Antibiotics disrupt essential processes or structures in the bacterial cell. This either kills the bacterium or slows down bacterial growth. Depending on these effects an antibiotic is said to be bactericidal or bacteriostatic.
Bactericidal and bacteriostatic antibiotics
A bactericidal antibiotic kills the bacteria while the bacteriostatic antibiotics stop bacterial growth without killing them. The human immune system is then needed to clear the infection.
Antibiotic targets in bacteria
There are several classes of antibiotics with different mechanisms of action and bacterial targets. In principal, there are three main antibiotic targets in bacteria:
- The cell wall or membranes that surrounds the bacterial cell
- The machineries that make the nucleic acids DNA and RNA
- The machinery that produce proteins [the ribosome and associated proteins]
These targets are absent or structurally different in human and mammalian cells, which means that antibiotics usually do not harm our cells. However, antibiotics can in some cases have unpleasant side effects. Read more under Why should I care? – Risks for the individual and society.
Narrow-spectrum and broad-spectrum antibiotics
Antibiotics can either have a narrow or broad spectrum of activity. Narrow-spectrum antibiotics are more specific and are only active against certain groups or strains of bacteria. Broad-spectrum antibiotics instead inhibit a wider range of bacteria. Narrow-spectrum antibiotics are generally preferable since the effect on other non-disease causing bacteria is more limited. Unfortunately, broad-spectrum antibiotics are often used since it can be difficult for doctors to diagnose the infectious agent due to a lack of training and/or available diagnostic tools. For more information, see How did we end up here – Use and inappropriate use – In human medicine.
See also these selected resources for more details on different antibiotics and their mechanisms of action.
Selected Resources
ResourceDescriptionEric’s Medical Lectures: Mechanisms and classification of antibioticsVideo. Narrated lecture about antibiotics and their mechanism of action [24 min, YouTube].How antibiotics workVideo. Short video describing the difference between bacteriostatic and bactericidal antibiotics. Outlines why antibiotics are not effective against viruses [3 min, YouTube].A brief overview of classes of antibioticsFact sheet. Short description of different classes of antibiotics and their mode of action.Antibiotics and bacterial resistance in the 21st centuryJournal article with short descriptions of clinically used antibiotic classes as well as examples of bacterial resistance mechanisms.Antimicrobial Resistance Learning Site – PharmacologyEducational material. Learn about concepts related to medical use of antimicrobials and of resistance.
Antibiotic is a term used to define a chemical substance produced by one microorganism that stunts the metabolism and development of other organisms [1]. The antibiotic term was used initially for naturally acquired substances; however, now the term encompasses both natural and synthetic antimicrobial substances. Although penicillin was the first antibiotic isolated from the mold, it was superseded by sulfa drugs used by physicians to treat infections successfully [2]. Due to antibiotic use, the infectious disease death rate has declined from 280 per 100,000 to 60 per 100,000 in the 1950s [3]. A common belief is that cidal antibiotics are efficient than static antibiotics with no clinical evidence supporting it. Both cidal and static are invitro terms which, refer to the effect of antibiotic concentrations affecting bacterial growth at a predefined threshold. They cannot predict the infection outcome in vivo. Antibiotics targeting the organism’s cell wall are mostly bactericidal, whereas those targeting protein syntheses are bacteriostatic. MIC [minimum inhibitory concentration] is the lowest antibiotic concentration, which prevents visible growth at 24 hours. MBC [minimum bactericidal concentration] is the minimal concentration of antibiotics that causes bacterial death. Breakpoints for antibiotic MIC’s are set by the the European Committee on Antimicrobial Susceptibility Testing [EUCAST] and National Committee for Clinical and Laboratory Standards Institute [CLSI]. A bactericidal antibiotic MBC is less than or equal to four folds above the MIC, accounting for a 1000-fold decline in bacterial density [4]. A bacteriostatic antibiotic achieves a > 1000-fold reduction at eight-fold above MIC or a 500-fold reduction in bacterial density at 4-fold above its MIC. They are still labeled as static despite the clear demonstration of bacterial killing. An antibiotic becomes more bactericidal as the MIC moves closer to the MBC. Bacteriostatic agents have an MBC to MIC ratio > than that for bactericidal antibiotics.
