excellent activity versus anaerobes and Gram (+) cocci – Strep and Staph, including ~ 50% of community-acquired MRSA, but NOT enterococci
2. Used as empiric drug for cellulitis due to Strep/Staph coverage (non-MRSA). Also indicated for its antitoxin effect in toxic shock syndrome or necrotizing fasciitis (group A streptococci)
3. Does not penetrate CSF. Hence, no indication in CNS pathologies.
4. Causes the highest rate of C. difficile among all antibiotics (~10%)
5. Doses: 150–450 mg PO q6-8 h; not to exceed 1.8 g/day, OR 1.2–2.7 g/day IV/IM divided q6-12 h (max. dose 4.8 g/day)
6. If MRSA appears susceptible – always have lab check “D-test” (looks for inducible resistance to clindamycin in strains that are resistant to erythromycin). If D-test positive, do not use clindamycin.

1. Aminoglycosides are active against various Gram (+) and Gram (−) types of organisms, particularly potent against members of the Enterobacteriaceae family, including E. coli, K. pneumoniae, and Proteus spp.
2. The class also has good activity against S. aureus, including MRSA and vancomycin-resistant isolates, P. aeruginosa and to a lesser extent Acinetobacter family
3. Synergistic effects with beta-lactams against Gram (+), especially in endocarditis (best evidence for Strep and enterococcal endocarditis, less for S. aureus).
4. Can be used as a double coverage agent versus Gram (−) with beta-lactams for hospital-acquired Pseudomonas
5. Dosing methods: “Traditional” dosing – q8-q12 h. dosing, versus “Once Daily” dosing, utilizes the extended “postantibiotic effect” (which continues to kill or inhibit bacteria even after the antibiotic is eliminated) and concentration-dependent killing with the added advantage of lower toxicity
6. Side effects: Nephrotoxicity-acute tubular necrosis (classically manifests after ~ 5 days) and ototoxicity – may be irreversible!!!

• CIPROFLOXACIN – Best Gram (−) coverage of fluoroquinolones (FQs), with virtually no Gram (+) coverage



• ALL FQs have atypical coverage (but ciprofloxacin – relatively weaker against Chlamydia and Mycoplasma, but good vs. Legionella) [Table 2]
• Used for many purposes (UTIs, double coverage of Pseudomonas including for hospital-acquired P. aeruginosa (PNA), prostatitis, and GI/intra-abdominal coverage – often with Flagyl).

Table 2: Common fluoroquinolones Click here to view




• Levofloxacin (Levaquin) – “Respiratory Fluoroquinolone” - Excellent activity versus Gram (+) in particular S. pneumoniae, slightly less reliable Pseudomonas coverage than ciprofloxacin.



• Good for atypicals
• Used for community-acquired PNA (can use as monotherapy), also UTIs, and double coverage of Pseudomonas, including hospital-acquired PNA.



• Moxifloxacin (Avelox) – also a respiratory FQ – with limitation versus levofloxacin is virtually no urine activity and no Pseudomonas activity (no role in hospital-acquired pneumonia).



• Best Gram (+), atypical, and anaerobic coverage out of FQs and also approved for complicated intra-abdominal infections
• Pazufloxacin (Pazace, Pazflo, and Pazmac)
• 
  
  Pazufloxacin (PZFX) has activity against Gram (+) and Gram (−) bacteria, including a variety of resistant strains and anaerobic bacteria
• Pazufloxacin has similar or 2-fold greater activity than other quinolones, against the Enterobacteriaceae, E. coli, Klebsiella, Enterobacter, Hafnia, Citrobacter, Proteus, Providencia, Serratia, Shigella, Salmonella, Aeromonas, and Yersinia against P. aeruginosa
• The antibacterial activities of PZFX are superior to those of ceftazidime (CAZ), ceftriaxone, imipenem/cilastatin, and meropenem against: MRSA, ampicillin-resistant H. influenzae, K. pneumoniae (ESBL type), and imipenem/cilastatin (IPM/CS)-resistant P. aeruginosa



• Pazufloxacin mesylate I.V. infusion is indicated for the following infections caused by susceptible microorganisms:



• Pneumonia and lung abscess
• UTIs such as cystitis, pyelonephritis, and prostatitis
• Abdominal infections such as peritonitis, cholecystitis, liver abscess, and other intra-abdominal abscesses and endometritis also.

