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Antimicrobial chemotherapy 

Antimicrobial chemotherapy
Chapter:
Antimicrobial chemotherapy
Author(s):

R.G. Finch

DOI:
10.1093/med/9780199204854.003.070205_update_001

Update:

Addition of new treatments for HCV and HIV; addition of echinocandins; update on antimalarials; novel antituberculosis agents; emergence of drug-resistant organisms, e.g. XDR TB, VISA, and VRSA.

Updated on 31 May 2012. The previous version of this content can be found here.
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Essentials

The practice of medicine changed dramatically with the availability of effective antimicrobial agents. Fatal diseases such as bacterial meningitis and endocarditis became treatable; much minor community infectious morbidity became readily controlled; many surgical procedures became much safer, and developments in solid organ and bone marrow transplantation became possible. However, the very success of antimicrobial chemotherapy has led to overuse, misuse and inappropriate pressures from the public to prescribe. In many countries, antibiotics are freely available to the public for purchase ‘over the counter’, with few controls or guidance to ensure their safe and effective use. The emergence and spread of antimicrobial resistance worldwide and the decline in development and licensing of new antimicrobials threaten the future successful treatment of bacterial infections.

Antimicrobial drugs

Pharmacological characteristics and antimicrobial spectrum—antibacterial drugs can be divided according to their mode of action into those that (1) inhibit cell wall synthesis—e.g. penicillins and cephalosporins; (2) interfere with protein synthesis—e.g. tetracyclines, aminoglycosides; (3) inhibit bacterial nucleic acid synthesis—e.g. fluoroquinolones; and (4) act on metabolic pathways—e.g. sulphonamides and trimethoprin. The antimicrobial spectrum of a drug is determined by the mode of action and ability to reach the relevant target site. Antibiotics active against a few particular bacteria are considered narrow spectrum (e.g. vancomycin), while others are active against many bacteria and are labelled broad spectrum (e.g. meropenem). Some antimicrobials are only active against anaerobically dividing bacteria (e.g. metronidazole).

Clinical effectiveness—to be effective clinically, sufficient drug must reach the infection site. The pharmacokinetic characteristics of absorption, distribution, metabolism and excretion are critical to defining dose, efficacy and often safety. Poorly absorbed agents are often administered parenterally, some topically. Hydrophobicity and hydrophilicity are important in defining tissue and extracellular fluid concentrations, as are factors such as molecular size and pH. Highly protein-bound drugs such as flucloxacillin may achieve lower tissue concentrations in selected body sites.

Excretion, metabolism and drug monitoring—many drugs are metabolically degraded in the liver and/or excreted by the kidney via glomerular filtration or tubular secretion. It should therefore be anticipated that dose modification may be necessary to avoid toxicity in patients with compromised hepatic or renal function. Therapeutic drug monitoring is important in ensuring therapeutic and nontoxic concentrations of some drugs, e.g. gentamicin and vancomycin.

Antiviral, antifungal, and antiparasitic drugs—the availability of drugs to treat herpesvirus infections (herpes simplex, varicella–zoster and cytomegalovirus), and the development of new drugs active against hepatitis viruses, influenza viruses, and HIV have revolutionized the treatment of viral infections. Advances in the management of invasive fungal disease have been slower: the reliance on polyenes, e.g. amphotericin, has only recently been eclipsed with the availability of potent azoles and triazoles and echinocandins. In the case of many parasitic diseases, advances have been extremely slow, but the importance of malaria has led to new compounds being developed (e.g. the artemisin derivatives), also new ways of using established drugs in combination.

Resistance to antimicrobial drugs

Resistance mechanisms—loss of efficacy through resistance mechanisms is unique to antimicrobial drugs. There are four main types: (1) drug inactivation or destruction, (2) target site alteration, (3) reduced cell wall permeability (porin mutation) or increased removal from the cell (efflux resistance); and (4) inhibition as a result of metabolic bypass. Individual drugs can be subject to one or more mechanisms of resistance, which may vary by infecting microorganism.

Spread of resistance—genetic mutations that confer resistance do not just affect the target pathogen in the treated individual. They can disseminate both horizontally and vertically as a result of person-to-person or indirect spread of the pathogen. Spread through genetic mechanisms via plasmids, transposons, integrons, and phages between bacteria of the same and different species are common, as is spread between genera. Likewise, resistance mechanisms can spread to organisms making up the normal flora of the gut and skin.

Clinical impact—antibiotic resistance is of increasing medical and public concern, and affects all aspects of medicine. Infections become unresponsive to initial therapy, sometimes with fatal consequences in the seriously ill. In others, reassessment and alternative therapy with agents are often more toxic and more expensive are required, leading to increased morbidity and increased costs through prolonged hospitalization. The spread of resistant pathogens within hospitals, nursing homes and the community is a very significant concern. High rates of meticillin-resistant Staphylococcus aureus (MRSA) infections are present in many countries, including the United States of America, the United Kingdom, and soutern Europe. Public confidence in health care has been eroded, leading to major government initiatives in the European Union, North America, and Australia in efforts to contain these resistant pathogens.

Prescribing of antimicrobial drugs

A set of principles has emerged to support safe and effective prescribing, covering issues of choice of drug, dose and route of administration, duration of therapy, strategies to minimize adverse reactions, and what factors need to be considered should initial treatment fail. The complexity of modern therapeutics has led to the development of formularies and practice guidelines, the latter increasingly being evidence based, with the twin goals of supporting cost-effective safe prescribing whilst minimizing the risks of emergence of antibiotic resistance.

Introduction

The discovery and clinical application of antibiotics and antimicrobial chemotherapeutic agents is one of the major achievements in medicine. Life-threatening infections such as meningitis, endocarditis, and typhoid fever are now treatable, whereas before they were generally fatal. Likewise, the morbidity associated with many infectious diseases of a less life-threatening nature, such as urinary tract infections, skin and soft tissue infections, and bone and joint sepsis, has been substantially reduced. Major advances in medicine, such as solid organ and especially bone marrow transplantation, as well as the use of cancer chemotherapy, have become safer because of the availability of effective antimicrobial agents. In the field of surgery, perioperative prophylactic use of antibiotics has reduced the risk of infections complicating procedures such as large bowel and gall bladder surgery, vaginal hysterectomy, and implant surgery such as the insertion of prosthetic heart valves, joints, and neurosurgical shunting devices.

Antimicrobial chemotherapy is the use of antibiotics and chemotherapeutic substances to control infectious disease. The term ‘antibiotic’ was coined by Waksman to describe a substance derived from naturally occurring microorganisms and possessing antimicrobial activity in high dilution. The latter characteristic is essential in defining its selective toxicity to other microorganisms. True antibiotics include penicillin, derived from the mould Penicillium notatum, streptomycin from Streptomyces griseus, and the cephalosporins from Cephalosporium spp. Many chemotherapeutic substances with antimicrobial activity have been artificially synthesized, such as the sulphonamides, quinolones, and isoniazid. However, the term ‘antibiotic’ is loosely applied to both the true antibiotics and other antimicrobial agents.

Antibiotics are among the most widely prescribed drugs, accounting for an international expenditure of $33 billion. In the United Kingdom, around 80% of all prescribing is in the community where the emphasis is largely on oral agents; the remainder are used in hospitals where there is a greater emphasis on injectable drugs. More than 125 different antibiotics are available, but a relatively small number are necessary to deal with most prescribing needs. It is important that clinicians who prescribe these drugs are familiar with the principles of antimicrobial chemotherapy and that they adopt a continuous learning approach throughout their professional lives to ensure safe and effective prescribing. Table 7.2.5.1 summarizes the agents available for the treatment of bacterial, mycobacterial, fungal, viral, protozoal, and helminthic infections. More agents have been developed for the treatment of viral infections, but globally viral, fungal, and parasitic infections predominate. In recent years, there have been major advances in the availability of antiviral drugs particularly for the treatment of the herpesviruses and HIV. Likewise, safe and effective systemic antifungal agents have resulted from the discovery of azoles, triazoles, and echinocandins.

Table 7.2.5.1 Antimicrobial agents available by class or indication effective against bacterial, fungal, viral, protozoal, and helminthic infection (indicative number of agents availablea)

Antibacterial (68)

Antifungal (14)

Antiviral (37)

Antiprotozoal (9)

Anthelminthics (15)

Penicillins

Polyenes

Hepatitis B & C agents

Antimalarials

Anticutaneous larva migrans

Cephalosporins

Caspofungin

Herpesvirus agents

Amoebicides

Antihydatid agents

Carbapenems

Echinocandin

HIV nucleoside analogues

Trichomonacides

Antistrongyloidiasis

Monobactams

Tetracyclines

Flucytosine

HIV non-nucleoside agents

Antigiardials

Antithreadworm/hookworm

Aminoglycosides

Griseofulvin

HIV protease inhibitors

Leishmaniacides

Ascaricides

Macrolides

Azoles

HIV fusion entry inhibitor

Trypanocides

Filaricides

Ketolides

HIV integrase inhibitors

Lincosamides

Triazoles

Ribavirin

Antipneumocystis agents

Schistosomicides

Chloramphenicol

Terbinafine

Amantadine/rimantadine

Taeniacides

Sodium fusidate

Foscarnet

Glycopeptides

Neuraminidase inhibitors

Linezolid

Quinupristin/dalfopristin

Colistin

Sulphonamides

Trimethoprim

Antituberculous

Antileprotic

Nitroimidazoles

Quinolones

Urinary antiseptics

a Based on agents listed in the British National Formulary (www.bnf.org)

The very success of antimicrobial chemotherapy has led to widespread and often excessive use, particularly in community practice where prescribing is largely empirical and clinical distinction between viral and bacterial infections is difficult. Antibiotics are used extensively in animal husbandry both for the treatment and prevention of infectious disease and, more controversially, in some countries as growth-enhancing agents among commercially raised poultry and swine. This has raised concerns about the emergence and spread of antibiotic resistance, which affects many classes of antibiotic, may be intrinsic to a particular pathogen, or may result from genetic mutation, and in 2006 led to the European Union banning the use of all such agents as growth promoters. Resistance may be caused by enzymatic inactivation (β‎-lactamase), failure of drug penetration into the bacterial cell (porin mutation), alteration of the target binding site (e.g. penicillin-binding protein alteration in penicillin-resistant Streptococcus pneumoniae), or from efflux resistance whereby the drug is extruded from the bacterial cell (e.g. chloroquine-resistant Plasmodium falciparum). Organisms can also develop alternative metabolic pathways which bypass drug inactivation.

Resistance may be transferable between the same species or genera but may also spread between genera. Coding for multiple antibiotic resistance has been increasingly observed and results from several mechanisms, in particular plasmid transfer.

