Antibiotics in the emergency department

Essentials

1
Patients with infections and infectious diseases commonly present to emergency departments.
2
There are also changing patterns of infectious disease, largely due to immunosuppression from chemotherapy, continuing development of bacterial resistance, HIV-associated infections and new and emerging infections.
3
Many bacteria are becoming increasingly resistant to available antimicrobials, with some resistant to multiple agents including many community-acquired infections.
4
The growing world trade in wildlife, factory farming, increasing air travel and increased population density increases the risk of infectious disease transmission.
5
There are relatively few new antimicrobials to counter these changing patterns of resistance.
6
Antimicrobial prescribing should follow evidence-based guidelines or infectious disease consultant advice.
7
Some patients with infection can be treated wholly as outpatients using parenteral therapy or after early discharge once the acute toxic phase is over.
8
Early administration of guideline-based antibiotics combined with supportive therapy is the key to a good outcome in patients with serious infections.
9
The increasing incidence of terrorism may result in patients presenting with novel, unusual or clusters of infections caused by biological agents.

Principles of antimicrobial therapy

Antibiotic stewardship

The first decision to be made regarding antimicrobial therapy is whether the administration of these agents is truly indicated. The growing incidence of antibiotic resistance is rapidly increasing. In many cases, antibiotics are administered without clear indications. This practice is potentially dangerous, as some agents can cause serious toxicity or allergic reactions, diagnoses may be masked if appropriate cultures are not taken prior to therapy, serious adverse events can result and microorganism resistance may emerge.

Ideally, antibiotic therapy is determined by the isolation of the organism(s) involved and determination of the antibiotic susceptibility pattern. As this information is rarely available, it is necessary to make treatment decisions without precise knowledge of the infectious source or microbial species, in which case empiric treatment is commenced based on the type of infection (if known) and the likely organisms involved utilizing recognized guidelines.

In specific situations (e.g. suspected meningitis, meningococcal infection, necrotizing fasciitis, sepsis, peritonitis, febrile neutropaenia and pneumonia), early empiric therapy can be lifesaving.

The choice of an appropriate antimicrobial agent requires consideration of the following factors.

The microorganism

The identity of the infecting organism(s) needs to be identified or suspected. In the emergency department (ED) setting, almost all antimicrobial decisions will be made without the benefit of cultures, with treatment commencing based on the most likely to cause infection in a given clinical setting. However, certain ‘rapid methods’ of microbial identification may be employed. These include Gram-stain preparations (bacterial, some fungal and leucocyte identification) and immunological methods for antigen detection (enzyme-linked immunoabsorbent assay, latex agglutination, polymerase chain reactions).

Another way of guiding appropriate use and prescription of antibiotics is to use defined criteria, examples are shown in Box 9.9.1 .

Box 9.9.1

Diagnostic Criteria for Community-Acquired Pneumonia

Reference: Therapeutic Guidelines Antibiotic.

Clinical features suggest pneumonia + consolidation on CXR → Pneumonia likely
CAP score—determine if CAP score ‘severe’ using CORB ^a

a CORB (C-confusion, O-Oxygen saturation 90% or less. R-RR 30 bpm or greater, B-SBP <90 mm Hg or DBP 60 mm Hg or less)

or SMART-COP ^b

b SMART-COP (SBP <90 mm Hg, M-multilobar involvement on CXR, A-albumin <35 g/L, R-RR 25 bpm or greater, T-tachycardia 125 bpm or greater, C-confusion [acute], O-PaO ₂ <70 mm Hg, or O ₂ saturation 93% or less, or PaO ₂ /FiO ₂ less than 333, P-pH <7.35)
Admit to hospital or discharge with antibiotic treatment based on CORB or SMART-COP

Other examples include:

Systemic inflammatory response syndrome (SIRS), Sepsis and Septic Shock Criteria
Renal, age, purulence, infection source, and dietary factors (RAPID) for pleural infection