1. Wide spectrum of activity – Gram (+) (S. aureus including most MRSA, some S. pneumoniae) and most Gram (−) but not Pseudomonas.
2. Uses: Pneumocystis pneumonia (drug of choice), community-acquired MRSA skin infections, UTIs, Nocardia, Listeria, Gram (+), Gram (−) including Salmonella and Shigella, and Stenotrophomonas
3. Note: Good choice for cellulitis due to MRSA coverage (MRSA coverage out of oral antibiotics except for linezolid), but weak Streptococcus (group A Strep) coverage (consider adding cephalexin for strep)
4. Many side effects: Bone marrow suppression, renal damage (ATN), hyperkalemia, hypersensitivity (sulfas) and rashes, hemolysis in G6PD deficiency, falsely elevated creatinine, transaminitis/cholestasis
5. Allergy and reactions to sulfa antibiotics are approximately 3%, close to penicillin.

1. Reliable activity versus E. coli and Staphylococcus saprophyticus, also some Enterococcus including vancomycin-resistant Enterococcus, and some others Gram (−)
2. Excreted into urine, where its active metabolites attack multiple sites within bacteria. Only used for UTIs (cystitis), not pyelonephritis or any other infection
3. Not used much anymore due to potentially very bad side effects: Hypersensitivity pneumonitis and chronic pulmonary fibrosis
4. Contraindicated in renal failure
5. Dose: One 100 mg capsule every 12 h for 7 days.

1. Covers Staph/Strep/non-VRE Enterococcus. No Gram (−) coverage. Used for all sorts of Gram (+) infections, including bacteremia, meningitis, PNA, and skin/soft-tissue infections. PO form is not absorbed (fecal excretion) – administered orally, vancomycin is indicated in adult and pediatric patients for the treatment of Clostridium difficile-associated diarrhea and for enterocolitis caused by S. aureus (including methicillin-resistant strains)
2. Side effects: Red man syndrome (due to histamine release, therefore, slow infusion rate is must), low rate of nephrotoxicity (ATN), and ototoxicity (reversible), bone marrow suppression: Leukopenia > thrombocytopenia
3. Dosing – typical = 15 mg/kg (actual body weight) q12 h. Often dosed by levels, must adjust for renal function, check trough prior to the 4^th dose. Goal trough 15 mcg/mL to 20 mcg/mL for severe MRSA infections, 10 mcg/mL to 20 mcg/mL for most other infections, including cellulitis and against coagulase (−) Staphylococcus.

1. Covers all Gram (+) including Strep, MRSA, and VRE – has both PO and IV forms. As no strains resistant to linezolid were detected, this antibiotic seems a promising candidate to treat infections caused by anaerobes
2. Approved for empiric treatment of VAP/hospital-acquired pneumonia
3. Also has good TB coverage
4. Side effects: Bone marrow suppression, especially thrombocytopenia
5. MAO inhibitor action – possible risk of serotonin syndrome with SSRIs. Long-term usage can lead to mitochondrial toxicity resulting in lactic acidosis, peripheral neuropathy, optic neuritis, and blindness
6. Dose: Oral form has 100% bioavailability; adults and children 12 years of age and older – 400 or 600 mg every 12 h. Children (10 mg/kg, 8–12 h.)

1. Only covers Gram (+) including MRSA and VRE, no Gram (−) activity
2. Indicated for complicated skin/soft-tissue infections, also being used more for bacteremia/endocarditis (age >1 year), diabetic foot, and VP shunt infections.
3. Do not penetrate in lung parenchyma due to inactivation by surfactants so no use in pneumonia by Gram (+) organisms
4. Main side effect is rhabdomyolysis → check weekly creatinine kinase levels.

1. Tigecycline has a broad spectrum of activity, including drug-resistant Gram (+) organisms, anaerobes (B. fragilis, Peptostreptococcus, and Propionibacterium), and atypical type of organisms (Chlamydia, Mycoplasma, and Legionella)
2. The New Delhi metallo-β-lactamase multidrug-resistant (MDR) Enterobacteriaceae has also shown susceptibility to tigecycline
3. It has no activity against Pseudomonas spp. or Proteus spp.
4. Doses: Tigecycline is given by slow intravenous infusion (over 30–60 min). A single dose of 100 mg is given first, followed by 50 mg every 12 h after that. Patients with impaired liver function need to be given a lower dose. No adjustment is needed for patients with renal disease. It is not licensed for use in children
5. Tigecycline has similar side effects to tetracyclines. The most common side effects of tigecycline are diarrhea, nausea, and vomiting that showed an increased mortality in patients treated for hospital-acquired pneumonia, especially ventilator-associated pneumonia.

1. It is effective in vitro against both aerobic and anaerobic types of bacteria that are included in the Gram (+) class, especially MRSA and E. faecalis
2. Common indications of use are endocarditis, osteomyelitis, peritonitis, respiratory infections, septicemia, skin infections, soft-tissue infection, and urinary tract infections; Orally, teicoplanin is effective against pseudomembranous colitis and C. difficile-associated diarrhea, with comparable efficacy to vancomycin
3. Combination of teicoplanin and vancomycin or teicoplanin and linezolid is more effective against resistant bacteria
4. Dosage: IV/IM – Serious Gram (+) infections initial: 6 mg/kg on the 1^st day, then 3 mg/kg/day. Severe infection: 6 mg/kg twelve hourly for the 1^st 3 doses, then 6 mg/kg/day or 400 mg OD followed by 200 mgOD IV/IM.