Despite the advances in antimicrobial chemotherapy, fresh challenges remain. These include the treatment of viral causes of enteric infection, hepatitis A and E, and viral meningitis, all of which are still without effective chemotherapy. Tuberculosis and malaria are among the world’s major infectious disease killers and here problems of antibiotic resistance have escalated. In the case of tuberculosis, the continuing reliance on lengthy and complex regimens continue to frustrate disease management as a result of cost, toxicity, and patient compliance with these regimens. Recent advances include the development of new agents with novel mechanisms of action: for example, TMC 207 (a mycobacterial ATP synthase inhibitor) and PA 824 (a nitroimidazole), both of which look promising in early clinical trials.

Among the more worrying trends in antibiotic resistance is the emergence within hospitals of meticillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Hospital-acquired MRSA has now spread into the community, largely among nursing home residents. Furthermore, more virulent strains of MRSA have recently arisen in the community in the United States of America and Australia. Streptococcus pneumoniae is another community pathogen which has rapidly become less sensitive to penicillin causing clinical failures when causing meningitis or otitis media. Internationally, multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, and multidrug-resistant salmonellae, including Salmonella typhi, are of major concern.

Resistance is not confined to bacteria. Fungal resistance is increasing (e.g. Candida albicans and C. krusei to fluconazole). Resistance of the HIV to the nucleoside, non-nucleoside, and protease inhibitors is rapidly emerging with many treatment-naive patients acquiring virus resistant to one or more agents. Antiviral resistance resulting in virological treatment failure is now a major factor responsible for progression of HIV disease.

Pharmacology

Mode of action

Knowledge of the pharmacological mode of action of an antimicrobial agent permits an understanding of the diverse mechanisms of microbial inhibition and the opportunities for drug resistance. This is best established for antibacterial and antiviral agents. In the case of antifungal and especially antiparasitic agents the modes of action are less well defined. This reflects the process of drug discovery whereby an understanding of the biochemical and molecular action of agents derived from natural or chemical sources has not always been a priority in establishing efficacy and safety, especially with regard to older agents.

Antibacterial drugs

Antibacterial agents may affect cell wall or protein synthesis, nucleic acid formation, or may act on critical metabolic pathways (Table 7.2.5.2).

Table 7.2.5.2 Microbial site of action and targets for selected antibacterial drugs

Site of action

Drugs

Target

Cell wall peptidoglycan

Penicillins

Transpeptidase

Cephalosporins

Transpeptidase

Vancomycin

Acyl-d-alanyl-d-alanine

Teicoplanin

Acyl-d-alanyl-d-alanine

Daptomycin

Binds to bacterial membranes

Ribosome

Chloramphenicol

Peptidyl transferase of 50S subunit

Clindamycin

50S ribosomal subunit transpeptidation

Linezolid

Blocks initiation phase

Macrolides

50S ribosomal subunit

Tetracyclines

Ribosomal A site

Aminoglycosides

Initiation complex and translation

Fusidic acid

Elongation factor G

Nucleic acid

Quinolones

DNA gyrase

Metronidazole

DNA strands

Rifampicin

RNA polymerase

Folic acid synthesis

Sulphonamides

Pteroic acid synthetase

Trimethoprim

Dihydrofolate reductase

The β‎-lactams (penicillins, cephalosporins, carbapenems, and monobactams (aztreonam)) and the glycopeptides (vancomycin and teicoplanin), inhibit cell wall synthesis. The β‎-lactams, which share the common β‎-lactam ring, act on cell wall transpeptidases to inhibit cross-linking of peptidoglycan. The glycopeptide antibiotics act at an earlier stage of cell wall synthesis by binding to acyl-d-alanyl-d-alanine. Despite their similar mode of action, the glycopeptides are less efficient bactericidal agents than the β‎-lactams.

Inhibitors of protein synthesis

Antibacterial agents that inhibit protein synthesis act on the 30S ribosomal subunit responsible for binding mRNA, or the 50S subunit which binds aminoacyl tRNA. The aminoglycosides, tetracyclines, and macrolide antibiotics are the most widely used inhibitors of protein synthesis. Chloramphenicol, clindamycin, and the recently introduced agent linezolid also act at this site.

Inhibitors of nucleic acid

Nucleic acid synthesis is targeted by quinolones, metronidazole, and rifampicin. The bacterial DNA gyrase is essential for the supercoiling of bacterial DNA. This, together with the enzyme topoisomerase IV, are the major targets for the quinolones. These enzymes are absent in humans, explaining the selective activity of these drugs. Rifampicin and other rifamycins interfere with DNA-dependent RNA polymerase, preventing chain initiation.

Metabolic inhibitors

The best known metabolic inhibitors are the sulphonamides and trimethoprim which interfere with folic acid synthesis by sequentially inhibiting the enzymes dihydropteroic acid synthetase (EC 2.5.1.15) and dihydrofolate reductase (EC 1.5.1.3). The two drugs act sequentially on the metabolic pathway, resulting in a combined antibiotic effect. The selective activity of these compounds is dependent on the fact that humans are unable to synthesize folic acid and require preformed folic acid in their diet.

Antiviral agents

Viruses live and replicate within the host cell. Antiviral chemotherapy therefore presents a particular challenge if it is to be selectively toxic. The cycle of viral replication provides several opportunities for therapeutic intervention. Most available antiviral agents are nucleoside analogues, largely used in the treatment of HIV or herpesvirus infections (Table 7.2.5.3). The recent growth in numbers of antiviral agents has benefited greatly from HIV-related research through the identification of new drug targets (Fig. 7.2.5.1). Interference with cell surface attachment through ligand blockade of surface receptors provides a theoretical, but so far unfulfilled, target. Penetration into the host cell may be through a process of translocation or direct fusion between the outer lipid membrane of the virus and the cell membrane, before uncoating and release of viral nucleic acid. Replication differs among viruses, thereby providing several therapeutic options. Viral mRNA becomes translated into multiple copies of viral proteins encoded by the viral genome either as a result of virus-specific enzymes or by co-opting host-derived protein. For example, HIV employs its own reverse transcriptase to convert RNA to DNA before integration into the host cell chromosome. Transcription and translation follow. Before the virus can be released, new viral particles must be assembled for which host cell proteins and mechanisms of phosphorylation and glycosylation may be recruited. The protease inhibitors act at this stage and have been particularly successful. Virus release is the result of either transportation and budding or host cell lysis.

Table 7.2.5.3 Mode of action of selected antiviral drugs

Drug

Target virus

Antiviral activity

Aciclovir

HSV, VZV

Nucleoside analogue

Cidofovir

HSV and CMV

Nucleoside analogue

Famciclovir

VZV

Nucleoside analogue

Foscarnet

CMV

Inhibits DNA polymerase

Ganciclovir

CMV

Nucleoside analogue

Valaciclovir

HSV, VZV

Valyl ester of aciclovir

Valganciclovir

CMV

Valyl ester of ganciclovir

Interferon

HBV, HCV

Induce interferon stimulated genes and block viral protein synthesis

Adefovir

HBV

Nucleotide reverse transcriptase inhibitor

Entecavir

HBV

Nucleoside analogue

Telbivudine

HBV

Nucleoside analogue

Ribavirin

HCV, RSV

Inhibits replication of DNA and RNA viruses, inhibits initiation and elongation of RNA fragments

Boceprevir

HCV

Binds to NS3 serine protease of HCV

Telaprevir

HCV

Binds to NS3 serine protease of HCV

Oseltamivir

Influenza A and B

Inhibits viral neuraminidase

Zanamivir

Influenza A and B

Inhibits viral neuraminidase

Amantadine

Influenza A

Uncoating and assembly

Rimantadine

Influenza A

Uncoating and assembly

Abacavir

HIV

Nucleoside reverse transcriptase inhibitor

Didanosine

HIV

Nucleoside reverse transcriptase inhibitor

Emtricitabine

HIV

Nucleoside reverse transcriptase inhibitor

Lamivudine

HIV, HBV

Nucleoside reverse transcriptase inhibitor

Stavudine

HIV

Nucleoside reverse transcriptase inhibitor

Tenofovir

HIV

Nucleoside reverse transcriptase inhibitor

Zalcitabine

HIV

Nucleoside reverse transcriptase inhibitor

Zidovudine

HIV

Nucleoside reverse transcriptase inhibitor

Delavirdine

HIV

Non-nucleoside reverse transcriptase inhibitor

Efavirenz

HIV

Non-nucleoside reverse transcriptase inhibitor

Etravine

HIV

Non-nucleoside reverse transcriptase inhibitor

Nevirapine

HIV

Non-nucleoside reverse transcriptase inhibitor

Rilpivirine

HIV

Non-nucleoside reverse transcriptase inhibitor

Amprenavir

HIV

Protease inhibitor

Atazanavir

HIV

Protease inhibitor

Darunavir

HIV

Protease inhibitor

Fosamprenavir

HIV

Protease inhibitor

Indinavir

HIV

Protease inhibitor

Lopinavir

HIV

Protease inhibitor

Fosamprenavir

HIV

Protease inhibitor

Nelfinavir

HIV

Protease inhibitor

Ritonavir

HIV

Protease inhibitor

Saquinavir

HIV

Protease inhibitor

Tipranavir

HIV

Protease inhibitor

Enfurvitide

HIV

Fusion entry inhibitor

Raltegravir

HIV

Integrase inhibitor

Maraviroc

HIV

CCR5 antagonist

CMV, cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; RSV, respiratory syncytial virus; VZV, varicella zoster virus

Fig. 7.2.5.1 Sites of inhibition of HIV replication by current antiretroviral drugs.

Fig. 7.2.5.1
Sites of inhibition of HIV replication by current antiretroviral drugs.

Antifungal agents

The polyene antifungals (amphotericin B and nystatin) act on ergosterol within the fungal cell membrane. Ergosterol is largely absent from bacteria and humans, explaining the selective toxicity of these agents. The azole antifungals include the imidazoles (e.g. clotrimazole, miconazole, and ketoconazole) and the triazoles (fluconazole, itraconazole, and voriconazole) which bind preferentially to fungal cytochrome P450 to inhibit 14-α‎-methylsterol demethylation to ergosterol. The echocandins (e.g. caspofungin, micafungin, and anidulafungin) act on fungal cell wall β‎(1-3)d-glycan to inhibit growth.

Antiparasitic agents

The mechanism of action of many antiparasitic drugs is only partially known. Among the antimalarials, chloroquine interferes with the metabolism and utilization of haemoglobin by malaria parasites. It also concentrates within parasite acid vesicles and raises internal pH, inhibiting parasite growth. Amodiaquine is similar in structure to chloroquine and there is cross-resistance between the two drugs.