A systematic literature review revealed no confirmation that cidal agents are better than static agents [5]. In addition, there was no substantial difference in efficiency, including critically ill patients with severe infections and sepsis. Six trials demonstrated the superiority of static agent linezolid over cidal agents such as vancomycin [5]. A single trial showed the efficiency of cidal agent imipenem over tigecycline; however, the dose of tigecycline was small, and with increased appropriate dosing, the efficacy disappeared [6, 7]. A rapidly bactericidal agent such as daptomycin does not perform better than a slowly cidal agent such as vancomycin to treat right-sided infective endocarditis [IE] and staphylococcal bacteremia [8] . A synergistic combination of beta-lactam with aminoglycosides enhances the bactericidal effect with rapid blood clearance [9]. However, this synergistic combination has not improved clinical outcomes or mortality [10]. In the initial studies, static agents such as tetracyclines and macrolides were inferior to cidal agents in IE therapy [11]. This assumption can be erroneous as the static agents do not achieve adequate low blood concentrations to treat infective endocarditis effectively. A bacteriostatic antibiotic such as linezolid can attain sufficient bloodstream concentrations resulting in higher cure rates for IE [12]. Daptomycin, a rapidly bactericidal agent, is inferior to vancomycin in left-sided IE [13]. For an individual antibiotic to be effective, the importance of its pharmacokinetic-pharmacodynamic properties and attaining adequate drug levels at the infection site is substantial than static versus cidal properties used in predicting clinical efficacy. An intact immune system is critical for the efficacy of bacteriostatic agents, and bactericidal agents are preferred in immunosuppressed patients. Broad-spectrum agents cover many susceptible pathogens, whereas narrow-spectrum agents cover a limited number of pathogens. Broad-spectrum agents are used empirically in the therapy of lung and abdominal infections. Narrow-spectrum agents are used in a limited number of indications.
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2. Bacteriostatic antibiotics
These include folate inhibitors [sulfonamides and trimethoprim] in Table 1 [2A I], tetracyclines in Table 2 [2A II], glycylcyclines in Table 3 [2A III], macrolides in Table 4 [2A IV], lincosamides in Table 5 [2A V], oxazolidinones in Table 6 [2A VI] and fusidic acid in Table 7 [2A VII].
OriginSulfonamides are sulfanilamide derivatives identical to para-aminobenzoic acid [PABA] required for folic acid synthesis in most bacteria.
Trimethoprim is a synthetic derivative from trimethoxybenzyl-pyrimidine [14].Mechanism of actionSulfonamides antagonize PABA inclusion into dihydropteroate by its greater affinity for tetrahydropteroic acid synthetase in microorganisms resulting in decreased dihydrofolic acid, a substrate for dihydrofolate reductase [DHFR] [15, 16].
Trimethoprim is a potent bacterial inhibitor of DFR, preventing the formation of tetrahyrofolic acid needed for purine and deoxyribonucleic acid [14].
Thus, sulfonamides and trimethoprim together stop two consecutive steps essential in the folic acid synthesis. A combination of both is synergistic and bactericidal in trimethoprim and the sulfa ratio of 1:20 [17].RoutesSulfonamides are available in oral, intravenous [IV], topical, and ophthalmic formulations.
Trimethoprim is available in oral and intravenous formulations.IndicationSulfonamides: Nocardiosis, Toxoplasmosis, Plasmodium falciparum malaria, Nongonococcal urethritis,
Trimethoprim: Acute urinary tract infection [UTI], Recurrent UTI
Trimethoprim and sulfamethoxazole [TMP-SMX]: Above indications plus UTI, Skin and soft tissue infections [SSTI] due to Staphylococcus aureus, Pneumocystis jiroveci[PCJ] pneumonia, and prophylaxis, Melioidosis, Whipple disease, Alternative in Listeria meningitisResistanceSulfonamides: Point mutations in folP gene modifying dihydropteroate synthetase resulting in decreased affinity for sulfonamide [18]. PABA binding site alteration due to F28L/T and P64S mutations [19]. Integrons sul1, sul2, and sul3 coding drug resistance enzymes [20].
Trimethoprim: Plasmid-mediated resistant DHFR enzymePharmaco-kineticsSulfonamides: Well distributed throughout the body, and protein binding predicts the blood and tissue levels. It is metabolized in the liver [CYP2C9 & CYP3A4 hepatic enzyme system] and excreted via renal excretion. Chronic kidney disease results in decreased renal clearance [21]. It can interact with multiple other drugs resulting in increased serum levels and toxicity especially antiseizure medications.ToxicitySkin: Rashes, Steven-Johnson syndrome [SJS], Toxic epidermal necrolysis [TEN] [22, 23].
Blood: Anemia, agranulocytosis, thrombocytopenia, methemoglobinemia [24].
Renal: Hyperkalemia, Acute renal failure, Interstitial nephritis,
Lactic acidosis [24, 25, 26].
Gastrointestinal [GI]: Pseudomembranous colitis, Pancreatitis, and Fulminant liver failure [27, 28, 29].
Others: aseptic meningitis
Table 1.
2AI folate inhibitors: Sulfonamides & trimethoprim.
OriginTetracycline is derived from catalytic dehalogenation of chlortetracycline obtained from Streptomyces rimosus[30].