Microorganism susceptibility

This information is unlikely to be available and therapeutic decisions will generally be based on evidence-based guidelines and a knowledge of likely susceptibilities. For example, group A streptococci remain susceptible to the penicillins and cephalosporins, and virtually all anaerobes (except Bacteroides spp.) are susceptible to penicillin G. However, when the identity or susceptibility of the infecting organism is sufficiently in doubt, the patient’s clinical condition is atypical, serious or potentially serious or where antimicrobial resistance is suspected, it is good practice to obtain appropriate specimens for culture and susceptibility testing prior to empirical broad-spectrum antimicrobial therapy ( Table 9.9.1 ).

Table 9.9.1

Antimicrobial agents of choice in selected infections

Microorganism	Diseases	First choice	Second choice
Gram positive cocci
Staphylococcus aureus ^a	Abscesses penicillinase-negative: Osteomyelitis	Benzylpenicillin (penicillin G), phenoxymethyl penicillin (penicillin V)	Cephalosporin (G1), clindamycin
	Bacteraemia penicillinase-positive:	Nafcillin, oxacillin	Cephalosporin (G1)
	Endocarditis		Vancomycin, clindamycin
	Pneumonia methicillin-resistant:	Vancomycin ± rifampicin	Co-trimoxazole + rifampicin
	Cellulitis		Ciprofloxacin + rifampicin
Streptococcus (A, B, C, G and bovis )	Pharyngitis, scarlet fever, otitis media, cellulitis, erysipelas, pneumonia, bacteraemia, endocarditis, meningitis	Benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin	Erythromycin Cephalosporin (G1) Vancomycin
Streptococcus pneumonia ^a	Pneumonia, arthritis, sinusitis, otitis media, meningitis, endocarditis	Benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin, penicillin G	Erythromycin, cephalosporin (G1–3) Vancomycin + rifampicin Ceftriaxone
Streptococcus viridians ^a	Bacteraemia, endocarditis	Benzylpenicillin (penicillin G) ± gentamicin	Ceftriaxone, vancomycin ± gentamicin
Enterococcus	Bacteraemia, endocarditis, urinary tract infection	Ampicillin + gentamicin, benzylpenicillin (penicillin G) + gentamicin	Vancomycin + gentamicin, nitrofurantoin Fluoroquinolone, ampicillin + clavulanic acid
Gram negative cocci
Moraxella catarrhalis	Otitis, sinusitis, pneumonia	Co-trimoxazole	Cephalosporin (G2,3)
		Amoxicillin + clavulanic acid	Erythromycin, tetracycline
Neisseria gonorrhoeae	Gonorrhoea, disseminated disease	Ceftriaxone, ampicillin + probenecid	Ciprofloxacin, doxycycline spectinomycin
Neisseria meningitides	Meningitis, carrier state	Benzylpenicillin (penicillin G) rifampicin	Cephalosporin (G3), chloramphenicol
Gram positive bacilli
Clostridium perfringens ^a	Gas gangrene Tetanus	Benzylpenicillin (penicillin G)	Clindamycin, metronidazole, cephalosporin
Clostridium tetani	Tetanus	Benzylpenicillin (penicillin G), vancomycin	Doxycycline, clindamycin
Clostridium difficile	Antimicrobial-associated colitis	Metronidazole (oral)	Vancomycin (oral)
Corynebacterium diphtheriae	Pharyngitis, tracheitis, pneumonia	Erythromycin	Benzylpenicillin (penicillin G), clindamycin
Listeria monocytogenes	Meningitis, bacteraemia	Ampicillin ± gentamicin	Co-trimoxazole, erythromycin
Gram negative bacilli
Brucella	Brucellosis	Doxycycline + gentamicin	Co-trimoxazole + gentamicin/rifampicin
Campylobacter jejuni ^a	Enteritis	Fluoroquinolone	Erythromycin, azithromycin
Escherichia coli ^a	Urinary tract infection, bacteraemia	Ampicillin, co-trimoxazole,	Ampicillin + gentamicin
		cephalosporin (G1)	Fluoroquinolone, nitrofurantoin
Enterobacter species	Urinary tract and other infections	Fluoroquinolone imipenem	Gentamicin + broad-spectrum penicillin, co-trimoxazole
Haemophilus influenza ^a	Otitis, sinusitis, pneumonia	Co-trimoxazole, ampicillin, amoxicillin	Amoxicillin + clavulanic acid, azithromycin, Cefuroxime
	Epiglottitis, meningitis	Cephalosporin (G3)	Chloramphenicol
Klebsiella pneumonia ^a	Urinary tract infection, pneumonia	Cephalosporin ± gentamicin	Co-trimoxazole, fluoroquinolone
Legionella pneumophila	Legionnaires disease	Erythromycin ± rifampicin	Ciprofloxacin, azithromycin, co-trimoxazole
Pasteurella multocida	Animal bite infections, abscesses, bacteraemia, meningitis	Benzylpenicillin (penicillin G) amoxicillin + clavulanic acid	Doxycycline, cephalosporin
Proteus mirabilis ^a	Urinary tract and other infections	Ampicillin, amoxicillin	Cephalosporin, co-trimoxazole, gentamicin
Proteus (other species) ^a	Urinary tract and other infections	Cephalosporin (G3), gentamicin	Co-trimoxazole, fluoroquinolone
Pseudomonas aeruginosa ^a	Urinary tract infection, pneumonia, bacteraemia	Broad-spectrum penicillin ± gentamicin	Ceftazidime ± gentamicin Fluoroquinolone ± gentamicin
Salmonella species ^a	Typhoid fever, paratyphoid fever, bacteraemia, gastroenteritis	Fluoroquinolone, ceftriaxone	Ampicillin, co-trimoxazole, chloramphenicol
Shigella ^a	Acute gastroenteritis	Fluoroquinolone	Ampicillin, co-trimoxazole
Vibrio cholera	Cholera	Doxycycline, fluoroquinolone	Co-trimoxazole
Miscellaneous agents
Chlamydia species	Pneumonia, trachoma, urethritis, cervicitis	Doxycycline	Azithromycin, erythromycin
Mycoplasma pneumonia	Atypical pneumonia	Erythromycin, doxycycline	Azithromycin
Pneumocystis carinii	Pneumonia in impaired host	Co-trimoxazole	Trimethoprim + dapsone, pentamidine
Rickettsia	Typhus fever, Q fever,	Doxycycline	Chloramphenicol
	Rocky Mountain spotted fever
Treponema pallidum	Syphilis	Benzylpenicillin (penicillin G)	Ceftriaxone, doxycycline

