Antimicrobials (by Class) — Mechanisms, Spectrum & Resistance

Overview & definition

Antimicrobials — by the target: the cell wall, the protein synthesis, the DNA, the RNA, the folic acid. The bactericidal vs the bacteriostatic. The PK/PD (the time-dependent vs the concentration-dependent). The resistance.[1]

The ICU intensivist must know: (1) which class covers which organism; (2) the mechanism at the target (cell wall, ribosome, DNA, RNA, folate) — this predicts synergy, antagonism and resistance; (3) the PK/PD index that drives killing — T>MIC (time-dependent) vs Cmax/MIC or AUC/MIC (concentration-dependent) — because this dictates dosing strategy (prolonged/continuous infusion vs once-daily); (4) the toxicity profile (nephrotoxicity, QT, marrow suppression, C. difficile); and (5) the resistance mechanism (beta-lactamases, target modification, porin loss, efflux) — because this dictates escalation to newer agents (ceftazidime-avibactam, ceftolozane-tazobactam, colistin, plazomicin).[1][13]

By target

Beta-lactam antibiotics

All share the beta-lactam ring; all bind penicillin-binding proteins (PBPs) — transpeptidases that cross-link peptidoglycan — and are bactericidal (autolysis of a defective wall). Bacterial killing is time-dependent (T>MIC). The four sub-families differ in their ring fusion (and therefore PBP affinity and beta-lactamase stability).[1]

Penicillins (thiazolidine + beta-lactam = penam ring)

Beta-lactamase inhibitors (suicidal, "suicide substrates"): clavulanate, tazobactam, sulbactam — inhibit class A serine beta-lactamases (staph penicillinase, TEM, SHV) but NOT AmpC or carbapenemases; avibactam and relebactam (diazabicyclooctanes) additionally restore activity against some AmpC and KPC carbapenemases; vaborbactam (boronic acid) inhibits KPC.[13]

Cephalosporins (dihydrothiazine + beta-lactam = cephem ring)

Generated by successive modification; each generation broadens gram-negative cover (incl. Pseudomonas from the 3rd) at some cost to gram-positive activity (especially 4th-gen loses staph cover). Cross the placenta and BBB (1st-gen poorly; 3rd-gen well — used in meningitis).[3]

Ceftaroline is unique: its bulky side-chain binds the PBP2a of MRSA (ceftaroline-fosamil is the prodrug). It has no anti-pseudomonal activity and is not stable against ESBL/AmpC/carbapenemases.[4]

Carbapenems (carbon replacing sulphur + trans double bond — small, penetrates porins)

Carbapenems are the workhorse for ESBL and AmpC; they are NOT reliable when a carbapenemase (KPC, NDM, VIM, IMP, OXA-48) is present.[6][12]

Monobactams (single beta-lactam ring, no fusion)

Aztreonam — the only monobactam. Binds PBP3 of gram-negatives only; active against Pseudomonas, ESBL Enterobacterales, H. influenzae; no gram-positive cover, no anaerobe cover. Unique: minimal cross-reactivity with other beta-lactams (the side-chain, not the ring, drives allergy) — therefore safe in penicillin/cephalosporin allergy (including anaphylaxis), and is the renal-friendly option in patients needing ceftazidime-like cover. Ceftazidime and aztreonam share a side-chain, so avoid if ceftazidime-allergic.[3]

Glycopeptides — vancomycin & teicoplanin

Bind D-Ala-D-Ala terminus of the peptidoglycan precursor, sterically blocking transglycosylation/transpeptidation (cell wall). Bactericidal (slow, time-dependent — AUC/MIC driver). Active only against gram-positive organisms (the large molecule cannot cross the gram-negative outer membrane).[1][4]

• Vancomycin — MRSA, MRSE, ampicillin-resistant enterococci, Clostridioides difficile (oral, non-absorbed). Loading 25-30 mg/kg (IBW), then 15-20 mg/kg q8-12h guided by trough 15-20 mg/L (severe/MRSA bacteraemia) or AUC/MIC 400-600 (now preferred — Bayesian dosing). Nephrotoxicity (especially with piperacillin-tazobactam — "vanc-piptazo AKI"), infusion-related histamine release (red-man syndrome — rate-related, NOT IgE; slow infusion, antihistamine), ototoxicity (rare, at high levels), thrombocytopenia.
• Teicoplanin — longer half-life (so once-daily), less nephrotoxic than vancomycin, no red-man syndrome (can bolus). Used where available (Europe/ANZ, NOT USA). Needs loading (6 mg/kg q12h ×3, then daily).[4]

