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Chapter 10
Antibiotic Therapy

What factors influence antibiotic choice in critically ill

patients?

Patients often require empirical antimicrobial therapy before microbiological

diagnosis. There should be close collaboration with the microbiology team, with
the choice of agents influenced by:
1 Likely site of infection and causative organism(s)
2 Likelihood of resistant organisms as assessed by:
– Recent courses of antibiotics
– LOS in hospital/ICU
– Whether they were admitted from home or another institution
– Recent travel, e.g. some parts of Spain have high rates of carbapenem-
resistant enterococci (CRE)
– Occupation
– Results from screening (e.g. methicillin-resistant S. aureus [MRSA]) and
surveillance (e.g. vancomycin-resistant enterococci [VRE]) cultures
– Local and national patterns of resistance
3 Severity of infection (fulminant infection should be treated aggressively with
broad-spectrum antibiotics that should cover more unusual organisms)
4 Patient allergy status
5 Risk of side effects including C. difficile infection
6 Potential drug interactions
7 Pharmacokinetic considerations, e.g. need for blood-brain barrier penetra-
tion in meningitis, poor lung penetration with aminoglycosides (should be
used in conjunction with another agent in pseudomonal pneumonia)

Broadly speaking, how do antibiotics work?

Antibacterial drugs may be:
1 Bacteriostatic – limit bacterial growth allowing the immune system to remove
the bacteria from the body
2 Bactericidal – cause bacterial death whilst the host cells remain undamaged;
rely on intact immune system to clear the infection
Table 10.1 details which antibiotics are bactericidal and bacteriostatic.

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 Chapter 10: Antibiotic Therapy 57

Table 10.1 Bactericidal and bacteriostatic

antibiotics

Bactericidal Bacteriostatic

Penicillins Macrolides
Cephalosporins Tetracyclines
Aminoglycosides Lincosamides
Glycopeptides Sulphonimides
Quinolones Trimethoprim
Nitroimidazoles
Rifampicin
Nitrofurantoin

What mechanisms are involved in antibiotic activity?

There are three principal mechanisms of antibacterial drug action:
1 Inhibition of cell wall synthesis
These drugs act on bacteria that have a cell wall consisting of a lattice work of
murein, by preventing cross linkage (mammalian cells lack these cell walls so
are unaffected)
2 Inhibition of DNA synthesis or function
3 Inhibition of tetrahydrofolate (THF) synthesis
4 Inhibition of protein synthesis

Table 10.2 classifies antimicrobial agents by mechanism of action.

What is time-dependent and concentration-dependent

killing?
Time-dependent killing refers to agents whose activity depends on the amount
of time the serum concentration is above the minimum inhibitory concentration
(MIC). These agents include β-lactams, erythromycin, clindamycin, linezolid,
vancomycin. They are therefore dosed regularly to keep the serum levels
above MIC as long as possible. Their half-life may be increased by the addition
of a drug that reduces elimination of the antibiotic, e.g. probenecid given in
penicillin treatment. Infusions may also be useful.
Concentration-dependent killing refers to agents whose activity correlates with
peak serum concentration. Such agents include aminoglycosides and quino-
lones. High doses are used, with lower frequency of administration. However,
this may impact on toxicity, e.g. aminoglycoside toxicity relates to tissue accu-
mulation (i.e. trough levels) rather than peak serum concentration and they
work best at 10–12 times MIC.

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Table 10.2 Mechanism of action of antimicrobial agents