<ce:sup>a</ce:sup> G1 , First-generation cephalosporin; G2 , second-generation cephalosporin; G3 , third-generation cephalosporin. All strains should be examined in vitro for sensitivity to various antimicrobial agents.

Host factors

An adequate history of drug allergies must be obtained to prevent the administration of an antimicrobial that may have serious or fatal consequences. Where this is not possible, avoid the administration of penicillin and associated antimicrobials. The age of the patient may have clinically significant effects on drug absorption (e.g. penicillin absorption is increased in the young and the elderly), metabolism (e.g. reduced chloramphenicol metabolism in the neonate) and excretion (e.g. declining renal function with age may reduce the excretion of penicillins, cephalosporins and aminoglycosides). Furthermore, tetracyclines bind and discolour the developing bone and tooth structures in children aged 8 years or less. Pregnant women and nursing mothers may pose certain problems in the selection of appropriate antimicrobial agents, as all of these agents cross the placenta to varying degrees. The administration of antibiotics to pregnant patients must be based on guidelines. Whether or not antibiotic use has an effect on the efficacy of combined oral contraceptive pills (OCPs) has been a matter of controversy. A significant pharmacokinetic interaction between combined OCPs and antibiotics, apart from rifampicin and griseofulvin, has not been proven. It has been suggested that if an interaction does exist, it is likely that it occurs in a small number of predisposed individuals. It is not possible at this time to predict who is at risk for potential interaction. Other host factors that may require consideration include the patient’s renal and hepatic function, their genetic (e.g. liver acetylation rate) or metabolic abnormalities (e.g. diabetes mellitus) and the site of the infection.