Lipopeptides — daptomycin

Binds the bacterial cytoplasmic membrane (calcium-dependent insertion) → depolarisation, potassium efflux, cell death — a mechanism independent of cell wall or ribosome, so no cross-resistance with beta-lactams/glycopeptides. Bactericidal, concentration-dependent (Cmax/MIC). Active against gram-positive only (cannot cross gram-negative membrane): MRSA, VRE (E. faecium), penicillin-resistant pneumococci. 4-6 mg/kg IV once-daily (10 mg/kg for endocarditis).[4]

Killed by surfactant → CONTRAINDICATED in pneumonia (use vancomycin/linezolid). Monitor creatine kinase weekly (skeletal-muscle toxicity — rhabdomyolysis rare); statins potentiate. Eosinophilic pneumonia is rare but reported with prolonged therapy.[6]

Aminoglycosides — gentamicin, amikacin, tobramycin

Bind the 30S ribosomal subunit (16S rRNA, A-site) → misreading of mRNA → faulty proteins inserted into the membrane → bactericidal (one of the few static-ribosomal agents that is cidal). Concentration-dependent killing + significant post-antibiotic effect (PAE) → once-daily extended-interval dosing (e.g. 5-7 mg/kg gentamicin, Hartford nomogram) optimises Cmax/MIC and reduces accumulation/ototoxicity. Active against gram-negative aerobes (Enterobacterales, Pseudomonas) and synergy with cell-wall agents for enterococci/streptococci (gentamicin + ampicillin in enterococcal endocarditis); no anaerobic activity (needs aerobic uptake — oxygen-dependent transport).[1]

Toxicity (both concentration-and duration-dependent): (1) nephrotoxicity — proximal tubular (accumulates in renal cortex) — usually reversible on stopping; potentiated by vancomycin, amphotericin, loop diuretics, hypovolaemia; (2) ototoxicity — cochlear (amikacin) and vestibular (gentamicin) hair-cell destruction — irreversible; (3) neuromuscular blockade (rare, myasthenia). Avoid in pregnancy (8th-nerve foetal damage). TDM essential (trough <1 mg/L, or area-under-curve monitoring). Amikacin is least susceptible to aminoglycoside-modifying enzymes.[1]

Fluoroquinolones — ciprofloxacin, levofloxacin, moxifloxacin

Inhibit DNA gyrase (gram-negatives) and topoisomerase IV (gram-positives) → double-strand DNA breaks → bactericidal, concentration-dependent (AUC/MIC). Excellent tissue penetration (intracellular — Legionella, Mycoplasma, Chlamydia, Mycobacteria; prostate, bone, lung) and high oral bioavailability (PO ≈ IV).[1]

Adverse effects (the FQ "boxed warnings"): QT prolongation (torsades — avoid with other QT drugs, hypokalaemia); tendinopathy/tendon rupture (Achilles — risk within weeks, worse with steroids, age >60); aortic dissection/aneurysm (Marfan/Ehlers-Danlos caution); CNS (confusion, seizures, psychosis — lower threshold with theophylline); dysglycaemia (both hypo and hyper); C. difficile. Avoid in pregnancy/children (cartilage damage in animal studies). Chelates with Ca/Mg/Fe/Al/sucralfate (separate by 2 h).[5]

Macrolides — azithromycin, clarithromycin

Bind the 50S ribosomal subunit (23S rRNA, P-site of peptidyl transferase) → block translocation → bacteriostatic (bactericidal at high concentration). Cover: gram-positives (strep, pneumococcus), atypicals (Legionella, Mycoplasma, Chlamydia), Bordetella, Helicobacter, some non-tuberculous mycobacteria. CYP3A4 inhibitors (clarithromycin > erythromycin; azithromycin does NOT inhibit CYP3A4 — preferred for drug-interaction risk).[1]

Adverse: QT prolongation (erythro > azithro; torsades risk); nausea/diarrhoea (motilin-agonist — erythromycin used as a prokinetic); cholestatic hepatitis; ototoxicity (high dose, renal failure); clarithromycin interacts with statins (rhabdomyolysis), warfarin (↑INR), calcineurin inhibitors (↑levels), tacrolimus. P450 inhibition — avoid with many drugs.[13]

Tetracyclines & glycylcyclines — doxycycline, tigecycline

Bind the 30S ribosomal subunit (A-site) → block tRNA binding → bacteriostatic. Wide spectrum: atypicals, Rickettsia, Borrelia (Lyme), Chlamydia, Mycoplasma, Vibrio, Leptospira, Plasmodium (doxy malaria prophylaxis), MRSA, Acinetobacter; anaerobes (tigecycline).[1]