Doxycycline and Minocycline are semisynthetic derivatives of oxytetracycline.Mechanism of actionReversibly binds 30S ribosomal subunit of the bacteria and inhibits protein synthesis. In protozoa, it additionally binds to 70S ribosome and stops protein synthesis [30, 31].RoutesOrally via capsules, tablets, syrups, and IV formulations.IndicationCommunity-acquired bacterial pneumonia [CABP], MSSA &MRSA SSTI, Stenotrophomonas infections, Helicobacter pyloriinfection, Nongonococcal urethritis, Lyme disease, Rickettsial infections, Nocardiosis, Falciparum malaria, Cholera, Anaplasmosis, and Ehrlichiosis. Q fever, Brucellosis, Melioidosis, Acne vulgarism, the second line in syphilis, and a part of the combination regimen in pelvic inflammatory disease [PID].ResistanceIt is mediated mainly by active efflux pumps and ribosomal protection proteins. Other minor mechanisms include antibiotic enzymatic lysis, a decline in-wall permeability, and binding site alterations [32].Pharmac-okineticsUnlike tetracycline, food does not substantially alter doxycycline and minocycline absorption, and both have excellent bioavailability [33]. Lipid solubility determines the tissue and fluid levels of which minocycline > doxycycline > tetracycline. At higher doses, doxycycline reaches adequate levels in the cerebrospinal fluid [CSF] [34]. The clearance mechanism is via both renal [tetracycline] and hepatic [doxycycline and minocycline].Toxicity/ Adverse effectsGI: pill-induced esophagitis, heartburn, epigastric pain, nausea, vomiting, acid reflux disorder [35]. Hepatotoxicity from IV tetracycline [36]. Skin: photosensitive rash and hyperpigmentation of body parts [37]. Nephrogenic diabetes insipidus: by demeclocycline [38]. Central Nervous System[CNS]: Vestibular symptoms, Pseudotumor cerebri Teeth, and Bone: tooth staining, enamel hypoplasia, and diminished bone growth in premature infants exposed to tetracycline [39]. Hypersensitivity reactions: facial swelling, drug-induced lupus, anaphylaxis, urticaria [40]. Tetracyclines are teratogenic and reach the fetus via the placenta.
OriginTigecycline is a semisynthetic derivative of minocycline developed against resistant organisms [41].Mechanism of actionIts reversal binding to 30S ribosomes is stronger by five times, and ribosomal protection proteins do not affect it [42, 43].RoutesDue to poor oral absorption, it is available in IV formulations.IndicationComplicated SSTI, Complicated intraabdominal infections [cIAIs], CABP, Used as salvage therapy in critically ill patients when no other alternatives exist for multidrug-resistant infections [MDR].ResistanceIt is due to increased efflux pumps such as AcrAB and MexAB-OprM after detecting the drug [44]. Pseudomonas is intrinsically resistant due to MexXY efflux pump presence [45].Pharmac-okineticsAdequate tissue distribution was observed with a half-life of 37 to 67 hours and a plasma protein binding of about 80% [46]. No dose adjustment is required in renal impairment and mild to moderate hepatic impairment. Dose adjustment is needed for severe hepatic impairment. It is not removed by hemodialysis [47]. It is excreted by the liver and minimally by the kidney.Toxicity/Adverse effectsGI: nausea, vomiting, transaminase elevation, acute pancreatitis. Others: infection, phlebitis, headache, dizziness, skin rash [47]. It is associated with increased mortality compared to other antibiotics used for the same indication. 13 clinical trials have validated this pooled analysis [48].
OriginErythromycin was obtained from Streptomyces erythreuspresent in the soil. Azithromycin and Clarithromycin are semisynthetic derivatives from erythromycin, which improve stability in gastric acid [49].Mechanism of actionMacrolides bind to 23S ribosomal ribonucleic acid [rRNA], a subunit of the 50S subunit of the bacterial ribosome, and stop the RNA-based synthesis of proteins [50]. Bactericidal activity is seen against , Hemophilus influenzae,and Streptococcus pneumoniae.RoutesIt is available as oral liquid, tablet, capsule, IV, ophthalmic and topical preparations.IndicationErythromycin: used as an alternative to penicillin [PCN] in allergic patients. Treatment and preexposure prophylaxis in pertussis. Azithromycin: CABP, Pertussis, Trachoma, Chancroid, Babesiosis, Mycobacterium avium complex[MAC] infections, alternative for Lyme disease, sinusitis, pharyngitis, and acute otitis media. Clarithromycin: Helicobacter pyloriinfection, Nontubercular mycobacterial infection, Campylobacterenteritis, MACinfectionsResistance50S ribosomal protein mutations or 23S rRNA receptor alterations confer resistance to macrolides [M], lincosamides [L], and streptogramin B [SB] [MLSB phenotype]. Erm[erythromycin ribosome methylation] genes present on transposons or plasmids mediate this effect [51, 52].Pharmac-okineticsErythromycin is metabolized by hepatic CYP3A cytochrome subclass of cytochrome 450 system. It is incompatible with other IV preparations [53, 54]. It follows total body water distribution [55] and persists in tissues longer than in blood. Oral azithromycin bioavailability is around 37% [56]. It is well distributed in tissues with levels > than in blood by 10 to 100 fold. It is excreted primarily unchanged via hepatic clearance into the feces. No dose adjustments are required for renal and hepatic impairment. Clarithromycin oral bioavailability is 55%, has excellent tissue distribution, and undergoes mainly hepatic clearance with 30% clearance vis the kidneys [50]. Dose adjustment is needed for renal failure only [57].Toxicity/Adverse effectsErythromycin: GI side effects [nausea, vomiting, and abdominal pain], Thrombophlebitis, Allergic reactions, Ototoxicity, Torsades de pointes. Clarithromycin and Azithromycin: GI side effects as above, Acute mania, Torsades de pointes, reversible cholestatic hepatitis [58, 59, 60].