Route of administration

In general, the oral route is chosen for infections that are mild and can be managed on an outpatient basis. In this situation, consideration needs to be given to compliance with treatment, the variability of absorption with food in the stomach and interaction of the agent with concomitant medications. The parenteral route is used for agents that are inefficiently absorbed from the gastrointestinal tract and for the treatment of patients with serious infections in whom high concentrations of antimicrobial agents are required. Intramuscular administration (not in patients on anticoagulants or who are coagulopathic) will provide adequate serum concentrations for most infections and may be appropriate where antimicrobial depots are desirable; for example, procaine penicillin injections where patient compliance with oral medication is doubtful. Intravenous administration allows large doses of drugs to be given with a minimal amount of discomfort to the patient; for example, infection prophylaxis in compound fractures, life-threatening infections and shock. For intravenous administration, large veins should be used followed by saline flushing of the veins to help to minimize the incidence of venous irritation and phlebitis.

Supportive care

Supportive care in association with antimicrobial therapy is essential in many infections, fluid resuscitation, vasopressors and compliance with sepsis guidelines being essential for a good outcome in suspected sepsis/sepsis.

Adverse drug events involving antibiotics

Antibiotics are one of the top medication classes resulting in ED visits for adverse drug events.

There is a 1:1000 risk that an individual prescribed an antibiotic will require a visit to the ED because of an antibiotic side effect.

Antibiotics are responsible for 19% of ED visits for adverse drug events:

in children (<18 years), antibiotics are the most common cause of ED visits for adverse drug events
79% of ED visits for documented antibiotic-associated adverse drug events are due to allergic reactions.

Antibiotic resistance

Bacteria can be resistant to an antimicrobial agent because the drug fails to reach the target or is inactivated or because the target is altered. Bacteria may produce enzymes that inactivate the drug or have cell membranes impermeable to the drug. Having gained entry into the microorganism, the drug must exert a deleterious effect. Natural variation or acquired changes at the target site that prevent drug binding or action can lead to resistance.

Resistance is most commonly acquired by the horizontal transfer of resistance determinants from a donor cell, often of another bacterial species, by transformation, transduction or conjugation. Resistance also may be acquired by mutation and passed vertically by selection to daughter cells. Antimicrobial agents can affect the emergence of resistance by exerting strong selective pressures on bacterial populations favouring those organisms capable of resisting them.

The increasing emergence of antibiotic resistance is a very serious development that threatens the end of the antibiotic era. Penicillin-resistant strains of pneumococci account for >50% of isolates in some European countries. The worldwide emergence of Haemophilus and gonococci that produce β-lactamase is a major therapeutic problem. Methicillin-resistant strains of Staphylococcus aureus (MRSA) are widely distributed among hospitals and are increasingly being isolated from community-acquired infections. There are now strains of enterococci (vancomycin-resistant Enterococcus), Pseudomonas and enterobacters that are resistant to all known drugs. Epidemics of multiple drug-resistant strains of Mycobacterium tuberculosis are increasingly being reported.

A more responsible approach to the use of antimicrobial agents is essential to slow the development of multidrug-resistant organisms. Their use is unnecessary in viral infections; their use in prophylaxis and in established bacterial infections must be on evidence-based guideines. The use of narrow-spectrum antimicrobial agents to which the organism is susceptible is encouraged and, in certain circumstances, the use of combinations of agents may prevent the emergence of resistant mutants during therapy.