• Doxycycline — once/twice-daily, well-tolerated, the atypical/rickettsial agent; oesophagitis (take with water, upright); photosensitivity; chelation (Ca/Mg/Fe — separate); avoid in pregnancy/children <8 (tooth discolouration, bone).
• Tigecycline (glycylcycline, broad-spectrum, IV only) — active against MRSA, VRE, ESBL, anaerobes, atypicals; NOT Pseudomonas, NOT Proteus/Providencia/Morganella (intrinsic resistance). FDA black-box: increased mortality in ventilator-acquired pneumonia (VAP) — failure of Acinetobacter/Pseudomonas; reserve for cSSTI/cIAI. Nausea common; hypoalbuminaemia lowers unbound levels.[10]

Oxazolidinones — linezolid

Bind the 50S ribosomal subunit (23S rRNA, A-site) → block initiation complex formation (distinct site from macrolides/chloramphenicol) → bacteriostatic. Active against gram-positives only: MRSA, VRE (E. faecium, E. faecalis), penicillin-resistant pneumococci; 100% oral bioavailability (PO ≡ IV).[4]

Adverse (duration-dependent): thrombocytopenia (and anaemia/neutropenia) — risk >14 days, monitor FBC; peripheral + optic neuropathy (long courses); serotonin syndrome (linezolid is a weak reversible MAO inhibitor — avoid/co-monitor with SSRIs, tramadol, linezolid-tyramine foods); lactic acidosis (mitochondrial toxicity); non-specific Cheyne-Stokes reported. No renal dose adjustment (linezolid metabolites cleared renally but active drug is hepatic). Teixobactin (investigational) — unrelated membrane-acting agent, no cross-resistance.[11]

Nitroimidazoles — metronidazole

Prodrug — reduced inside the organism (anaerobes, microaerophilic; ferredoxin) → cytotoxic radical intermediates damage DNA → bactericidal, concentration-dependent. Cover: anaerobes (Bacteroides, Clostridium, Fusobacterium), protozoa (Giardia, Entamoeba, Trichomonas), H. pylori, C. difficile (oral for CDI). 100% bioavailability. Disulfiram-like reaction with alcohol; peripheral neuropathy (long courses); encephalopathy/cerebellar signs (rare); metallic taste. Warfarin potentiation (CYP2C9 inhibition). Excellent CSF penetration (brain abscess).[5]

Antifungals — azoles, amphotericin, echinocandins

Empiric candidemia in non-neutropenic ICU: echinocandin (caspofungin/micafungin/anidulafungin) is first-line; step-down to fluconazole when C. albicans and stable.[8] Invasive aspergillosis: voriconazole is first-line.[9]

PK/PD principles

• Time-dependent (beta-lactams, macrolides, linezolid) — the efficacy depends on the TIME the free drug exceeds the MIC (T above MIC). The prolonged infusion / the continuous infusion optimises.[1][3]
• Concentration-dependent (aminoglycosides, fluoroquinolones, daptomycin, metronidazole, amphotericin) — the efficacy depends on the PEAK (Cmax/MIC). The once-daily dosing (the aminoglycoside) optimises.[1]
• Concentration-dependent with time component (fluoroquinolones, linezolid, vancomycin, azithromycin, tigecycline, daptomycin) — the AUC/MIC ratio is the best PK/PD predictor (vancomycin AUC/MIC 400-600 for MRSA; fluoroquinolone AUC/MIC >125 gram-neg / >30 gram-pos).[4]

[3]

ICU empiric therapy principles — broad spectrum then narrow

In sepsis/septic shock, the priority is to deliver effective antibiotics within 1 hour of recognition — each hour of delay in hypotensive septic shock increases mortality ~4-8% (Kumar 2006; Seymour 2017). The Surviving Sepsis Campaign 2021 gives a strong recommendation for empiric broad-spectrum therapy within one hour for septic shock or high-likelihood sepsis.[2][13]

Principles:[6]