OriginLincomycin is derived from Streptomyces lincolnensispresent in the soil. Clindamycin is semisynthetically by chemically modifying lincomycin resulting in increased potency and bioavailability [61].Mechanism of actionIt binds to 50S ribosomal sites and inhibits protein synthesis, and competes with macrolides for the same site.RoutesAvailable in IV, oral capsules and liquid solution, topical gel, foam or solution, and vaginal cream or suppository.IndicationGram-positive or anaerobic SSTI, acne vulgaris, part of the combination regimen against toxoplasmosis, falciparum malaria, and Pneumocystis jirovecipneumonia.ResistanceMLSB phenotype regulated by the ermA or ermC genes [62]. rRNA mutations, including the receptor site, 23S rRNA nucleotide methylation, and adenylation of clindamycin [51, 63, 64, 65].Pharmac-okinetics90% oral bioavailability with good tissue levels except in CSF [61, 66]. It is metabolized by the liver, and excretion occurs via feces and urine [67]. Dosing adjustment is needed in severe renal and hepatic impairmentToxicity/Adverse effectsCutaneous drug reactions in patients with [human leukocyte antigen]HLA-B*51:01 genotype including maculopapular eruptions, erythema multiforme, urticaria, drug rash with eosinophilia, and systemic symptoms [DRESS], SJS, TEN [68]. GI: diarrhea, pseudomembranous colitis by Clostridioides difficile,reversible transaminitis [69]. Others: agranulocytosis, thrombocytopenia, and neutropenia which are transient.
OriginLinezolid and Tedizolid are derived from 5-[halomethyl]-3-aryl-2-oxazolidinones [organic synthesis] by chemical modification. Unique structure with no cross-resistance seen.Mechanism of actionHalts bacterial protein synthesis by binding to the V-domain of 23S RNA, a part of the 50S ribosomal unit [70]. Efficacy is proportional to the drug level area under the curve AUC/MIC ratio.RoutesAvailable as oral tablets and IV formulations.IndicationLinezolid: MSSA/MRSA nosocomial pneumonia, CABP, Gram-positive complicated and uncomplicated SSTI, Vancomycin-resistant Enterococcus[VRE] infections, Nocardiosis. Tedizolid: Gram-positive SSTI.ResistanceIt is 8 mg/kg/day] results in elevation of serum creatinine phosphokinase [CPK] levels with no muscle cell lysis or fibrosis [123]. CPK level monitoring during therapy is a must. Peripheral neuropathy with paraesthesia and dysesthesia. Acute eosinophilic pneumonia [after ten days of therapy]
OriginAminoglycoside with the name ending in mycin is derived from Streptomyces[124]. Aminoglycoside with the name ending in micin is derived from Micromonospora spp.Fermentation products: Neomycin, Gentamicin, Kanamycin Semisynthetic derivatives: Amikacin, NetilmicinMechanism of actionCationic aminoglycosides bind to the anionic lipopolysaccharides and disrupt their structure resulting in cell wall leaks and altered permeability. Once in the cytosol, it binds reversibly to ribosomal decoder acceptance site on 16S reverse transfer RNA portion of messenger RNA [mRNA], a 30S subunit of prokaryotic ribosomes. This decreases the mRNA translocation and translation stopping protein synthesis [125, 126, 127, 128]. They demonstrate the postantibiotic effect, synergistic behavior with other antibiotics, and concentration-dependent effect.RoutesAvailable in IV and oral formulations.IndicationEmpirical therapy of aerobic gram-negative bacilli [GNB] including Pseudomonas spp.As a part of a combination therapy for HAP, Enterococcalbacteremia, and IE due to enterococcusand streptococcus spp. Acute urinary tract infection and cystic fibrosis exacerbations. Preoperative prophylaxis in gastrointestinal and genitourinary procedures.ResistanceAltered cell wall membrane with diminished interaction, active efflux pumps resulting in lesser concentration in the cytosol [129, 130]. Decreased ribosomal binding due to mutation or methylation of the binding site [131]. Inactivation of the aminoglycosides by phosphorylation, adenylation, and nucleotidation [132]. Induce biofilm formation [133].Pharmac-okineticsPlasma protein binding is low, highly soluble in water, with distribution resembling extracellular fluid compartments [134, 135]. Appropriate concentrations are attained in all body fluids except for CSF and vitreous humor [136, 137, 138]. They undergo renal clearance unchanged with minimal excretion via feces [139]. Dose adjustment is needed in renal failure.Toxicity/Adverse effectsNephrotoxicity Ototoxicity includes both cochlear and vestibular Neuromuscular blockade
OriginInitially derived as a byproduct of chloroquine synthesis, the newer quinolones are semisynthetic with chemical modifications to increase their efficacy and absorption.Mechanism of actionInhibit deoxyribonucleic acid [DNA] synthesis by inhibiting DNA gyrase and topoisomerase IV. It also leads to hydroxy radicals, damaging the bacterial cellular molecules causing bacterial cell death [140, 141].RoutesAvailable as oral, IV, and eye drop formulationsIndicationAcute cystitis, Acute uncomplicated, and cUTI. Acute Bacterial prostatitis, Sexually transmitted disease, PID, Chlamydiae trachomatis, Hemophilus ducreyi. Acute bacterial gastroenteritis due to Shigella spp, Campylobacter jejuni, Cholera, Typhoid, Nontyphoidal Salmonellaegastroenteritis in specific patients.