Quinine acts by depressing oxygen uptake and carbohydrate metabolism and by intercalating into DNA, disrupting parasite replication and transcription. Mefloquine is a quinolone methanol compound structurally similar to quinine. Primaquine disrupts mitochondria, disrupts DNA, and eliminates the tissue exoerythrocytic forms of Plasmodium falciparum. The exact mechanism of action of lumefantrine is unknown but it may inhibit the formation of β‎-haematin by complexing with haemin.

Sulfadoxine–pyrimethamine inhibits tetrohydrofolic acid synthesis. Atovaquone inhibits parasite electron transport in mitochondria, resulting in inhibition of ATP and nucleic acid synthesis. Proguanil inhibits dihyrofolate reductase. Together, atovaquone and proguanil affect the erythrocytic and exoerythrocytic stages of parasite development.

Artemisin derivatives include artemether, arteether, dihydroartemisinin, and artesunate. They appear to act by binding iron, breaking down peroxide bridges leading to the generation of free radicals that damage parasite proteins. They kill all blood stages of Plasmodium spp. and have the fastest parasite clearance times of any antimalarial.

Metronidazole is active against several protozoa such as Entamoeba histolytica and Giardia lamblia as well as anaerobic bacteria. It acts as an electron sink, by reduction of its 5-nitro group activated by nitroreductase within the target pathogen, thus interrupting DNA synthesis.

Among the anthelmintic drugs, piperazine and praziquantel act by selectively inducing muscle paralysis in the target helminth. Others, such as thiabendazole, inhibit parasitic ATP synthesis and energy production.

Antimicrobial spectrum of activity

The antimicrobial spectrum of an agent is dependent on target site susceptibility among pathogenic organisms at clinically achievable drug concentrations. Some microorganisms are intrinsically resistant to certain antibiotics. For example, the aminoglycosides are inactive against anaerobic bacteria because cell entry is an energy-dependent process relying on respiratory quinones, which are absent in anaerobic bacteria. Certain strains of Pseudomonas aeruginosa are resistant to the aminoglycosides as a result of altered protein porin channels, which inhibit antibiotic penetration.

The antimicrobial spectrum of a drug in part dictates its clinical indications. While information on this spectrum is more easily determined in vitro, in vivo efficacy can only be confirmed through clinical use, which can be supported by animal model data during drug development. For example, in vitro Salmonella typhi is susceptible to gentamicin, but the drug is not effective clinically.

Narrow-spectrum and broad-spectrum agents

There are few truly narrow-spectrum agents. Fusidic acid, mupirocin, the glycopeptides (vancomycin and teicoplanin), and linezolid target specific pathogens and are mainly used to treat microbiologically confirmed infections.

Broad-spectrum agents, such as the quinolone antibiotics and the parenteral cephalosporins such as cefotaxime and ceftriaxone, are active against many Gram-positive and Gram-negative pathogens. Metronidazole has activity against a large number of anaerobic bacteria and, because of this restricted activity, is considered to have a narrow spectrum. The aminoglycosides, although active against staphylococci and aerobic Gram-negative bacilli are inactive against streptococci and anaerobes and are, therefore, frequently prescribed in combination. The carbapenems (imipenem, meropenem, and ertapenem) possess the broadest spectrum of activity which includes most aerobic and anaerobic bacterial pathogens. Ertapenem differs from the other carbapenems in its lack of activity against pseudomonas. Broad-spectrum agents are often used empirically in the initial management of severe infection. However, they frequently affect the normal flora so that superinfection with Clostridium difficile and yeasts are more likely to arise.

Susceptibility testing

Antibiotic susceptibility testing of clinical isolates is important for appropriate prescribing and for gathering epidemiological data. It is determined in vitro by using either broth-based or agar-based methods. Pathogens are exposed to known concentrations of an antibiotic and their degree of inhibition compared to a standard control. Disc susceptibility testing is the most widely used method. Zones of inhibition around the antibiotic-containing disc are measured, compared to a standard, and the pathogen designated sensitive, resistant, or of intermediate susceptibility to the drug. Currently, such methods require the isolate to be tested in pure culture. It is, therefore, difficult to obtain information on the susceptibility of a pathogen in less than 36 to 48 h from sample collection.

The minimum inhibitory concentration (MIC) in milligrams per litre provides more precise in vitro information on the activity of a drug against a bacterial pathogen. It is more time consuming and costly to determine, although automated systems and commercial strip tests are available (Fig. 7.2.5.2). Defining susceptibility by MIC determination permits greater predictive benefit in the treatment of certain infections such as gonorrhoea, bacterial endocarditis, and pneumococcal meningitis. Knowledge of the in vitro susceptibility of common pathogens to antimicrobial agents (Fig. 7.2.5.3) is helpful in selecting drug therapy but is only relevant to the achievable drug concentrations, which is important in predicting performance as discussed below.

Fig. 7.2.5.2 Staph. aureus resistant to penicillin (MIC 8 mg/litre) on the left and sensitive to vancomycin (MIC 1.0 mg/litre) on the right, as demonstrated by a commercial strip test.

Fig. 7.2.5.2
Staph. aureus resistant to penicillin (MIC 8 mg/litre) on the left and sensitive to vancomycin (MIC 1.0 mg/litre) on the right, as demonstrated by a commercial strip test.

Fig. 7.2.5.3 Sensitivity of selected pathogenic bacteria to some common antibacterial agents.

Fig. 7.2.5.3
Sensitivity of selected pathogenic bacteria to some common antibacterial agents.

Combined drug therapy

In hospital practice, it is common to combine agents when dealing with mixed infections or where initial broad-spectrum empirical therapy is required. Another important reason for combining drugs is to prevent the emergence of antibiotic resistance, such as in the treatment of tuberculosis, HIV, and malaria. Antituberculosis regimens have been developed to ensure that naturally occurring minority populations of Mycobacterium tuberculosis resistant to isoniazid or rifampicin do not emerge during therapy. By combining isoniazid and rifampicin with pyrazinamide and ethambutol for the initial phase of therapy (2 months), resistance is usually avoided. Therapy can be restricted to isoniazid and rifampicin for the continuation phase (4 months). The regimen is extended in those patients unable to tolerate pyrazinamide and in the treatment of tuberculous meningitis (Box 7.2.5.1).

a Central nervous system and disseminated tuerculosis should be treated for 10 months after the initial phase of four drugs.

b If pyrazinamide is contraindicated or not given, the continuation phase is extended to 7 months.

HIV infection is treated with multidrug regimens. The success of highly active antiretroviral therapy, in which nucleoside analogues and protease inhibitors are combined in a three-drug regimen, is not only based on greater efficacy of the combined regimen but also on its ability to slow the emergence of drug-resistant mutants. The non-nucleoside reverse transcriptase inhibitors, such as efavirenz, appear to be equally effective in combination with nucleoside analogues but have a lower barrier to resistance. The options for treating HIV infection are summarized in Box 7.2.5.2 (see also Chapter 7.5.23).

a See Table 7.2.5.3 for agents available.

b The recommended NRTI conformulation is tenofovir and emtricitabine.

c The recommended NNRTI is efavirenz.

d The recommended boosted PI combinations are atazanavir + ritonavir or darunavir + ritonavir.

Occasionally, drugs are combined for the purpose of achieving a synergistic effect based on evidence that the in vitro activity of the combination is shown to be greater than the sum of the activity of the individual agents. Most drugs in combination will simply be additive in effect. One of the more frequently prescribed synergistic combinations is that of penicillin (or ampicillin) and streptomycin (or gentamicin) in the treatment of endocarditis caused by Enterococcus spp. The aminoglycoside alone is generally inactive against enterococci but in combination with ampicillin achieves synergistic killing (Fig. 7.2.5.4). A similar effect is employed in the treatment of viridans streptococcal endocarditis with this combination.

Fig. 7.2.5.4 Effects of ampicillin (0.5 mg/litre) and gentamicin (2 mg/litre) alone and in combination on a strain of Enterococcus faecalis from a patient with infective endocarditis. A synergistic effect is observed with the combined agents.

Fig. 7.2.5.4
Effects of ampicillin (0.5 mg/litre) and gentamicin (2 mg/litre) alone and in combination on a strain of Enterococcus faecalis from a patient with infective endocarditis. A synergistic effect is observed with the combined agents.

Another widely used example of synergistic inhibition is the combined effects of an antipseudomonal β‎-lactam, such as ceftazidime or piperacillin, and an aminoglycoside, such as gentamicin, tobramycin, or amikacin. This combination is used to treat documented or suspected P. aeruginosa infections occurring in neutropenic states complicating bone marrow transplantation, cytotoxic chemotherapy, and burn wound infections.

Antibiotic resistance

General considerations

Antibiotic resistance has been recognized since the introduction of effective antibiotics. For example, penicillin-resistant strains of Staph. aureus became widespread shortly after the introduction of this agent; penicillin-sensitive strains are now uncommon. Resistant strains of Gram-negative bacteria, such as Klebsiella, Enterobacter, Acinetobacter, and Pseudomonas spp. are commonly found in high-dependency units where they may cause epidemics. The international emergence of epidemic MRSA infections, initially within hospitals but increasingly in the community, is worrying. Conventional approaches to controlling these infections have been largely unsuccessful. The emergence of MRSA together with multiple-antibiotic-resistant coagulase-negative staphylococci has rapidly increased the use of vancomycin. Vancomycin-resistant enterococci have emerged in specialist hospital facilities such as dialysis and haematology units; therapeutic options are limited. Vancomycin intermediate sensitivity S. aureus (VISA) and vancomycin resistant S. aureus (VRSA) have also been reported. Other problems include the emergence of penicillin-resistant pneumococci, β‎-lactamase-producing Haemophilus influenzaa, and carbapenemase-producing Enterobacteriaceae.

At present, there is great international concern among professionals, politicians, and, increasingly, the public about antibiotic resistance. In the United Kingdom, the House of Lords published an influential document in 1998 reviewing the issues surrounding this problem. This led to several initiatives including: (1) reducing the use of antibiotics, particularly in the treatment of minor upper respiratory tract infections in the community; (2) education strategies for prescribers and the public; and (3) better enforcement of infection control policies. Within the European Union, similar measures have been proposed together with a ban on the use of antibiotics as growth promoters in livestock animals. However, antibiotic resistance is a global problem. An increasing number of multidrug-resistant infections caused by Salmonella and Mycobacterium tuberculosis are being imported from developing countries where the availability or prescribing of antibiotics is less controlled. The recent emergence of extensively drug-resistant tuberculosis (XDR-TB) is a major cause for concern.