1. Broad-spectrum empiric cover from the first dose — aim to cover all likely pathogens at the suspected source. The regimen is dictated by source, patient risk, local resistance — not by "strongest drug". Typical regimens:
   • Community sepsis (lung/urine/biliary) — benzylpenicillin/amoxycillin + gentamicin ± metronidazole; or ceftriaxone ± azithromycin (CAP); or amoxycillin-clavulanate (biliary).
   • Hospital-acquired / VAP / intra-abdominal / neutropenic sepsis — anti-pseudomonal beta-lactam (piperacillin-tazobactam, ceftazidime, cefepime, meropenem) ± second agent for MRSA (vancomycin/linezolid) ± aminoglycoside/fluoroquinolone for resistant gram-negatives; cover anaerobes (metronidazole or a carbapenem/piperacillin-tazobactam already covers them).
   • Suspected MRSA (line infection, healthcare exposure, severe CAP) — add vancomycin or linezolid.[4]
   • Suspected ESBL/CRE (recent healthcare, known colonisation, prior carbapenem, travel to endemic regions) — meropenem; if carbapenemase suspected, colistin/polymyxin B + meropenem ± fosfomycin/aminoglycoside, consult ID.[6][12]
   • Neutropenic sepsis — anti-pseudomonal beta-lactam monotherapy (piperacillin-tazobactam, ceftazidime, cefepime, meropenem); empiric vancomycin only if line infection/soft tissue/severe sepsis/mucositis.[13]
   • Invasive fungal risk (prolonged neutropenia, transplant, ICU >7 days + TPN + broad-spectrum antibiotics + multiple sites colonised) — add echinocandin empiric for candidemia.[8]
2. Source control within 6-12 hours (drain infected fluid, debride necrotic tissue, remove infected device) — antibiotics fail without it.
3. De-escalate at 48-72 hours — once cultures and susceptibilities return: narrow to the narrowest effective agent, stop if no infection (negative cultures + alternative diagnosis), shorten duration (procalcitonin-guided, e.g. PRORATA).[2][10]
4. Reassess daily — every antibiotic day counts for resistance, C. difficile, AKI and cost.
5. Dose for the patient — loading dose in sepsis (increased Vd), augmented renal clearance (need MORE), RRT/Crrt (drug-specific dosing), obesity (consider IBW/adjusted), hepatic failure, protein binding.

PK/PD considerations in the ICU

Continuous / prolonged infusion of beta-lactams — for time-dependent drugs, maximising T>MIC by prolonged (over 3-4 h) or continuous (over 24 h) infusion improves PK/PD target attainment, particularly with ARC, severe sepsis and resistant organisms. BLING II (Dulhunty 2015, n=432) compared continuous vs intermittent piperacillin-tazobactam/ticarcillin-clavulanate/meropenem in severe sepsis: no difference in 90-day ICU-free days (primary) but improved 14-day clinical cure in the sickest patients.[3] Recommended for severe sepsis with Pseudomonas, ESBL, ARC, or VAP; give a loading dose first.

[3]

Adverse effects — the high-yield toxicity table

[12]

Resistance mechanisms

[12] [12] [3] [12] [12]

Clinical pearls

[3]

Red flags

[3]

References

1. [1]Karnad DR, Nor MBM, Richards GA, et al. Intensive care in severe malaria: Report from the task force on tropical diseases by the World Federation of Societies of Intensive and Critical Care Medicine. Journal of critical care, 2018.PMID 29132978
2. [2]Evans L, Rhodes A, Alhazzani W, et al Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med, 2021.PMID 34605781
3. [3]Dulhunty JM, Roberts JA, Davis JS, et al A Multicenter Randomized Trial of Continuous versus Intermittent Beta-Lactam Infusion in Severe Sepsis (BLING II). Am J Respir Crit Care Med, 2015.PMID 26200166
4. [4]Liu C, Bayer A, Cosgrove SE, et al Clinical practice guidelines by the IDSA for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis, 2011.PMID 21217178
5. [5]Bartlett JG Clostridium difficile Infection. Infectious disease clinics of North America, 2017.PMID 28779831
6. [6]Endimiani A, Paterson DL Optimizing therapy for infections caused by enterobacteriaceae producing extended-spectrum beta-lactamases. Semin Respir Crit Care Med, 2007.PMID 18095228
7. [7]Triplett JD, Lawn ND, Chan J, et al Cephalosporin-related neurotoxicity: metabolic encephalopathy or non-convulsive status epilepticus? J Clin Neurosci, 2019.PMID 31201049
8. [8]Pappas PG, Kauffman CA, Andes DR, et al Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the IDSA. Clin Infect Dis, 2016.PMID 26810419
9. [9]Patterson TF, Thompson GR 3rd, Denning DW, et al Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the IDSA. Clin Infect Dis, 2016.PMID 27481947
10. [10]Kalil AC, Metersky ML, Klompas M, et al Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 IDSA Clinical Practice Guidelines. Clin Infect Dis, 2016.PMID 27418577
11. [11]Harris PNA, Tambyah PA, Lye DC, et al (MERINO) Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance (MERINO). JAMA, 2018.PMID 30208454
12. [12]Kumarasamy KK, Toleman MA, Walsh TR, et al Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study (NDM-1). Lancet Infect Dis, 2010.PMID 20705517
13. [13]Boucher HW, Talbot GH, Bradley JS, et al Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis, 2009.PMID 19035777