Acute intraabdominal infections, Spontaneous bacterial peritonitis [SBP]. Acute CABP, Acute bronchitis, Aspiration pneumonia, Lung abscess, HAP, stenotrophomonasinfections. Acute osteomyelitis, Acute native and prosthetic joint infections, SSTI. MDR pulmonary tuberculosis, Nontuberculous mycobacterial infections, GNB susceptible organisms causing meningitis, Prophylaxis in neutropenic patients.ResistanceChromosomal gene mutations alter DNA gyrase, and topoisomerase IV decreases cell membrane permeability. Plasmid-mediated genes enabling acetylation and efflux pumps decreasing efficacy.Pharmac-okineticsExcellent oral bioavailability and food can alter absorption [142]. Plasma protein binding is low except for delafloxacin and gemifloxacin. Tissue distribution is excellent, with above serum levels seen in bile, prostate, kidney, lung, and stool [143]. Levofloxacin and moxifloxacin attain adequate CSF penetration [144]. Levofloxacin, ofloxacin, ciprofloxacin undergo renal clearance, whereas moxifloxacin undergoes hepatic metabolism. Dose adjustment is needed in renal insufficiency [145].Toxicity/Adverse effectsGI: vomiting, nausea, abdominal discomfort, diarrhea, Clostridioides difficileassociated diarrhea [146]. CNS: headache, dizziness, mood changes, peripheral neuropathy [147, 148]. Skin: allergy and skin reactions such as maculopapular rash, phototoxicity [149, 150]. Others: hypoglycemia, prolongs QT interval, increased risk of aortic aneurysm and dissection, retinal detachment, tendinitis with arthropathy [151, 152, 153, 154, 155].
OriginPCN was isolated from Penicillium chrysogenumin 1928 by Alexander Fleming [156]. Chemical modifications created numerous semisynthetic PCNs. Natural PCNs: PCN V, PCN G. Penicillinase resistant PCN: Methicillin. Nafcillin, Oxacillin. Aminopenicillins: Amoxicillin, Ampicillin. Carboxypenicillins: Ticarcillin and Carbenicillin. Ureidopenicillins: Piperacillin, Azlocillin and Mezlocillin.Mechanism of actionPCNs bind to multiple PBP simultaneously, stopping the cell wall synthesis and creating hydroxy radicals that permanently damage the cell. PCNs do not affect dormant bacteria [141, 157].RoutesOral, IV, and intramuscular [IM] formulations are available.IndicationIV PCN G is the antibiotic of choice for PCN susceptible strains causing pneumococcal and meningococcal meningitis, streptococcal IE, and neurosyphilis. Benzathine PCN is used in syphilis treatment and for rheumatic fever prophylaxis. Oral PCN V or G or Benzathine PCN are used to stop outbreaks of streptococcal infection. Intrapartum prophylaxis with PCN is used at membrane rupture or at labor to prevent Streptococcal agalactiaeinfections in colonized patients. PCNase resistant PCNs are the agent of choice for MSSA infections and an alternative to treat streptococcal infections. AminoPCNs treat UTI, Upper and lower airway infections, Gastroenteritis, IE, Meningitis by susceptible non-beta- lactamase organisms. IV ampicillin is the treatment of choice for Enterococcus faecalisIE and other infections. Amoxicillin is a part of the combination regimen against Helicobacter pylori.Oral amoxicillin or ampicillin are used as prophylaxis in asplenic or agammaglobulinemia patients to prevent infections by capsulated organisms. Ampicillin-sulbactam is the drug of choice for aspiration pneumonia. Piperacillin-tazobactam is an antipseudomonal and is also used for necrotizing fasciitis, susceptible GNB infections.ResistancePresence of beta-lactamase [158]. Alteration of cell membrane permeability with a decreased intracellular entry [absence of porin] [159]. Presence of efflux pumps [159]. Synthesis of PBP with decreased affinity for the beta-lactam [160].Pharmac-okineticsPCNs vary in their oral absorption and plasma protein binding. The tissue distribution is more than adequate in most tissues. The primary route of excretion is via the renal system, whereas some undergo biliary excretion too.Toxicity/Adverse effectsHypersensitivity reactions: rash, anaphylaxis, exfoliative dermatitis, allergic vasculitis, SJS, and TEN [161]. GI: nausea, vomiting, diarrhea, Clostridioides difficile associated diarrhea, liver function test abnormality with oxacillin in patients with HLA-B 5701 [162, 163]. Hematological: neutropenia [164]. Renal: Nephrotoxicity, allergic interstitial nephritis [165]. CNS: Myoclonic seizures.