Antibiotic resistance drives changes in patterns of prescribing and is a major impetus to the pharmaceutical industry in its search for new therapies. Microorganisms differ in their ability to develop resistance, which may affect a particular drug, a class, or multiple classes of antibiotics. Genetic mutations select for antibiotic resistance, which frequently occurs under the influence of antibiotic pressure. The major mechanisms of resistance are summarized in Table 7.2.5.4. Resistance to single or multiple antibiotics may be either chromosomally or plasmid mediated, or both. In turn, genes may code for resistance to a single or multiple antibiotics. In addition to plasmid-mediated resistance, other transposable genetic elements (transposons) and insertion sequences (integrons) incapable of self-replication may exist within a chromosome, plasmid, or bacteriophage.

Table 7.2.5.4 Examples of resistance mechanisms for selected antibiotics

Enzymatic/inactivation

Altered target site

Altered permeability

Efflux

Metabolic bypass

Aminoglycosides

Erythromycin

β‎-Lactams

Tetracycline

Sulphonamides

β‎-Lactams

Chloramphenicol

Quinolones

Quinolones

Trimethoprim

Chloramphenicol

Fusidic acid

β‎-Lactams

Streptomycin

Resistance genes are most frequently transferred between organisms by conjugation. This occurs between the same or different species of bacteria and also between different genera. Other mechanisms of transferring resistance include transduction via a bacteriophage and, less commonly, transformation in which naked DNA released during cell lysis is taken up by other bacteria.

Transposon-mediated resistance reflects transfer of discreet sequences of DNA between chromosomes or plasmids whereby individual or groups of genes can be inserted into the host bacterial cell. Integrons may contain one or more gene cassettes which carry determinants of combinations of resistance genes within the bacterial chromosome, plasmid, or transposons. The antibiotic resistance genes are bound on each side by conserved segments of DNA. These individual resistance genes can be inserted or removed between the conserved structures and act as expression vectors for antibiotic resistance genes.

While the molecular mechanisms of antibiotic resistance are legion, the ability of drug-resistant microorganisms to survive, disseminate, and cause disease varies widely. In many instances, antibiotic resistance may give a survival advantage only in the presence of continued antibiotic exposure to such agents. This is reflected in the occurrence of epidemic infections in high-dependency units such as intensive care facilities where antibiotic usage is often high. However, it is also clear that once the genetic mechanism for evading antimicrobial activity has been acquired, it is rarely lost and adds to the continuously expanding genetic memory that has steadily eroded the efficacy of many antimicrobial drugs.

Enzymatic inactivation

Aminoglycoside-modifying enzymes include adenylating, acetylating, and phosphorylating enzymes. Gentamicin is the most susceptible and amikacin the least susceptible to such inactivation. However, the largest group of inactivating enzymes are the β‎-lactamases (E.C. 3.5.2.6) which hydrolyse the β‎-lactam ring common to all penicillins and cephalosporins. Penicillinase was the first β‎-lactamase to be identified and is the reason why most strains of Staph. aureus are resistant to this drug. Another important β‎-lactamase is TEM-1, which is responsible for resistance to ampicillin by Haemophilus influenzae. The major impetus to the development of the broad-spectrum penicillins and cephalosporins was to extend their activity by resisting inactivation by β‎-lactamases present in many aerobic Gram-negative bacilli. However, new inactivating enzymes continue to emerge, including the extended-spectrum β‎-lactamases, which are now limiting the clinical utility of third-generation cephalosporins. A further example is the carbapenemase group of β‎-lactamases which hydrolyse imipenem, meropenem, and ertapenem.

Impermeability resistance

Drug uptake of antibiotics such as the penicillins, tetracyclines, and quinolone antibiotics by bacteria is through protein channels (porins) which cross the outer membrane. Alterations in the permeability of the outer membrane of Gram-negative bacteria is an increasingly important mechanism of drug resistance. Mutations in porin structure are responsible for resistance among pathogens such as P. aeruginosa and Serratia marcescens.

Alterations in target site

Another important mechanism of resistance is mutational modification of drug binding sites. This affects susceptibility to β‎-lactams, erythromycin, chloramphenicol, and rifampicin. Erythromycin and chloramphenicol bind to the bacterial 50S ribosomal subunit which is subject to genetic mutation. In contrast, the quinolones target DNA gyrase which is subject to subunit structure alteration resulting in one variety of resistance to drugs such as ciprofloxacin. The increasing resistance to penicillin among Strep. pneumoniae is the result of reduced binding of penicillin to several binding proteins (PBP2a and PBP2x). Staph. aureus resistance to meticillin is due to the presence of penicillin binding protein (PBP2a) which has reduced affinity for meticillin and other β‎-lactams and is encoded by the mecA gene.

The problem of vancomycin-resistant enterococci, which largely affects Enterococcus faecium, is the result of the production of enzymes (ligases) which permit continued cell wall synthesis despite the presence of vancomycin. To date, five different genes have been found responsible for this phenomenon (vanA to vanE) which result in different phenotypic patterns of resistance to the glycopeptides vancomycin and teicoplanin. The transfer of the vanA gene from E. faecium to S. aureus has resulted in the emergence of vancomycin resistant S. aureus (VRSA), of which 11 cases have been reported to date.

Metabolic bypass resistance

Bacteria must synthesize folic acid from the precursor p-aminobenzoic acid. The sulphonamide antibiotics competitively inhibit the enzyme dihydropteroate synthetase. Trimethoprim acts on the same metabolic pathway by inhibiting dihydrofolate reductase. The sequential inhibitory effects of trimethoprim and sulfamethoxazole (co-trimoxazole) result in synergistic bactericidal activity against many pathogens. Resistant organisms are able to synthesize their own enzymes thereby evading such competitive inhibition.

Surveillance of antibiotic resistance

Information on the susceptibility of pathogenic microorganisms is important. Such data can provide information on the relative frequency of pathogens and the pattern of susceptibility to prescribed agents. Surveillance, therefore, has a role in guiding prescribing, in developing prescribing policies, and in identifying and monitoring organisms that are subject to infection control measures. On a broader front, surveillance is also of value in alerting industry and health care planners to the need for new drug and vaccine strategies for disease control.

To be of maximum benefit, surveillance needs to be sensitive to a defined geographical base, which may simply reflect the catchment area of specimens submitted to a particular laboratory, providing information on the trends in community and hospital isolates. Within hospitals, more specific information can be provided about susceptibility patterns in high-dependency units, where antibiotic consumption is often greater, and more resistant pathogens such as Klebsiella, Serratia, Enterobacter, and Acinetobacter spp. and P. aeruginosa are found. Among Gram-positive pathogens, enterococci and, especially, Staph. aureus present an increasing challenge to prescribing and infection control practice.

National networks of surveillance often vary in their focus and include data on Gram-negative pathogens such as Escherichia coli and P. aeruginosa, Staph. aureus, penicillin resistance among pneumococci, and, more recently, vancomycin-resistant enterococci. There are important international networks which collect information on such pathogens as Legionella pneumophila and Mycobacterium tuberculosis. Drug-resistant tuberculosis is increasingly prevalent in the United Kingdom and elsewhere.

Surveillance of resistance to antiviral agents is largely confined to HIV in a few countries. Patient-specific data are increasingly sought in those with HIV infection to assess drug failure, guide change in management, and direct primary therapy in selected cases of person-to-person and mother-to-infant transmission. Determination of phenotypic resistance is still costly and time consuming, and most data relate to genotypic patterns of resistance to antiretroviral drugs among HIV isolates.

Pharmacokinetics

To be effective, antimicrobial agents must achieve therapeutic concentrations at the site of the target infection. This may be localized to a single anatomical site, such as the bladder or the cerebrospinal fluid, or involve major organs, such as the lung. Infections may also be generalized and affect many body sites. Drug selection must also take into consideration the fact that pathogens such as Mycobacterium tuberculosis, Legionella pneumophila, and Salmonella typhi replicate intracellularly. Antimicrobial drugs may be administered parenterally, orally, or topically to the skin, oral and genital mucosae, external auditory meatus, conjunctiva, and by intraocular application. In the case of systemically active agents, the effective drug concentrations are determined by the standard pharmacokinetic parameters of absorption, distribution, metabolism, and elimination. Since selective toxicity is crucial to safe prescribing, the dose regimen for each agent aims to avoid concentrations toxic to the host but inhibitory to the microorganism. This ‘therapeutic window’ varies by drug.

Bioavailability

The rate and degree of absorption from the gastrointestinal tract is not only important for plasma concentrations reflected in the pharmacokinetic parameters of Cmax and Tmax of a drug, but also for potential adverse effects on the bowel (Table 7.2.5.5). For example, ampicillin, the first of the aminopenicillins, commonly caused gastrointestinal side effects, most notably diarrhoea. These effects have been reduced by increasing the bioavailability of the active drug through the introduction of hydroxyampicillin (amoxicillin) and various esters and prodrugs of ampicillin.

Table 7.2.5.5 Bioavailability and intestinal elimination of some commonly prescribed antibacterial drugs after oral administration

Drug

Bioavailability (%)

Intestinal elimination

Penicillins

Amoxicillin

80–90

Concentrated up to 10-fold in bile

Ampicillin

50

Concentrated up to 10-fold in bile

Flucloxacillin

80–90

Negligible

Cephalosporins

Cefalexin

80–100

Concentrated up to 3-fold in bile

Cefixime

40–50

Concentrated up to 50-fold in bile

Cefuroxime axetil

30–40

Bile concentrations of up to 80% of serum

Quinolones

Ciprofloxacin

70–85

Concentrated up to 10-fold in bile

Nalidixic acid

90–100

Biliary concentrations similar to serum

Other antibacterials

Erythromycin

18–45

Concentrated up to 300-fold in bile

Metronidazole

80–95

Concentrations in bile similar to serum

Rifampicin

90–100

Concentrated up to 1000-fold in bile

Sulfamethoxazole

70–90

Concentrations in bile 40–70% of serum

Tetracycline

75

Concentrated up to 10-fold in bile

Trimethoprim

80–90

Concentrated up to 2-fold in bile

Note that drugs which are well absorbed may still achieve high concentrations in the faeces because of secretion into bile or other enteral secretions.

Some agents such as cefalexin, doxycycline, and several quinolone antibiotics are extremely well absorbed, achieving 80 to 100% bioavailability. In the case of some recent quinolones, the excellent bioavailability has raised the possibility of treating with oral antibiotics some severely ill patients who might normally require parenteral therapy. In contrast, drugs which are poorly bioavailable, such as cefixime and cefuroxime axetil, not only have a higher incidence of gastrointestinal side effects but also are more likely (although not uniquely) to select for C. difficile-associated large bowel disease.