• For serious infections due to multidrug-resistant Pseudomonas, Gram (−) superbugs such as carbapenem-resistant A. baumannii and K. pneumoniae, it is generally recommended to double cover with two antibiotics until susceptibilities identified, then narrow appropriately to one drug
• Double coverage involves a beta-lactam plus either FQ or aminoglycoside (use aztreonam if PCN-allergic)


Few important effectiveness is:


1. Zosyn (piperacillin/tazobactam)-93%
2. Carbapenems – Meropenem – 90%, imipenem ~ 83%. Remember: Ertapenem has no activity
3. Ceftazidime, cefepime (fourth-generation cephalosporin) – 81%
4. Aztreonam alone – 74%
5. FQs – Ciprofloxacin (~74% coverage) > levofloxacin (~70)
6. Aminoglycosides – Amikacin (94%), tobramycin (97%), and gentamicin (82%)
7. Colistin – also known as polymyxin E antibiotic (bactericidal)



1. Kept in reserve for MDR Gram (−), usually Pseudomonas and Acinetobacter
2. Often used in cystic fibrosis patients with resistant Gram (−) infections, sometimes used in aerosolized form
3. Had been abandoned for routine use due to its toxicity = Nephrotoxicity and neurotoxicity, but experiencing a comeback due to rise in resistant Gram-negatives
4. Dose: 2.5–5 mg/kg/day in divided dose q6-12 h IV/IM (max of 5 mg/kg/day).



8. Polymyxin B: Polypeptide antibiotic like colistin with sensitivity for multidrug-resistant strains of Enterobacteriaceae (last resort antibiotic), P. aeruginosa, and A. baumannii.



1. Polymyxin B has a comparatively narrow therapeutic index and so its use is limited and unlikely to be used first line
2. Main concern of nephrotoxicity, so renal adjustments may be needed
3. Doses: IV: 15,000–25,000 units/kg/day divided q12 h; not to exceed 25,000 units/kg/day. IM: 25,000–30,000 units/kg/day divided q4-6 h. Intrathecal (H. influenzae meningitis): 50,000 OD for 3–4 days; then every alternate day OD dose for at least 2 weeks after CSF cultures are negative.

1. Metronidazole (Flagyl) – Mechanism: Selectively taken up by anaerobic bacteria, reduced by proteins in the electron transport chain, and then disrupts DNA



1. Active versus anaerobes (including C. difficile), and protozoans: Giardia, Trichomonas, Entamoeba histolytica, and also Helicobacter pylori (part of triple therapy)
2. Primarily for anaerobes below the diaphragm for both Gram (+) and Gram (−) anaerobes
3. Side effects: Metallic taste, nausea, vomiting, diarrhea, dose-dependent and possibly cumulative peripheral neuropathy (especially used for long term for recurrent C. difficile), and a disulfiram effect with alcohol
4. Dose: Loading dose: 15 mg/kg IV; not to exceed 4 g/day; maintenance dose: 7.5 mg/kg PO/IV (over 1 h) q6 h × 7–10 days (or 2–3 weeks if severe). Oral Dose: Adults – 500 or 750 mg q8 h for 5–10 days, children: 35–50 mg/kg of body weight per day, divided into 3 doses, for 10 days



5. Clindamycin – better for Gram (+) anaerobes. Primarily for infections above the diaphragm – largely because some Bacteroides species exhibit resistance (Gram −ve anaerobes from GI tract)
6. Combined PCN/beta-lactamase inhibitors: Augmentin, ampicillin + sulbactam, piperacillin + tazobactam injection (Zosyn), and ticarcillin + clavulanate (Timentin)
7. Carbapenems (meropenem and imipenem)
8. Cephalosporins (2^nd generation): Cefoxitin and cefotetan
9. Moxifloxacin – shown to be roughly equivalent to Zosyn for intra-abdominal infections
10. Tigecycline.

1. Cefepime – main weakness is weak anaerobe coverage, also Enterococcus
2. Zosyn (piperacillin/tazobactam) – broader due to excellent anaerobe coverage, some non-VRE, Enterococcus<
3. Carbapenems (except ertapenem) – broadest yet due to strong anaerobes, some Enterococcus, plus ESBL.