Table 13.
3A VI penicillin [beta-lactams].
OriginSemisynthetic derivatives of Cephalosporin C isolated from Acremonium chrysogenum[166]. First-generation: cefazolin, cephalexin, and cefadroxil. Second generation: cefprozil and cefuroxime, cephamycin: cefoxitin Third generation: cefdinir, cefditoren, cefixime, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftriaxone. Fourth generation: Cefepime, Cefpirome. Fifth-generation: Ceftaroline, ceftobiprole. Siderophore cephalosporins: Cefiderocol.Mechanism of actionThey bind to PBPs and stop transpeptidation and block the cell wall synthesis resulting in a bactericidal effect with a postantibiotic effect [167]. MRSA active cephalosporins bind to PBP2A, whereas the other cephalosporins bind to PBP1A&B in gram negatives [168]. Cephalosporins active against gram-positive organisms bind to PBP 2&3 [186]. Cefiderocol binds to iron and enters the bacteria via siderophores into the periplasmic space and binds to PBP in addition to being a poor substrate for efflux pumps [169].RoutesFirst, second and third generations are available in oral and parenteral [IV/IM] formulations. The fourth and fifth-generation are available in IV formulations. Fifth-generation are available in IV formulations. Siderophore cephalosporins: available in IV formulations.IndicationFirst-generation: oral therapy for MSSA and StreptococcalSSTI outpatient, susceptible StreptococcalSSTI, MSSA IE, the prophylactic antibiotic of choice for prosthesis implantation and surgical procedures with a high risk of infection except for intraabdominal procedures. Second generation: as a part of a combination regimen for PID [cefoxitin], nontuberculous mycobacterial infection [cefoxitin], cefuroxime for acute otitis media, pharyngitis, maxillary sinusitis, and an alternative for Lyme disease [170, 171]. Third generation: treatment of susceptible GNB bacilli induced SSTI, Prosthetic joint infection [PJI], CABP, cUTI, and peritonitis [172]. Empirical therapy for CABP, acute bronchitis, and meningitis. IM single dose for Neisseria gonorrhea and chancroid [173]. Lyme disease and an alternative for PCN allergic patients with syphilis, typhoid fever, and shigellosis [174, 175]. Monotherapy for StreptococcalIE [176]. Ceftazidime is the drug of choice for susceptible Pseudomonas sppinfections, including CNS [177]. Fourth generation: antibiotic of choice for infections caused by AmpC [Class C beta-lactamases] inducible resistant organisms [178]. Febrile neutropenia monotherapy or a part of a combination regimen [179]. Empirical therapy in severe CABP, HAP by Pseudomonas sppor resistant Enterobacteriaceae[180]. It is an alternative for susceptible GNB meningitis, bacteremia, SSTI, PJI and cUTI. Fifth-generation: Ceftaroline used for MRSA pneumonia, CABP, SSTI, HAP, and in combination with daptomycin for daptomycin resistant MRSA infections [181, 182, 183]. Ceftobiprole also is an alternative for Pseduomonal sppinfections. Siderophore cephalosporins: approved for use in cUTI by Enterobacterales & P. aeruginosa,HAP, and VAP by the Enterobacterales, P. aeruginosa, and Acinetobacter baumannii complex[169].ResistanceBeta-lactamase hydrolyzes the antibiotic. Cell wall membrane changes alter the entry of antibiotics through the lipopolysaccharide layer. Efflux pumps removing the antibiotic from the periplasmic space. PBP changes to alter antibiotic binding.Pharmac-okineticsThe first three generations are water-soluble and come in oral and parenteral formulations, whereas the fourth and fifth-generation are parenteral only. Distribution is dependent on their lipid solubility and plasma protein binding. They reveal higher serum concentrations and lower tissue levels. The third and fourth generations attain adequate CNS concentrations. Most of them undergo renal clearance except for ceftriaxone and cefoperazone, which undergo biliary excretion. Probenecid inhibits tubular secretion of cephalosporins and increases their half-life. Renal failure will need a dose adjustment. Ceftriaxone dose is adjusted with simultaneous renal and hepatic impairment [184]. Cefiderocol is excreted renally and needs renal dose adjustment [185].Toxicity/Adverse effectsHypersensitivity reactions: immunoglobulin E [IgE]-mediated reactions occur in 30 μg/mL [220]. A higher AUC/MIC ratio is related to better clinical outcomes and decreased mortality with vancomycin therapy [221].
The lipoglycopeptides have a longer half-life and are currently undergoing trials for bacteremia, joint infections, osteomyelitis.