Distribution

Most drugs are distributed in the blood via the plasma before gaining access to the extracellular fluid. Tissue concentrations of a particular agent are affected by pH, drug ionizability, lipid solubility, and the presence of an inflammatory reaction whereby the capillary fenestrations are increased in size. In the case of agents administered intravenously by infusion or by bolus injection, the distribution phase is rapid in comparison with orally, rectally, or intramuscularly administered drugs. Drugs which are poorly lipophilic, such as the β‎-lactams and aminoglycosides, achieve low concentrations in tissues such as the brain. However, the β‎-lactams achieve therapeutic concentrations in the cerebrospinal fluid as a result of the inflammatory reaction which accompanies meningitis.

Drugs may also be taken up intracellularly, as in the case of macrolides and quinolones, resulting in a large volume of distribution compared to drugs confined to the extracellular space, such as the β‎-lactams and aminoglycosides. This is important in relation to the treatment of intracellular pathogens such as Mycoplasma pneumoniae, Legionella pneumophila, and Mycobacterium tuberculosis which can only be effectively treated by drugs that are concentrated and remain biologically active within the cell.

The plasma half-life (T½), which is the time required for the concentration of a drug in the plasma to fall by one-half, is affected by drug distribution and, in particular, its rate of elimination as a result of metabolism and excretion. This in turn affects the time taken to reach steady state. In the treatment of life-threatening infections, it is important that steady state kinetics are achieved rapidly and the administration of a loading dose may be required. This applies to the use of agents such as intravenous quinine in the case of life-threatening malaria and gentamicin for the treatment of serious Gram-negative infections where the pharmacokinetic behaviour can be altered by the severity of the disease in comparison with healthy subjects (Fig. 7.2.5.5).

Fig. 7.2.5.5 Average plasma quinine concentrations following administration of a loading dose of 20 mg (salt)/kg to patients with severe and uncomplicated malaria, compared with those predicted to occur in normal subjects.

Fig. 7.2.5.5
Average plasma quinine concentrations following administration of a loading dose of 20 mg (salt)/kg to patients with severe and uncomplicated malaria, compared with those predicted to occur in normal subjects.

(From White NJ (1992). Antimalarial pharmacokinetics and treatment regimens. Br J Clin Pharmacol, 34, 1–10, with permission.)

Drugs are commonly distributed in the blood and tissues bound to plasma proteins, mostly albumin, and they vary in their degree of protein binding. With agents such as flucloxacillin and ceftazidime it exceeds 95%. The importance of protein binding lies in the fact that the active moiety is the unbound drug. Dissociation from the bound to the unbound state is usually rapid, but this equilibrium may affect drug performance at certain sites such as the joints. The relationship between protein binding and drug performance has been emphasized from studies of the pharmacodynamics of drug activity (see below).

Metabolism

Antibiotics, like other drugs, are degraded at various sites in the body but predominantly within the liver. Degradation involves conjugation, hydrolysis, oxidation, glucuronidation, or dealkylation, according to the particular drug. Members of the hepatic cytochrome P450 group of enzymes play a dominant role in this process. Drug metabolites are usually but not always biologically inactive. For example, cefotaxime is degraded to desacetylcefotaxime and clarithromycin to hydroxyclarithromycin, both of which are biologically active and contribute to the overall antibacterial activity of these agents.

Excretion

Most drugs are excreted in the urine by glomerular filtration, tubular secretion, or a combination of these mechanisms. Thus high concentrations of drug will often be present in the urine; this has therapeutic importance in the treatment of urinary tract infections. Urinary pH affects the biological activity of many drugs; e.g. the activity of ciprofloxacin is markedly reduced at pH 5.5. Tubular excretion can be blocked by probenecid. This was formerly used to ensure higher plasma concentrations of penicillin and is still recommended in alternative treatment regimens for gonorrhoea when single doses of amoxicillin are prescribed. It is also important to note that any reduction in glomerular filtration rate will affect not only urinary concentrations of drug but also the plasma half-life and, in turn, serum concentrations of drugs which are primarily excreted by this route. In the case of antibiotics such as the aminoglycosides and vancomycin, the dose must be reduced in renal failure.

Biliary excretion is another important route for drug elimination either as the active compound or as a microbiologically active or inactive metabolite. Reabsorption from the gastrointestinal tract can result in enterohepatic recirculation, which in turn may affect plasma half-life. Drugs which achieve high concentrations in the bile are effective in the treatment of infections at this site such as cholecystitis. However, biliary obstruction or hepatic impairment may reduce therapeutic efficacy and require dose reduction to avoid toxic effects. Examples include clindamycin, efavirenz, mefloquine, and tetracyclines.

Therapeutic drug monitoring of some antibiotics is essential in order to ensure therapeutic yet nontoxic concentrations. This applies particularly to aminoglycosides which have a relatively narrow therapeutic index. Trough concentrations of gentamicin in excess of 2 mg/litre, if sustained, can result in nephrotoxicity and ototoxicity. The target cells for such toxicities are the renal tubular lining cells and the cochlear hair cells of the inner ear, respectively. Vancomycin is also frequently monitored, particularly in patients with impaired renal function.

Pharmacodynamics

The inter-relationship between drug, microorganism, and the infected host creates an important pharmacological dynamic. Antibiotics are unique in therapeutics in that they are targeted at an invading microorganism which may be present at a particular site or be more widely distributed in the body. The host’s response to infection may modify the pharmacokinetic handling of a drug. Many antibiotics have a measurable effect on a variety of bacterial and host cell functions, even at subinhibitory concentrations. It is difficult to establish the exact role that these factors play clinically, but they are likely to contribute to the overall effect of an antibiotic. Macrolides such as erythromycin illustrate this point since they affect a variety of virulence characteristics (Table 7.2.5.6) as well as affecting the host’s response to infection.

Table 7.2.5.6 Effect of macrolides on bacterial virulence at subinhibitory concentrations

Factor

Effect

Factor

Effect

Adhesins (pili, fimbriae)

Exoenzyme production:

Fibronectin binding

Elastase

Alginate production

Protease

Exotoxin A production

DNAse

β‎-Haemolysin activity

Coagulase

Serum susceptibility

Leukocidin

Flagellar function

From Shyrock TR, Mortensen JE, Baumholtz M (1998). The effects of macrolides on the expression of bacterial virulence mechanisms. J Antimicrob Chemother, 41, 505–12.

Exposure of microorganisms to sublethal concentrations of an antibiotic may temporarily inhibit growth which recommences following removal of the drug. The time to recovery is known as the postantibiotic effect. This varies with the drug and the microorganism; e.g. the quinolones have a longer postantibiotic effect than β‎-lactams (Table 7.2.5.7). The relevance of this observation to the in vivo situation, where plasma drug concentrations are often well above the inhibitory concentration and are sustained through repeat doses, remains uncertain. It may have greater relevance to tissue concentrations, which tend to be lower than plasma concentrations. The postantibiotic effect certainly contributes to the effects of agents that are administered once daily, such as gentamicin.

Table 7.2.5.7 Postantibiotic effects (h) of selected drugs against Staph. aureus, E. coli, and P. aeruginosa

Drug

Staph. aureus

E. coli

P. aeruginosa

Ampicillin

1.7

0.1

NT

Cefotaxime

1.4

0.2

0.3

Ciprofloxacin

2.0

2.1

2.4

Erythromycin

3.1

NT

NT

Gentamicin

2.0

1.8

2.2

Imipenem

2.6

0.5

1.5

Rifampicin

2.8

4.2

NT

Vancomycin

2.2

NT

NT

NT, not tested.

The relationship between the pharmacokinetic characteristics of a drug and bacterial inhibition is critical to therapeutic outcome (Table 7.2.5.8). In the case of agents such as penicillins and cephalosporins, the time that drug concentrations are maintained above the MIC predicts the response. This contrasts with agents such as the quinolones and aminoglycosides, where it is more important to achieve high Cmax to MIC ratios. Modelling the MIC of a particular organism against the dose response curve for a drug (Fig. 7.2.5.6) has established several important pharmacodynamic parameters, which have been supported by studies in animal models and man. For example, dosage regimens of quinolones such as ciprofloxacin and levofloxacin have been based on pharmacodynamic data. The ratio of Cmax to MIC has been refined in the parameter area under the inhibitory concentration, which is the ratio of the area under the time curve (AUC) to MIC. This is more predictive of outcome. The importance of protein binding for drug performance has also emerged as an important modifying factor in this modelling. The AUC to MIC ratio of the free drug is the most sensitive predictor of response. The manner in which these ratios differ for selected quinolones is shown in Table 7.2.5.9.

Table 7.2.5.8 Summary of major pharmacodynamic differences between aminoglycosides and β‎-lactams

Pharmacodynamic measurement

Aminoglycosides

β‎-Lactam

Rate of bacterial killing

Rapid and dose related

Slower with little or no increase at higher doses

Number of bacteria killed per dose administered

Concentration-dependent over a wide concentration range

Little increase in degree or rate of killing at concentrations above minimum bactericidal concentration (MBC)

Postantibiotic effect

Concentration-dependent over a wide concentration range for Gram-positive and Gram-negative pathogens

Unpredictable in Gram-negative bacteria, always short with little or no increase related to concentration

Experimental models

Large, infrequent doses more effective than smaller, more frequent doses which supports once-daily dosing for Gram-negative infections

Frequent (hourly) injection or constant infusion most effective

Clinical trials

High peak serum concentration to in vitro minimum inhibitory concentration (MIC) ratio is strongly related to treatment outcome for Gram-negative bacteraemia or pneumonia

Limited supportive data in patients with neutropenia or nosocomial pneumonia with dosing regimens that keep serum concentrations above the MIC throughout therapy

Clinical trials with amikacin, gentamicin, and netilmicin have shown single daily dosing to be effective

Fig. 7.2.5.6 Relationship between the minimum inhibitory concentration (MIC) of a drug and its pharmacokinetic profile.

Fig. 7.2.5.6
Relationship between the minimum inhibitory concentration (MIC) of a drug and its pharmacokinetic profile.