1. The preferred medication for treating nonsevere Candida infections, including C. albicans, except for C. glabrata and C. krusei (which can be treated with greater doses)
2. Also used for coccidioidomycosis, histoplasmosis, and Cryptococcus meningitis (maintenance phase for cryptococcal meningitis after induction with Ampho. B
3. Great CSF and urine penetration (only azole with good urine penetration)
4. Toxicity: Raised liver enzymes and also GI side effects
5. Dose: Oral candidiasis: 200 mg PO day 1, followed by 100 mg qDay x 2–3 weeks. Cryptococcal meningitis: 400 mg PO day 1, followed by 200 mg PO qDay × 10–12 weeks.

1. Used for nonsevere histoplasmosis, also blastomycosis, sometimes cocci, Paracoccus infections, and onychomycosis
2. Commonly used for prophylaxis in transplant patients
3. Toxicity: Deranged liver enzymes and also negative inotrope – can worsen or cause CHF in predisposed pts (”black box warning”).

1. Drug of choice for invasive aspergillosis (superior to Ampho. B and better tolerated)
2. Also effective against most Candida, but little reason to use over fluconazole as not effective against mucormycosis
3. Liver toxicity, also visual toxicity – transient visual changes, but also rare visual hallucinations
4. Dose: 6 mg/kg IV q12 h for the first 24 h, then 4 mg/kg IV q12 h or 200 mg PO q12 h with median duration of treatment: IV 10 days (range: 2–90 days); PO 76 days (range: 2–232 days).

1. Newest azole with broad spectrum of activity: Yeast, molds, endemic fungi, and zygomycetes (only azole with activity)
2. Only available PO, and must be given with fatty foods for maximal absorption
3. Used as second-line/salvage therapy for many severe fungal infections


-Also used as prophylaxis in some bone marrow transplant centers.


4. Dose: 300 milligrams (mg) (three 100 mg delayed-release tablets) 2 times a day on the 1^st day, then 300 mg once a day.

1. Relatively new class of antifungals (caspofungin – approved in 2001)
2. Drug of choice for severe Candida infections – covers virtually all species including fluconazole-resistant C. krusei and C. glabrata
3. Also used second line for Aspergillus infections (often as combination therapy, never as monotherapy).



1. Caspofungin: First approved echinocandin. Loading dose: 70 mg IV qday, then 50 mg qday. Hepatically cleared so careful in liver pathology and monitor liver function tests
2. Micafungin: Similar to caspofungin for invasive and disseminated candidiasis. 100 mg/day IV infusion × 10–47 days (mean 15 days). Dose: 100 mg daily, no loading dose. Hepatically cleared
3. Anidulafungin: Newest echinocandin for invasive and disseminated candidiasis. Unique metabolism: Chemically degraded in the blood, no hepatic or renal clearance, so safe in liver/renal failure. Furthermore, no significant drug interactions. Load 200 mg IV once, then 100 mg IV qday.

1. Polyene – binds ergosterol in membrane and forms membrane pores
2. Treatment of choice for many severe fungal infections: Zygomycetes, cryptococcal meningitis, severe histoplasmosis/blastomycosis/coccidioidomycosis
3. Second line for invasive aspergillosis (voriconazole is DOC)
4. Approved only as the second line for Candida infections
5. Significant toxicity: Nephrotoxic, bradycardia, sometimes hypotension, fevers/chills during infusion, and rarely, seizures
6. Lipid preparations that are likely as effective and much less toxic (especially renal toxicity), although more expensive
7. Dose: Test dose: 1 mg IV over 20–30 min (in 20 mL of 5% dextrose solution); observe vitals every 30 min for 2–4 h followed by loading dose: 0.25 mg/kg IV qday.

Table 3: Newly approved antibiotics Click here to view

1. Methicillin-resistant S. aureus – I/V vancomycin (adjusted for creatinine ratio) be added to empiric regimens, particularly in septic shock patients for MRSA. Potential alternative agents to vancomycin (for example, daptomycin for nonpulmonary RSA and linezolid) should be considered for patients with refractory or virulent MRSA or with a contraindication to vancomycin

1. A third-generation (for example, ceftriaxone or cefotaxime) or fourth-generation cephalosporin (cefepime), or
2. A beta-lactam/beta-lactamase inhibitor (for example, piperacillin-tazobactam), or
3. A carbapenem (for example, imipenem or meropenem).

1. Antipseudomonal cephalosporin (for example, ceftazidime and cefepime), or
2. Antipseudomonal carbapenem (for example, imipenem and meropenem), or
3. Antipseudomonal beta-lactam/beta-lactamase inhibitor (for example, piperacillin-tazobactam), or
4. FQ with good antipseudomonal activity (for example, ciprofloxacin), or
5. Aminoglycoside (for example, gentamicin, amikacin), or
6. Monobactam (for example, aztreonam).



7. Nonpseudomonal Gram (−) organisms (for example, E. coli, K. pneumoniae) – well covered with third-generation cephalosporin or a carbapenem.

Summary

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