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Dosing in renal failure



Minimum inhibitory concentration: the minimum concentration of drug that completely inhibits bacterial growth.

Mode of action

  • action is dependent on selective toxicity ie the drug is toxic but only to target organisms
  • exploit the differences between human cells and those of bacteria. The most striking difference is that bacteria have cell walls as well as a cell membrane while human cells only have a cell membrane. The cell wall is the principal target of b lactam antibiotics. The other principal targets are intracellular. As a result the effectiveness of those antibiotics which act at these sites is dependent on their ability to penetrate the cell. Aminoglycosides, for example, have to be actively transported across the bacterial cell membrane. Glycoproteins (eg vancomycin, teicoplanin) are unable to penetrate the outer membrane of gram-negative organisms and thus have restricted activity against these organisms
  • precise sequence of events leading to death of bacteria still the subject of research



Principal target

Cell wall














Peptidyl transferase






? peptidyl transferase


Fusidic acid

Elongation factor G



Ribosomal A site



Initiation complex/translation



50S subunit

Nucleic acid


DNA gyrase



RNA polymerase



DNA strands

Cell membrane





Ion transport

Folate synthesis


Pteroate synthetase



Dihydrofolate reductase

  • in order for an antibacterial to be effective it needs to reach its target site in high enough concentrations and to remain there for long enough to kill the organism. Whether this occurs or not is dependent on both the microbiological activity of the agent and on pharmacokinetic factors
  • the relationship between concentration and killing differs between classes of antibiotics.
    • Vancomycin and beta-lactam antibiotics exhibit time-dependent killing, ie they kill bacteria best when the drug concentration remains constantly above the minimum inhibitory concentration (MIC). The rate and extent of killing remains relatively constant once concentrations are approximately 4 x MIC for the organism and thus the goal of therapy is to maintain these levels for as long as possible during the dosing interval. The optimum duration that the antibiotic concentration should remain above MIC is unknown.
    • Rate and extent of killing of aminoglycosides and daptomycin is more a function of concentration than of time, with killing most closely related to the peak concentrations achieved. This is related to their post-antibiotic effect (ie the persistence of a therapeutic effect even after disappearance of the drug). Re-exposure to aminoglycosides while the organism is recovering from a previous exposure results in little measurable bactericidal effect from the second dose (probably because the energy-dependent uptake mechanisms for aminoglycosides are not functioning at this time). ß lactams have no consistent post-antibiotic effect for gram negative bacteria and only a 1-2 h effect for gram positives.
    • Killing by fluoroquinolones appears to be related to both peak concentration and area under the concentration-time curve.
  • NB the clinical relevance of the post antibiotic effect of quinolones has not been established and the CNS toxicity of very high concentrations militates against the use of once daily dosing

Factors influencing the pharmacodynamics of antibacterial action


  • effects of macrolides are highly pH dependent: markedly reduced once the local pH falls below 7, as is likely in an abscess.
  • same is true of quinolones below a pH of 5. This may occur in lysosomes within phagocytes, where quinolones and macrolides are known to concentrate, but depends to some extent on the organism involved. Mycobacteria localize in the lysosome but their presence causes a rise in pH. In contrast Brucella spp do not have this effect and quinolones have been disappointing in clinical trials despite promising in vitro activity
  • aminoglycoside penetration into bacterial cells is reduced at low pH


  • uptake mechanism for aminoglycosides is oxygen dependent. Thus aerobic organisms that are able to grow anaerobically (eg E. coli, S. aureus) may be resistant when in an anaerobic environment despite apparent sensitivity on testing.


  • bacteria attached to surfaces (eg IV catheter) form biofilms.
  • biofilms are complex microenvironments in which one or more organisms are protected by a film of mucopolysaccharides
  • act as a physical barrier to antibacterials

Pharmacokinetic considerations

In order to achieve adequate concentrations at the target site several conditions have to be met. Each condition is dependent on the previous condition being met as well as other pharmacokinetic factors. The conditions are as follows:

  • adequate concentration in blood. This is dependent on:
    - dose administered
    - route of administration
    - volume of distribution
    - elimination
  • adequate free concentrations of drug in blood. Only free drug is microbiologically active. Depends on above plus:
    - plasma protein binding. For most antibacterials this is not a significant issue but ceftriaxone, cefoperazone and oxacillin are highly bound to albumin, while clindamycin is highly bound to alpha-1-acid glycoprotein. Protein binding not only affects free drug concentrations, it also may affect elimination. For example, ceftriaxone elimination is slowed by its high protein binding.
  • adequate concentrations in tissue extracellular fluid. Depends on above plus penetration of drug into extracellular fluid of infected tissue.
    - most tissues are supplied by fenestrated capillaries which allow free diffusion of antibacterials from plasma to ECF. This results in the average concentration in ECF being equal to that in plasma. However the profile of drug concentrations is different. The profile is related to the physical dimensions of the space containing the fluid. The higher the ratio of surface are to volume the more rapid the equilibration of concentrations between plasma and ECF. Peritoneal fluid equilibrates rapidly while fluid-filled cysts or any large collection of fluid equilibrates slowly. Although the average drug concentration in ECF is unaffected by speed of equilibration the peak concentration is. This may be important for drugs which exhibit concentration-dependent killing (eg aminoglycosides)
    - capillaries supplying the CNS, posterior chamber of the eye and the prostate are non-fenestrated. The endothelial barrier of these capillaries can only be crossed by lipid-soluble drugs (eg quinolones, rifampicin) which can pass through the endothelial cells. Concentrations of antibacterials cannot be predicted from a knowledge of plasma concentrations
    - avascular sites (eg following trauma, due to fibrin collection - as in cardiac vegetations). In these sites drug concentrations will clearly be considerably lower than blood concentrations
  • adequate concentrations in intracellular fluid (intracellular infections). Depends on an adequate concentration in ECF plus adequate penetration into intracellular fluid.
    - aminoglycosides and b lactams are poorly lipid soluble and do not achieve high concentrations in ICF
    - lipid soluble agents (eg macrolides, quinolones, rifampicin) may achieve higher concentrations in ICF than in ECF


This may be inherent or acquired

Mechanisms of resistance

  • production of drug-inactivating enzymes eg b lactamases. Common mechanism of resistance to aminoglycosides, b -lactams, macrolides and chloramphenicol
  • alteration in target site, eg alteration of a single amino acid in a bacterial enzyme may make the bacteria resistant. Increasingly common. Main mechanism of resistance to newer synthetic antibacterial drugs (eg quinolones). Also responsible for methicillin-resistance in S. aureus
  • change in permeability. Largely confined to gram negatives. The cell membrane of some species, eg Pseudomonas, have become less permeable to aminoglycosides, b lactams and quinolones. This has led to the development of resistance.
  • some bacteria are resistant to tetracycline because they have an active transport pump which removes tetracycline from with the bacteria

Acquisition of resistance

  • mutation
  • transfer of genetic material on plasmids. These can transfer complex mechanisms of resistance eg active efflux pump referred to above.

Emergence of resistance

Important factors:

  • use of antibacterials. International differences in prevalence of resistance can be explained, in part, by differences in consumption of antibacterials in different countries
  • characteristics of bacteria. Pseudomonas spp. have always been relatively resistant to antibacterials and have successfully acquired resistance to all antipseudomonal drugs that have been developed
  • use of sub-inhibitory concentrations of antibacterials is the best method of selecting drug-resistant strains in the lab. Probably also true in clinical practice.

Relationship between in vitro and in vivo effects

Effectiveness of a drug against a particular organism on in vitro testing does not necessarily mean that this drug will be effective in vivo. This is due, in part, to the factors affecting the concentration of drug at the target site but also to the factors related to in vitro testing:

  • a mechanism of resistance is not always fully expressed during in vitro susceptibility testing
  • certain drugs may give misleading results when used for susceptibility testing. Methicillin resistant S. aureus has altered penicillin-binding proteins (transpeptidases) which make them resistant to all b lactams. The best way to detect this altered protein is to test susceptibility of the bacteria to methicillin or oxacillin although these drugs are not widely used. Testing against cloxacillin or cephalosporins may give misleading results. Thus a drug may appear to be sensitive to cloxacillin but resistant to methicillin despite the fact that methicillin resistance implies the presence of altered penicillin-binding proteins and therefore resistance to all b lactams

Clinical considerations

Before prescribing antibacterials the following questions should be considered:

  • Does the clinical presentation warrant consideration of treatable infections?
  • Should empirical treatment cover all likely infecting strains or is it reasonable to prescribe a drug to which some strains are resistant?
    - depends on consequences of failure of empirical treatment. For surgical peritonitis it is important to get it right first time. Even if the patient survives a period of inappropriate treatment, appropriate treatment may not be effective if it is delayed until abscesses have formed. Other infections for which prompt appropriate treatment is essential include meningitis, septic shock, infections in neutropaenic patients, falciparum malaria, herpes encephalitis
  • How long should treatment be continued?
    - difficult
    - in general the longer treatment continues the more likely it is that the original infection will be eradicated. However the longer the treatment continues the smaller the additional benefit from continuing for another day and also the greater the risk of selecting resistant strains, of encouraging superinfection by other organisms and of dose-related adverse effects
  • What should be done if there is no response
    - is the clinical diagnosis wrong?
    - does the patient have an abscess that requires surgical or percutaneous drainage?
    - is the prescribed drug likely to reach the anatomical site of infection and the bacterial target site?
    - are the dose and route of administration appropriate?
    - is it possible that the patient’s infection is caused by a drug-resistant organism?

Families of antimicrobials








© Charles Gomersall November 1998


©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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