Table 7.2.5.9 Pharmacokinetic and pharmacodynamic parameters of some recent quinolone antibacterial drugs

Drug (dose mg)

Protein binding (%)

MIC90Strep. pneumoniae

AUC total (mg/h per litre)

AUC free (mg/h per litre)

AUIC (total drug)

AUIC (free drug)

Gatifloxacin (400)

20

0.5

51.3

41.0

102.6

82

Levofloxacin (500)

25

2.0

72.5

54.4

36.2

27.2

Moxifloxacin (400)

48

0.25

26.9

14.0

107.6

56.0

AUC, area under the concentration curve; AUIC, AUC to MIC ratio or area under the inhibitory concentration of total and free (unbound) drugs; MIC90, minimum inhibitory concentration active against 90% of isolates tested.

Principles of use

In comparison with many other classes of drugs, antimicrobial agents are usually prescribed in short courses ranging from a single dose to a few days. Prolonged therapy is required for certain infections such as tuberculosis and bone and joint infections, and for HIV infection treatment is lifelong.

Most antibiotic prescribing, especially within community practice, is empirical. Even among patients in hospital, where there are greater opportunities for diagnostic precision based on laboratory investigations, the exact nature of the infection is established in only a minority of cases. Most therapeutic prescribing requires a presumptive clinical diagnosis that, in turn, is linked to a presumptive microbiological diagnosis based on knowledge of the usual microbial causes of such infections. Among the most widely treated infections are those affecting the upper and lower respiratory tracts, the urinary tract, and skin and soft tissues for which the likely microbial aetiology is restricted. For example, urinary tract infections arising in the community are usually caused by E. coli and other Gram-negative enteric pathogens and, less commonly, by enterococci or Staphylococcus saprophyticus. Local knowledge of the susceptibility of these pathogens to commonly used agents such as trimethoprim, ampicillin, and a quinolone such as ciprofloxacin is helpful in recommending initial empirical antibiotic management.

In more severe infections, such as community-acquired pneumonia, prompt empirical therapy is essential. Although the range of possible pathogens is more extensive (Table 7.2.5.10), Strep. pneumoniae predominates and must always be targeted. Assessment of severity, based on validated criteria, assists in defining the initial empirical antibiotic regimen. This is illustrated by the British Thoracic Society’s recommendations for the initial empirical antibiotic management of community-acquired pneumonia (Table 7.2.5.11).

Table 7.2.5.10 Microbiological aetiology (%) of adult community-acquired pneumonia in the United Kingdom

Pathogens

Community (n=236)

Hospital (n=1137)

ICU (n=185)

Strep. pneumoniae

36.0

39.0

21.6

Haemophilus influenzae

10.2

5.2

3.8

Legionella spp.

0.4

3.6

17.8

Staph. aureus

0.8

1.9

8.7

Moraxella catarrhalis

?

1.9

?

Enterobacteriaceae

1.3

1.0

1.6

Mycoplasma pneumoniae

1.3

10.8

2.7

Chlamydophila pneumoniae

?

13.1

?

Chlamydophila psittaci

1.3

2.6

2.2

Coxiella burnetii

0

1.2

0

Viruses

13.1

12.8

9.7

Influenza A and B

8.1

10.7

5.4

Mixed

11.0

14.2

6.0

Other

1.7

2.0

4.9

None

45.3

30.8

4.0

ICU, intensive care unit.

From Lim WS, et al. (2009). The British Thoracic Society guidelines for the management of community-acquired pneumonia in adults. Thorax, 64 Suppl III, 1–61.

Table 7.2.5.11 Preferred and alternative initial empirical treatment regimens for community-acquired pneumonia as recommended by the British Thoracic Society

Pneumonia severity (based on clinical judgement supported by CURB65 severity score)

Treatment site

Preferred treatment

Alternative treatment

  • Low severity

  • (eg, CURB65 = 0–1 or CRB65 score = 0, < 3% mortality)

Home

Amoxicillin 500 mg tds orally

Doxycycline 200 mg loading dose then 100 mg orally or clarithromycin 500 mg bd orally

  • Low severity

  • (eg, CURB65 = 0–1, < 3% mortality) but admission indicated for reasons other than pneumonia severity (eg, social reasons/unstable comorbid illness)

Hospital

  • Amoxicillin 500 mg tds orally

  • If oral administration not possible: amoxicillin 500 mg tds IV

Doxycycline 200 mg loading dose then 100 mg od orally or clarithromycin 500 mg bd orally

  • Moderate severity

  • (eg, CURB65 = 2, 9% mortality)

Hospital

  • Amoxicillin 500 mg–1.0 g tds orally plus clarithromycin 500 mg bd orally

  • If oral administration not possible: amoxicillin 500 mg tds IV or benzylpenicillin 1.2 g qds IV plus clarithromycin 500 mg bd IV

Doxycycine 200 mg loading dose then 100 mg orally or levofloxacin 500 mg od orally or moxifloxacin 400 mg od orally*

  • High severity

  • (eg, CURB65 = 3–5, 15–40% mortality)

Hospital (consider critical care review)

  • Antibiotics given as soon as possible

  • Co-amoxiclav 1.2 g tds IV plus clarithromycin 500 mg bd IV (If legionella strongly suspected, consider adding levofloxacin†)

  • Benzylpenicillin 1.2 g qds IV plus either levofloxacin 500 mg bd IV or ciprofloxacin 400 mg bd IV

  • OR

  • Cefuroxime 1.5 g tds IV or cefotaxime 1 g tds IV or ceftriaxone 2 g od IV, plus clarithromycin 500 mg bd IV

  • (If legionella strongly suspected, consider adding levofloxacin)

bd, twice daily; IV, intravenous; od, once daily; qds, four times daily; tds, three times daily.

* Following reports of an increased risk of adverse hepatic reactions associated with oral moxifloxacin, in October 2008 the European Medicines Agency (EMEA) recommended that moxifloxacin “should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of this infection”.

† Caution – risk of QT prolongation with macrolide-quinolone combination.

From Lim WS, et al. (2009). The British Thoracic Society guidelines for the management of community-acquired pneumonia in adults. Thorax, 64 Suppl III, 1–61.

The use of empirical therapy depends on the ease with which a clinical diagnosis can be made, as well as disease severity and drug toxicity. In the case of herpesvirus infections, the empirical use of aciclovir for the treatment of mucocutaneous herpes simplex infections or of shingles in older people is now common. However, it would be inappropriate to start treatment for HIV or cytomegalovirus infections without laboratory support for these diagnoses in view of the toxicity and cost of the antiviral agents used to treat these infections.

Antibiotic prophylaxis

Antibiotics are used widely in the prevention of infection, in association with surgery, and in a range of medical conditions (see above). Antibiotic prophylaxis is used for selected surgical procedures where the risk of infection, although relatively low, is of serious import should it occur. Examples include prosthetic joint implantation and cardiac surgery in which prosthetic valves and intracardiac patches are inserted. The principles of antibiotic prophylaxis are based on the selection of an agent active against the known potential target pathogen(s). The drug should be present in high concentrations at the site and time of surgery and be relatively free from adverse reactions. One or two doses are generally effective depending on the length of the procedure. No regimen can be effective against all potential pathogens, hence the importance of postoperative follow-up.

A previously important medical indication for the use of prophylactic antibiotics was the prevention of bacterial endocarditis in adults and children with structural cardiac conditions (acquired valvular hear disease, valve replacement, structural congenital heart disease, hypertrophic cardiomyopathy, previous infective endocarditis). However, in 2008 the United Kingdom National Institute of Clinical Excellence recommended that routine antibiotic prophylaxis should no longer be given to those at risk of endocarditis undergoing dental procedures or nondental procedures of the gastrointestinal, genitourinary, and respiratory tracts. Another example of prophylaxis is the use of low-dose suppressive therapy to prevent Pneumocystis jirovecii pneumonia in those with advanced HIV infection. Co-trimoxazole is the preferred agent; dapsone, atovaquone, or inhaled pentamidine are also used.

Anatomical or functional asplenia is associated with a 12.6-fold increased incidence of severe sepsis compared with the general population. This risk is related to the patient’s age and, in those splenectomized, the reason for surgery and the period of time that has elapsed. Young children are particularly at risk, but this declines substantially after the age of 16 years. Hence the recommendation that immunization be supplemented with prophylactic oral penicillin (erythromycin for the intolerant) to prevent fulminant pneumococcal sepsis which predominates. Other recommended vaccines include Haemophilus influenzae type b (Hib) and meningococcal group C conjugate. Apart from good evidence for the benefit of prophylaxis in children with sickle cell disease, there is poor support for efficacy in other populations of splenectomized patients. There remain, therefore, differences of opinion about the recommendation for the continued use of chemoprophylaxis in adults, although some recommend that a period of 2 years is appropriate. Issues of cost, compliance, and drug-resistant pathogens add further fuel to the debate. What is clear is that the patient or legal guardian(s) should be educated concerning this risk.

Dose selection

Few antibacterial drugs are specific to a single pathogen, hence the dosage regimen must capture a range of susceptibilities of the various target microorganisms to ensure a successful response. The dosage regimen is determined initially by pharmacokinetic studies in healthy volunteers. This is supplemented by information from standardized animal models that simulate infections such as peritonitis, endocarditis, meningitis, thigh abscess, otitis media, pneumonia, and sepsis complicating neutropenia. In man, information on drug penetration into the cerebrospinal fluid, bile, joint fluid, and cutaneous blisters can be supplemented by data from biopsy specimens from sites such as tonsils, bronchus, and prostate. The role of pharmacodynamic assessment is of increasing importance in defining dose and predicting outcome as discussed earlier. Despite all this information, the definitive dosage regimen still requires support from large clinical trials in which the endpoints of response are precisely determined.

Bactericidal versus bacteriostatic agents

In the treatment of many common community infections which are usually of mild or moderate severity, the choice of either a bacteriostatic or a bactericidal antibiotic is of limited importance. However, in patients with severe infection, particularly when complicating an immunocompromised state, a bactericidal agent must be used. This applies particularly to those with severe granulocytopenia which is a common accompaniment of cytotoxic chemotherapy, especially in the treatment of haematological malignancies and following bone marrow transplantation. Another important indication for selecting a bactericidal regimen is in the treatment of infective endocarditis; although the infected vegetations are in the bloodstream, they are relatively protected from host phagocytic control. Effective penetration into the fibrin–platelet mass requires high concentrations of a bactericidal drug to sterilize the infected vegetations.

Duration of treatment

The duration of therapy for many common infections has not been rigorously determined. The treatment of many common conditions is based on custom and practice and often varies internationally. The duration of treatment has been more thoroughly determined in the following cases:

  • Gonococcal urethritis responds promptly to single-dose treatment with agents such as ceftriaxone, or a quinolone antibiotic such as ciprofloxacin or ofloxacin.

  • Uncomplicated urinary tract infection, particularly when affecting women of child-bearing years, responds promptly to selected agents such as trimethoprim and norfloxacin. Although bacteriuria can be eliminated with a single dose, the symptoms of dysuria and frequency take longer to subside, hence a 3-day course is preferred.