Retrospective data indicate higher cure rates and lower mortality when a higher dose [> 8 mg/kg/day] of daptomycin is used [222]. In the therapeutic failure of vancomycin therapy, a suggestion is to use a higher dose of daptomycin or combine it with a beta-lactam or aminoglycoside or TMP-SMX to increase its bactericidal activity. In VRE endocarditis with bacteremia, daptomycin with beta-lactam is an ideal combination to prevent the emergence of resistance [223, 224]. Due to lack of CNS penetration, it should not be used in the therapy for meningitis [225]. Daptomycin is inactivated by the pulmonary surfactant and is rendered ineffective in bronchoalveolar pneumonia but is adequate in hematogenous pneumonia [226]. In patients with chronic kidney disease and on dialysis, more frequent monitoring of CPK is ideal. CPK monitoring is a must if the patient is on statins for hyperlipidemia. It needs to be stopped if the CPK levels are >1000 units/L with clinical features of myopathy or > 2000 [ten times the upper limit] with no myopathy features [123].
Streptogramins are another class of lipopeptides rarely used currently. They are made up of two macrocyclic lactone peptolide components. They are labeled as streptogramin A, and streptogramin B. Quinupristin-Dalfopristin is a 30: 70 ratio IV formulation available for therapy. These components are bacteriostatic as dalfopristin ends protein synthesis by binding to 50S ribosomal unit and quinupristin prevents peptide elongation. Dalfopristin binding increases the affinity to quinupristin due to structural change resulting in synergistic bactericidal activity. It is currently used as an alternative for MSSA or streptococcal SSTI. It needs a central line for administration as it is an irritant and can cause thrombophlebitis [227].
Due to the lack of active intrinsic electron transport chain and cell membrane potential difference, the anaerobic bacteria are resistant to aminoglycosides. Enterococciare intrinsically resistant to aminoglycosides [228]. Once-daily dosing is effective as traditional multiple doses, decreases the risk of ototoxicity and nephrotoxicity, is straightforward, and is economical towards resources and time [229]. This dosing pattern does not decline neuromuscular function in sick intubated patients but needs evaluation in cystic fibrosis, meningitis, and osteomyelitis caused by aerobic gram-negative bacilli [230, 231, 232]. The once-daily dose should be used cautiously in IE patients [176]. Inhaled aminoglycosides used in conjunction with a beta-lactam reveal better clinical outcomes [233]. For endophthalmitis and intracranial infections, they need to be administered locally [direct intravitreal injection, intraventricular administration]. Aminoglycoside combination regimens diminish the emergence of resistant strains to the companion antibiotic and aminoglycoside. The synergistic antibiotic effect is observed when aminoglycoside is combined with an anti-cell wall antibiotic [beta-lactam]. This combination is effective in the therapy of MSSA, enterococci, pseudomonas spp,and Streptococcal viridansinfections but not in MRSA infections.
Plazomicin is a semisynthetic aminoglycoside derived from sisomicin. It is potent against MDR GNB, especially the ones with carbapenemase. It has been approved currently for the treatment of complicated UTI [cUTI] by aerobic gram-negative bacilli. It is synergistic with other beta-lactams, especially zosyn cefepime and doripenem [234]. The main side effects are tinnitus, headache, dizziness, and mild to moderate drowsiness.
Delafloxacin, a newer quinolone, has MRSA activity and can be used in native and prosthetic joint infections as an oral pill.
PCN skin tests are inaccurate in predicting skin reactions. In PCN or cephalosporin allergy patients, the clinical decision to use a different cephalosporin is decided by the severity of the reaction and the cephalosporin to be used. In patients with no severe reactions, a cephalosporin with a different side chain can be used. It is recommended not to use a cephalosporin in case of a severe reaction [235]. Cephalosporins are not active against atypical organisms responsible for CABP. An initial study disclosed increased mortality with cefepime than other cephalosporins compared to a beta-lactam plus beta-lactamase inhibitor [BLI], which was not observed in a more extensive meta-analysis [236, 237]. Cefepime is not recommended to be used in ESBL infections [238]. Siderophore cephalosporins Cefiderocol are active against all beta-lactamases and carbapenemase enzymes [239]. It is also active against the GNB lactose-non fermenters by its affinity for the PBP3.
Zosyn should not be used to treat ESBL infections with bacteremia due to higher mortality observed in trials compared to meropenem [240, 241].
Most Burkholderia cepacia, Stenotrophomas maltophilia, Acinetobacter baumanniistrains are resistant to aztreonam.
Lactose-non fermenters such as Stenotrophomonas maltophilia, B. cepacia,and Elizabethkingia meningosepticaare intrinsically resistant to all carbapenems due to intrinsic MBL synthesis. Similarly, Enterobacteriaceaecontaining KPC [Klebsiella pneumoniae], OXA [A. baumannii], or acquired MBL are resistant to carbapenems. They are an ideal choice for polymicrobial infections as they also cover MSSA. Pseudomonas aeruginosaresistance to carbapenems is primarily due to porin mutations and efflux pumps than the carbapenemase. Porin mutations affect the imipenem, whereas the efflux pumps affect the meropenem and doripenem [242, 243]. The duration of therapy for lactose-non fermenters causing VAP is controversial, as a shorter duration of seven days is associated with an increased recurrence rate [244].