Classification Drug Examples Mechanism Spectrum of activity, uses, notes

Inhibition of cell Penicillins Penicillin Transpeptidase inhibition Streptococci, enterococci, Neisseria, spirochetes
wall synthesis (enzyme that forms cross-
Flucloxacillin links in cell wall) β-lactamase resistant – covers MSSA
β-lactam ring confers anti-
Amoxicillin transpeptidase activity Improved Gram-negative cover, first-line for CAP
Co-amoxiclav β-lactamase-producing Clavulanic acid prevents the action of β-lactamase
Piperacillin/ organisms are penicillin- Gram-positive, Gram-negative and pseudomonal cover
tazobactam resistant Used as first-line in HAP, VAP and neutropenic sepsis
Carbapenems, e.g. β-lactamase resistant
meropenem Increased activity against Gram-negatives and anaerobes, may
be combined with another drug for improved Gram-positive
cover
Can be used for ESBL
Emerging resistance of enterococci (CRE)
No activity against MRSA, atypicals or stenotrophomonas
Cephalosporins 1st generation, Contain β-lactam ring as per Gram-positive
e.g. cephalexin penicillins
2nd generation, Some Gram-negative cover, e.g. E.coli, Klebsiella
e.g. cefuroxime
3rd generation, Improved Gram-negative, reduced Gram-positive cover
e.g. ceftriaxone, CNS penetration – can be used for meningitis
cefotaxime, Ceftazidime has pseudomonal cover
ceftazidime
Glycopeptides Vancomycin Exhibit slow, time- Vancomycin is highly polar and not absorbed from GI tract –
Teicoplanin dependent killing used in C. difficile colitis; vancomycin has poor chest
(vancomycin is used as an penetration (teicoplanin better)
infusion) Aerobic and anaerobic Gram-positive cover including MRSA
Polymixin E Colistin Binds to lipopolysaccharide Used in treatment of Acinetobacter and Pseudomonas,
in the cell wall of Gram- especially in CF
negative organisms Nebulised preparations exhibit less nephrotoxicity and ototoxicity
Inhibition of Nitroimidazoles Metronidazole Inhibits DNA synthesis – Activity against anaerobes and protozoa
DNA forms complexes with First-line for C. difficile colitis (oral or IV)
synthesis/ DNA and causes strand
function breakage
Rifamycins Rifampicin Inhibits DNA-dependent Has anti-staphylococcal (including MRSA) and anti-
RNA polymerase streptococcal activity
Mycobacterial infection (TB and leprosy)
Used as post-exposure prophylaxis in Neisseria/Haemophilus
meningitis
Quinolones Ciprofloxacin Inhibits DNA gyrase and Active against Gram-negatives, atypicals and some streptococci
topoisomerase-4 (DNA
synthesis)
Inhibition of THF Trimethoprim Inhibit conversion of Uncomplicated UTI
synthesis Sulphonamides Co-trimoxazole dihydrofolate (DHF) to Sulfamethoxazole affects a different step in the folate
tetrahydrofolate by metabolic pathway and is combined with trimethoprim
blocking DHF reductase synergistically to provide increased efficacy
THF is a co-enzyme required First-line for PCP, Stenotrophomonas maltophilia, Burkholderia
for the synthesis of DNA cephacia
and RNA Associated with neutropenia and epidermolysis
Dapsone Leprosy, acinomycoses, toxoplasmosis
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Table 10.2 (cont.)

Classification Drug Examples Mechanism Spectrum of activity, uses, notes

Inhibition of Tetracyclines Tetracycline Reversibly bind to 30s Gram-positive and Gram-negative cover
protein Oxytetracycline ribosomal subunit Used for atypicals, Ricketsiae and protozoa
synthesis Prevent tRNA binding with
Tigecycline mRNA Broad spectrum of activity but not anti-pseudomonal
Aminoglycosides Gentamicin Cause insertion of incorrect Gram-negative cover (also enterococci and MRSA)
Amikacin amino acid, producing No activity against anaerobes (oxygen needed for uptake of
false proteins and causing aminoglycoside into cell), poor anti-streptococcal activity
cell death Peak levels are associated with efficacy and trough levels with
toxicity
Chloramphenicol Inhibits peptide synthetase, Bacterial meningitis
preventing amino acid
linking
Macrolides Erythromycin Reversibly inhibit 50s Atypicals (mycoplasma has no cell wall, chlamydia is intracellular)
Clarithromycin ribosomal subunit Streptococcal and MSSA cover
Azithromycin Prevents ribosome moving Clarithromycin is used first-line in CAP in combination with a
along mRNA strand penicillin
Lincosamides Clindamycin Acts on 50s ribosomal Used in necrotising soft tissue infections
subunit (may compete Mixed aerobic/anaerobic infections, especially in penicillin-
with macrolides) resistance
Anti-exotoxin effect, so used in Group A streptococcal infections
Oxazolidinones Linezolid Inhibit 50s ribosomal subunit Gram-positive cover including MRSA and VRE
Has high oral bioavailability (approaching 100%)
Associated with myelosuppression, thrombocytopenia, peripheral
and optic neuropathy, lactic acidosis and MAOi-like effects

MSSA – methicillin-sensitive S. aureus; CAP – community-acquired pneumonia; ESBL – extended spectrum beta-lactamase; CNS – central nervous system;
CF – cystic fibrosis; TB – tuberculosis; DNA – deoxyribonucleic acid; RNA – ribonucleic acid; MAOi – monoamine oxidase inhibitor; UTI – urinary tract infection;
PCP – Pneumocystis jirovecii pneumonia
 Chapter 10: Antibiotic Therapy 61

Table 10.3 Gram staining of bacteria

Gram-positive cocci Gram negative cocci

Staphylococci Streptococci Neisseria

i β-haemolytic Moraxella
– Group A strep (Str. pyogenes)
– Group B strep (Str. agalactiae)
ii γ-haemolytic – enterococci
iii α-haemolytic
– Str. Pneumoniae
– Str. viridans
Gram positive bacilli Gram negative bacilli
Actinomyces Everything else
Bacillus
Clostridia
Diptheria (Corynebacterium)
Listeria

Table 10.3 provides a summary of Gram-positive and Gram-negative

bacteria.

Further Reading
Varley A J, Sule J, Absalom A R. Principles of antibiotic therapy. Contin Educ Anaesth Crit Care Pain
2009; 9(6): 184–188

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