  • Pharyngitis caused by Streptococcus pyogenes improves symptomatically within a few days of antibiotics such as penicillin, but eradication of the infecting organism from the throat often takes up to 10 days. It is acknowledged that this presents major difficulties with regard to drug compliance.

  • For pulmonary tuberculosis the current recommendation of an initial 2-month treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol, reducing to isoniazid and rifampicin for a further 4 months provided the isolate is confirmed to be susceptible, is based on extensive clinical trials (Box 7.2.5.1).

  • In cases of bacterial endocarditis, knowledge of the in vitro susceptibility of the infecting organism is crucial in determining dose, duration, and outcome of therapy. Highly penicillin-sensitive strains (MIC ≤0.1 mg/litre) of viridans streptococci are treated effectively with a 2-week regimen of parenteral penicillin and gentamicin or 4 weeks parenteral penicillin alone. Less sensitive strains should be treated with parenteral penicillin for a total of 4 weeks. If the infecting organism is an enterococcus, a minimum of 4 weeks’ treatment with parenteral penicillin (or ampicillin) and aminoglycoside is essential.

Infections caused by Staph. aureus are a particular challenge since the severity is highly variable and yet the potential for metastatic infection and chronicity, as in the case of osteomyelitis, must be kept in mind. The isoxazolyl penicillins such as flucloxacillin are preferred with or without the addition of fusidic acid. Clindamycin and linezolid are useful alternative agents. Many Staph. aureus infections of the skin and soft tissues respond promptly to 7 to 14 days oral therapy. Where there is a severe systemic response to infection, parenteral therapy is appropriate initially. Where there is evidence of dissemination, treatment should be extended for periods of up to 4 weeks.

In the case of septic arthritis, antibiotics should be given promptly and joint aspiration carried out, sometimes repeatedly, to avoid damage to the articular cartilage. The duration of therapy has not been rigorously determined. Most infections will resolve in 2 to 3 weeks. One of the most challenging infections is staphylococcal osteomyelitis. To avoid chronicity, it is customary to treat for 4 to 6 weeks. Treatment is generally administered parenterally. In centres where skill, experience, and administrative support exist, patients are increasingly being managed in the community by parenteral administration through peripherally inserted venous catheters. Under these circumstances, a glycopeptide such as teicoplanin is convenient since it is administered once daily.

For most infections, the duration of therapy remains uncertain. However, many mild to moderate uncomplicated infections will defervesce within a 3- to 5-day period suggesting that 5 to 7 days of treatment is usually adequate. There is little evidence to suggest that treatment periods of 7 to 14 days, or longer, are any more effective. They are also likely to be associated with an increased risk of side effects, superinfection, and the selection of antibiotic-resistant organisms, as well as being more costly.

The parenteral administration of antibiotics is appropriate in the management of severe life-threatening infections and when oral therapy is contraindicated, such as in the postoperative period, if the patient is vomiting, or where gastrointestinal absorption cannot be relied on. However, the need for continued parenteral therapy should be reviewed regularly. In the treatment of many common infections, the acute features of infection such as temperature, tachycardia, and an elevated circulating neutrophil count usually improve within a period of 48 to 72 h. Provided there is no contraindication to oral therapy, this should be considered early in the course of patient management. The advantages are not just in the reduced cost of medication; the risk of intravenous line associated complications, such as infection, is also eliminated and discharge from hospital may be hastened.

Adverse drug reactions

Overall, antimicrobial agents have an outstanding record of safety. Nonetheless, no drug is without the potential for side effects. The risk varies by agent and sometimes by dose, while host genetic factors and pathophysiological status can also be important.

Oral antibiotics are largely used in the community where they are generally well tolerated and used in the treatment of minor infections in large populations. Injectable agents selected for short-course perioperative prophylaxis have a well-established safety record. However, agents such as the antiretroviral drugs and amphotericin B carry a higher risk of more serious adverse drug reactions, which must be balanced against the life-threatening nature of their target infections.

While drug safety is assessed during drug development, the full repertoire of adverse reactions becomes apparent only during widespread clinical use, hence, the importance of adverse drug reaction reporting systems. In the United Kingdom, the ‘yellow card’ system has been very successful and relies on voluntary reporting of possible adverse drug events to the Medicines & Healthcare Products Regulatory Agency (MHRA, www.mhra.gov.uk) by doctors, dentists, coroners, pharmacists, nurses (including midwives and health visitors), radiographers, optometrists, and, most recently, patients. It is important to distinguish between adverse event reporting and adverse drug reaction reporting. The latter is more difficult to establish with certainty and may require rechallenge, which raises medical and ethical concerns.

It is essential to enquire about previous drug reactions as well as other forms of drug toxicities before prescribing. The relationship to a previously prescribed drug requires careful assessment. Hypersensitivity is among the more common of drug reactions and, in the case of β‎-lactam drugs, appears to be more a function of the five-membered thiazolidine ring (Fig. 7.2.5.7) of the penicillin molecule, since hypersensitivity reactions are less common with the cephalosporins which have a six-membered dihydrothiazine ring. The monobactam aztreonam has neither ring structure and hypersensitivity reactions appear to be rare. However, it is important to note that accelerated systemic hypersensitivity reactions (anaphylaxis) can be life-threatening such that any previous association with a β‎-lactam drug is an absolute contraindication to the use of all β‎-lactams.

Fig. 7.2.5.7 Chemical structure of the β‎-lactam antibiotics (penicillins, cephalosporins, and monobactams) identifying the common β‎-lactam ring component which is subject to hydrolysis by β‎-lactamases.

Fig. 7.2.5.7
Chemical structure of the β‎-lactam antibiotics (penicillins, cephalosporins, and monobactams) identifying the common β‎-lactam ring component which is subject to hydrolysis by β‎-lactamases.

Some drug toxicities are genetically determined. For example, people who are genetically slow acetylators of isoniazid are more at risk of side effects such as peripheral neuropathy. Those genetically deficient in the enzyme glucose-6-phosphate dehydrogenase (EC 1.1.1.49) are at risk of drug-induced haemolysis. This risk is more common in those of African, Mediterranean, or Far Eastern descent. Hence, it is important to screen for this red cell enzyme deficiency before the administration of oxidant drugs such as primaquine.

Adverse drug reactions may not always be acute in their presentation but reveal themselves after prolonged drug exposure. Oral flucloxacillin and co-amoxiclav when administered for several weeks, particularly in older patients, are more likely to induce drug-associated hepatotoxicity. Likewise, parenteral formulations of selected drugs may be more toxic than their oral formulation, as is the case with fusidic acid where prolonged parenteral administration frequently gives rise to hepatotoxicity.

Concentration-dependent adverse reactions (Table 7.2.5.12) are more likely to occur in the presence of organ system failure. Aminoglycoside toxicity is more common in older people, in those with preexisting renal failure, and after repeated aminoglycoside doses or other nephrotoxic drugs. Concentration-dependent bone marrow suppression characterizes the use of chloramphenicol whereby pancytopenia arises when plasma concentrations are in excess of 25 mg/litre. This is to be distinguished from the idiopathic aplastic anaemia that is a rare accompaniment of chloramphenicol use, but unfortunately is rarely reversible.

Table 7.2.5.12 Dose-related adverse effects of selected antimicrobials

Drug

Adverse effect

Comment

Antibacterial drugs

General

Superinfection by yeasts or C. difficile; selection of drug-resistant bacteria from the normal flora

These are universal adverse effects of antibacterial drugs and are generally related to the duration of exposure

β‎-Lactams

Myelosuppression

Neutropenia may occur after 1–2 weeks of high-dose IV therapy

Drug fever

Occurs during prolonged (>1 week), high-dose IV therapy (e.g. endocarditis)

Central nervous stimulation/convulsions

Can occur with overdose in renal failure

Aminoglycosides

Nephrotoxicity; ototoxicity

Monitoring of serum concentrations minimizes but does not avoid toxicity; risk of toxicity is related to the duration of the dose and concomitant therapy

Vancomycin

Nephrotoxicity; ototoxicity

May potentiate aminoglycoside nephrotoxicity

Macrolides (e.g. erythromycin)

Gastrointestinal stimulation

This is a prokinetic effect of erythromycin which does not occur with all macrolides

Ototoxicity; cardiac arrhythmias

Only with high-dose IV therapy

Drug interactions

Increased serum concentrations of theophylline and ciclosporin

Quinolones (e.g. ciprofloxacin)

Central nervous stimulation

Quinolones are weak GABA antagonists; this effect is potentiated by coadministration with NSAIDs, especially fenbufen

Drug interactions

May inhibit metabolism of theophylline

Oxazolidinone (e.g. linezolid)

Anaemia, neutropenia, thrombocytopenia; neuropathy; lactic acidosis

Limit treatment to 28 days to reduce risk of haematological toxicity

Antifungal/antiprotozoal/antiviral drugs

Amphotericin B

Nephrotoxicity

Decreased creatinine clearance and renal potassium wasting are universal at clinically effective doses

Rigors/hyperthermia/hypotension

Related to the rate of infusion

Ketoconazole

Inhibition of steroid synthesis

Occurs with prolonged (>1 week) high-dose therapy

Aciclovir

Central nervous adverse effects; crystalluria

Rare except with high-dose IV therapy

Quinine

Hypoglycaemia

GABA, γ‎-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drug.

Much has been learned about the structure–activity determinants of drug toxicity. For example, the quinolone antibiotics as a class have the potential to induce phototoxicity, arthrotoxicity, central nervous system (CNS) toxicity, cardiotoxicity, and interact with agents such as caffeine, theophylline, and nonsteroidal anti-inflammatory drugs (Fig. 7.2.5.8). Knowledge of such predictors has lead to the selection of agents with safer structural profiles. Despite this, adverse drug reactions have led to the withdrawal or modification of the licensed indications for several quinolones, notably temafloxacin, trovafloxacin and sparfloxacin, emphasizing the importance of clinical recognition and reporting of adverse events.

Fig. 7.2.5.8 Structure–activity side-effect relationships of the fluoroquinolone antibacterial drugs. GABA, γ‎-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drug.

Fig. 7.2.5.8
Structure–activity side-effect relationships of the fluoroquinolone antibacterial drugs. GABA, γ‎-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drug.

(Redrawn from Domagala JM (1994). Structure–activity and structure–side-effect relationships for the quinolone antibacterials. J Antimicrob Chemother, 33, 685–706.)