Compared to other antimicrobial classes, polymixins have been associated with poorer outcomes, but this appears to be a poor application of prior suboptimal dose adjustments based on the newer pharmacokinetics and pharmacodynamics data [245, 246]. Polymixin combination regimens should be used as a last resort in the absence of any alternative antimicrobial regimen.
Extreme consideration should be given to the possible drug interactions when rifamycins are used clinically due to their ability to induce the hepatic cytochrome system.
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4. Antibiotics in ICU
Antimicrobial prescription in the intensive care unit has three essential ideals to be followed: the correct time when to initiate the antimicrobial, what dose to be used, and how long the antimicrobial should be used. Initiate empirical regimen as early as possible once the infection is suspected to prevent poor clinical outcomes [247]. Trials reveal a positive association between earlier antimicrobial use and mortality in sepsis and septic shock [248]. 2016 surviving sepsis guidelines recommend administering appropriate antimicrobial therapy within one hour of sepsis and septic shock recognition based on the moderate quality of evidence [249]. The empirical regimen should be based on the clinical presentation and associated risk factors. The dose used should be based on the antimicrobial pharmacokinetics, and antibiotics are labeled as either time-dependent [beta-lactams], concentration-dependent [aminoglycosides and daptomycin], and concentration-dependent with time dependence [fluoroquinolones, linezolid] [250].
For time-dependent antimicrobials, the best way to achieve efficacy is a continuous infusion to keep the drug levels above the MIC for a longer time [251]. For concentration-dependent antimicrobials, once-daily higher doses are adequate as they demonstrate postantibiotic effect with reduced adverse events [252]. It is prudent to increase the antimicrobial dosage in patients with augmented renal clearance [burns, trauma, febrile neutropenia] to increase the antimicrobial dosage to achieve the target drug levels [253]. De-escalation of antibiotics is done via three different methods. First, once empirical therapy is initiated, follow the pending culture results, and on day three, when the antimicrobials have reached adequate therapeutic levels, the regimen can be de-escalated to a narrower spectrum based on the patient’s culture results and clinical diagnosis. Second, in patients with negative culture results, which is a common finding in ICU patients, the de-escalation process is unclear. For example, in patients treated for HAP who are clinically improving with negative sputum cultures for MRSA and P. aeruginosa, antibiotics covering these organisms can be stopped as per guidelines [254]. The third mechanism uses the empirical regimen for the shortest duration possible for a better clinical outcome [255]. This recommendation is based on expert opinion than clinical data.
Recent guidelines based on multiple trials conducted on the VAP antimicrobial therapy duration suggest using the treatment for seven days than 14 days [256]. However, they also recommend following the improvement in clinical, imaging, and laboratory parameters to decide the duration of therapy judiciously. Seven days of VAP therapy was associated with an increased recurrence of infections among lactose-non fermenter GNB such as Pseudomonas and Acinetobacter spp. [244]. Similarly, in MRSA and MSSA pneumonia, the duration is decided by the clinical picture, and most often, it is more than seven days and closer to 14 days.
Antibiotic use in the intensive care unit [ICU] usually follows two different thought processes. One way is to use a single or limited number of antimicrobials as workhorse agents as empirical therapy for infections which carries an inherent risk of resistance emergence via selective pressure [antibiotic homogeneity]. This was initiated to control resistance. Another way is to select the antibiotics based on clinical presentation and comorbid risk factors associated with decreased resistance [antibiotic heterogeneity]. This is a newer initiation in managing resistance. It is recommended to use antibiotic heterogeneity as much as possible to prevent antimicrobial resistance emergence [257]. Antibiotic stewardship is a must in this modern era for better clinical outcomes, prevent antibiotic adverse events and resistance using local data, reduce the costs by selecting the correct antibiotic dose duration and route. An ideal stewardship team should include an infectious disease consultant, clinical microbiologist, infectious disease trained clinical pharmacist. The current guidelines recommend two strategies to attain this objective. First, reduce the future antibiotic use by auditing institutional antimicrobial usage with feedback to the prescribers. Second, it is ideal to restrict certain antimicrobials to prevent inappropriate usage and decrease institutions’ economic burden. Measures taken to enhance the ICU staff education boosts the stewardship process and increases its acceptance among health care workers.
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5. Conclusion
Antibiotic resources are finite and need to be managed judiciously with principles based on antimicrobial stewardship. Management of sick patients in ICU will need timely appropriate antimicrobial adjustments based on new laboratory results and clinical parameters. It seems reasonable to utilize a stewardship team to support the intensivist in the ICU for better outcomes. It seems appropriate to extend the stewardship program to progressive care units or step-down units where antimicrobial utilization is greater than the floors. Education of the ICU staff and positive feedback to antibiotic prescribers can change prescription behavior from antibiotic homogeneity to antibiotic heterogeneity to prevent the emergence of MDR organisms.