Few infectious conditions require lifelong therapy. The management of HIV infection has challenged this tenet. To date, drugs directed at the causative viruses or complicating opportunistic infections are suppressive rather than achieving eradication. It is also important to note that the drugs used in the treatment of HIV and AIDS are often licensed with limited information concerning their long-term safety. The potential for adverse reactions and especially interactions is considerable and requires careful attention to their detection and management. This has become an increasingly important challenge as life expectancy for those with HIV infection improves. It is important to balance drug safety while encouraging compliance and the maintenance of a reasonable state of health.

Failure of antibiotic therapy

Antimicrobial therapy may fail for several reasons. The agent selected may be inappropriate for the particular infection and fail to inhibit the target organism, or fail to reach the site of infection in sufficient concentration. For example, drugs such as nitrofurantoin and norfloxacin, while achieving high urinary concentrations, fail to deal adequately with parenchymatous infection of the kidney or bacteraemia which may complicate acute pyelonephritis.

The prostate also presents a chemotherapeutic challenge owing to the relatively low pH (c.6.4) in chronic bacterial prostatitis. Drugs which are weak bases, such as trimethoprim either alone or in combination with sulfamethoxazole (co-trimoxazole), are preferred, especially since they are also lipid soluble. Ciprofloxacin has similar characteristics and has also produced favourable results. However, treatment of acute bacterial prostatitis sometimes needs to be prolonged (4–6 weeks and occasionally longer), especially if there is a history of chronic relapsing infection.

The drug may be appropriate, but the dose selected may be inadequate. This may apply to such conditions as unsuspected bacterial endocarditis where high-dose parenteral antibiotic is required. Likewise, the concentration of penicillin required to deal with pneumococcal meningitis greatly exceeds that effective in the treatment of pneumococcal pneumonia; occasionally the two diseases may coexist. Infections caused by Legionella pneumophila and Chlamydia spp. require drugs that achieve high intracellular concentrations such as the macrolides, tetracyclines, or quinolones.

Resistance emerging during treatment is an uncommon cause of clinical failure but should be considered. Drug resistant Mycobacterium tuberculosis can develop on therapy as a result of the emergence of minority populations of organisms resistant to such first-line drugs as rifampicin and isoniazid. The current multidrug regimens are, in part, designed to avoid this occurrence. Likewise, in those with HIV infection, drug-resistant virus is an increasingly important cause of treatment failure and requires good compliance with multidrug regimens to slow its rate of emergence.

Mixed infections are commonly associated with intra-abdominal sepsis and occasionally with infections of the lung. They may fail to respond to treatment unless the regimen covers the full range of bacterial pathogens. In the case of intra-abdominal sepsis, the regimen should be active against anaerobic as well as aerobic bacterial pathogens.

Another important cause of antibiotic failure is the continued presence of a focus of infection. This may be an abscess that requires surgical drainage or the removal of an implanted medical device such as an intravascular catheter. Much more serious is infection of a prosthetic heart valve, hip joint, or CNS shunt where revision surgery carries significant risks. Many antibiotics fail to achieve therapeutic concentrations within abscess cavities, or are pH sensitive. Implant-associated infections present a similar challenge since bacteria often replicate slowly within a biofilm that is protective against normal host defences.

Finally, it should be remembered that a persistently elevated temperature in the presence of what appears to be adequate antibiotic treatment can reflect drug fever or indeed fever complicating a nonmicrobial diagnosis. This emphasizes the importance of monitoring the response to treatment and repeated patient assessment.

Practice guidelines and formularies

The plethora of therapeutic agents currently available presents a considerable challenge to the prescriber. Guidance on the choice of agent and the management of disease is becoming increasingly important. This is not only to ensure that the selection of treatment is appropriate for the target infection and consistent with current patterns of antimicrobial susceptibility but also that it reflects an acceptable safety profile as well as being sensitive to the appropriate use of health care resources. Such guidance is increasingly provided within formularies designed for local use, within either a hospital or a community practice. These frequently offer information on preferred and alternative regimens for particular infections. Formularies should include drugs currently tested by the diagnostic laboratory, since changing patterns of susceptibility may require modification of recommended drugs.

Within hospital practice, it is common for such formularies to identify drugs which may be prescribed freely according to specific indications and those for which expert advice from a clinical microbiologist or infectious disease specialist should be sought. The latter applies particularly to drugs that require specific skill and experience in their use, need drug levels to be monitored, or are expensive. For example, the treatment of deep-seated fungal infections with amphotericin B requires careful clinical assessment and guidance on dosage and monitoring. Likewise, the treatment of HIV infection is increasingly a specialist area. Antibiotics which are expensive to prescribe such as parenteral quinolones, third-generation cephalosporins, and the carbapenems may be restricted. The policy may also have recommendations for the timing of transfer from parenteral to oral therapy in order to minimize the use of injectable agents.

Formularies are educational and allow the prescriber to become familiar with indications and safety of the most commonly used agents. Their use should be supported by educational activities both at undergraduate and postgraduate level. Ideally, the selection of agents for inclusion in the formulary should be based on sound evidence of efficacy, safety, and economic benefit. However, such evidence-based medicine is often lacking or incomplete for commonly treated infections, since clinical trials of antibiotics, although increasingly robust in their design, are largely conducted to support licensing requirements rather than to address clinical use. They generally demonstrate the equivalence (or noninferiority) of a new agent in comparison with existing therapies. As a result, the recommendations of formularies and practice guidelines are based on a matrix of information derived from knowledge of the in vitro profile of an agent, its pharmacokinetic parameters, its clinical and microbiological efficacy, and its safety profile. This, in turn, is modified by custom and practice which explains why there is local and, sometimes, national and international variation in recommendations for some common indications such as community-acquired pneumonia and bacterial meningitis.

In developing countries, where medical resources are much more limited, greater reliance is placed on low-cost agents. The World Health Organization regularly updates its list of recommended essential drugs which includes anti-infective agents (Table 7.2.5.13). Despite the emphasis on low-cost agents, the drugs offered cover the majority of infections and prescribing needs of developing countries. The agents available in individual countries often vary according to local interpretation of the needs for these ‘essential’ drugs.

Table 7.2.5.13 The World Health Organization (2007) model list of essential drugs (anti-infectives)

Anthelmintics

Antibacterials

Antituberculosis medicines

Antifungals

Antivirals

Antiprotozoals

Albendazole

Amoxicillin

Ethambutol

Amphotericin B

Abacavir

Amodiaquine

Levamisole

Ampicillin

Isoniazid

Flucytosine

Aciclovir

Diloxanide

Mebendazole

Benzathine benzylpenicillin

Isoniazid + ethambutol

Potassium iodide

Didanosine

Metronidazole

Niclosamide

Benzylpenicillin

Pyrazinamide

Nystatin

Emtricitabine

Meglamine

Praziquantel

Cloxacillin

Rifampicin

Clotrimazole

Emtricitabine + Tenofovir

Pentamidine

Pyrantel

Phenoxymethylpenicillin

Rifampicin + isoniazid

Fluconazole

Lamivudine

Amphotericin B

Ivermectin

Procaine benzylpenicillin

Rifampicin + isoniazid + pyrazinamide

Griseofulvin

Stavudine

Amodiaquine

Praziquantel

Amoxicillin + clavulanic acid

Rifampicin + isoniazid + pyrazinamide + ethambutol

Stavudine + Lamivudine + Nevirapine

Artemether + Lumefantrin

Triclabendazole

Cefazolin

Streptomycin

Tenofovir

Chloroquine

Oxamniquine

Cefixime

Amikacin

Efavirenz

Primaquine

Ceftazidime

p-Aminosalicylic acid

Efavirenz + Emtricitabine + Tenofovir

Doxycycline

Ceftriaxone

Capreomycin

Nevirapine

Mefloquine

Imipenem + cilastatin

Cycloserine

Ribavirin

Sulfadoxine + Pyrimethamine

Azithromycin

Ethionamide

Ritonavir

Artemether

Chloramphenicol

Kanamycin

Lopinavir + Ritonavir

Artesunate

Ciprofloxacin tablet

Ofloxacin

Nelfinavir

Mefloquine

Doxycycline

Saquinavir

Paromomycin

Erithromycin

Zidovudine

Proguanil

Gentamicin

Zidovudine + Lamivudine

Pentamidine

Metronidazole

Zidovudine + Lamivudine + Nevirapine

Pyrimethamine

Nitrofurantoin

Sulfamethoxazole + Trimethoprim

Spectinomycin

Melarsoprol

Sulfadiazine

Pentamidine

Sulfamethoxazole + trimethoprim

Suramin sodium

Trimethoprim

Eflornithine

Clindamycin

Benznidazole

Vancomycin

Nifurtimox

Clofazimine

Dapsone

Rifampicin

Recent developments in economically advanced countries have included an assessment of health care technologies for current management, national need, and the resources available. In the United Kingdom, the National Institute of Clinical Excellence (NICE, www.nice.org.uk) was established in 1999 to assess a variety of health care technologies including procedures as well as new therapies. Such assessments place greater emphasis on ensuring that new technologies are evaluated in a manner that more closely resembles clinical practice as well as demonstrating economic benefit, in contrast to drug licensing which addresses the quality, safety, and efficacy of new therapies. This new emphasis is likely to require a greater partnership between health care systems and pharmaceutical companies to ensure that the place of new technologies is rapidly assessed and that their use is consistent with health care strategies.

Further reading

American Thoracic Society, Centers for Disease Control and Infectious Diseases Society of America (2003). Treatment of tuberculosis. www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm#top

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    Domagala JM (1994). Structure–activity and structure–side-effect relationships for the quinolone antibacterials. J Antimicrob Chemother, 33, 685–706.Find this resource:

    Elliott TSJ, Foweraker J, Gould FK (2004). Guidelines for the antibiotic treatment of endocarditis in adults: report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother, 54, 971–81.Find this resource:

    Finch RG, Williams RJ (1999). Baillières clinical infectious diseases: antibiotic resistance. Baillière Tindall, London.Find this resource:

      Finch RG, et al. (2003). Antibiotic and chemotherapy, 8th edition. Churchill Livingstone, Edinburgh.Find this resource:

        Gould FK, Elliott TSJ, Foweraker J (2006). Guidelines for the prevention of endocarditis: report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother, 57, 1035–42.Find this resource:

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            NICE Short Clinical Guidelines Technical Team (2008). Prophylaxis against infective endocarditis: antimicrobial prophylaxis against infective endocarditis in adults and children undergoing interventional procedures. National Institute for Health and Clinical Excellence, London.Find this resource:

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                  World Health Organisation (2007) Model list of essential medicines (15th edition) http://www.who.int/medicines/publications/essentialmedicines/eu