Prophylactic use of antibiotics

Antimicrobial prophylaxis is the use of antimicrobial agents in order to prevent infection developing. It is indicated in many circumstances, including the prevention of recurrent rheumatic fever, endocarditis, meningitis, tuberculosis and urinary tract and surgical infections. Antimicrobial prophylaxis in the ED is usually indicated to prevent trauma-related infection following contamination of soft tissue, crush injuries, bites, clenched fist injuries and compound fractures. Other risk factors for wound infection include ‘old’ wounds (>18 hours), penetrating injuries, contaminated wounds, co-morbid illness, shock, colon injury and massive haemorrhage.

Antimicrobial prophylaxis should be considered where there is a significant risk of infection, but cannot be relied upon to overcome excessive soiling, damage to tissues, inadequate debridement or poor surgical technique. Adequate wound care, with splinting and elevation of the affected area as indicated, will continue to be important factors in trauma-related infection prophylaxis.

Antimicrobial prophylaxis should be directed against the likely causative organism(s). However, an effective regimen need not necessarily include antimicrobials that are active against every potential pathogen. Regimens that only reduce the total number of organisms may assist host defences and prevent infection. The type, dose, duration and route of administration of antimicrobial therapy will vary according to the nature, site and aetiology of the injury, as well as host factors, and should be based on established guidelines. In all cases of open traumatic injury, no matter how trivial, tetanus prophylaxis must be considered.

Penicillins

Chemistry and mechanism of action

The penicillins constitute one of the most important groups of antimicrobial agents and remain the drugs of choice for a large number of infectious diseases. The basic structure of the penicillins consists of a thiazolidine ring connected to a β-lactam ring, and a side chain. The penicillin nucleus is the chief structural requirement for biological activity, whereas the side chain determines many of the antibacterial and pharmacological characteristics of the particular type of penicillin.

Peptidoglycan is an essential component of the bacterial cell wall and provides mechanical stability by virtue of its highly cross-linked latticework structure. Penicillin is thought to acetylate and inhibit a transpeptidase enzyme responsible for the final cross-linking of peptidoglycan layers. Penicillin also binds to penicillin-binding proteins (PBPs), causing further interference with cell wall synthesis and cell morphology. The lysis of bacteria is ultimately dependent on the activity of cell wall autolytic enzymes: autolyses and murein hydrolases. Although the relationship between the inhibition of PBP activity and the activation of autolysins is unclear, the interference with peptidoglycan assembly in the face of ongoing autolysis activity might well lead to cell lysis and death.

Bacterial resistance to penicillins

Microorganisms may be intrinsically resistant to the penicillins because of structural differences in PBPs. Resistance may be acquired by the development of high molecular weight PBPs that have reduced affinity for the antibiotic. Bacterial resistance also can be caused by the inability of the agent to penetrate to its site of action. Unlike gram positive bacteria, gram negative bacteria have an outer membrane of lipopolysaccharide which functions as an impenetrable barrier to some antibiotics. However, some broader-spectrum penicillins, such as ampicillin and amoxicillin, can diffuse through aqueous channels (porins) of this outer membrane to reach their sites of action.

Bacteria can destroy penicillins enzymatically. Different bacteria elaborate a number of different β-lactamases and individual penicillins vary in their susceptibility to these enzymes. In general, gram positive bacteria produce a large amount of β-lactamase, which is secreted extracellularly. Most of these enzymes are penicillinases, which disrupt the β-lactam ring and inactivate the drug. In gram negative bacteria, β-lactamases are found in relatively small amounts strategically located between the inner and outer bacterial membranes for maximal protection.

Classification of penicillins

Benzylpenicillin (penicillin G) and phenoxymethyl penicillin (penicillin V)

These drugs are the so-called ‘natural penicillins’. The antimicrobial spectra of benzyl penicillin (penicillin G) and phenoxymethyl penicillin (penicillin V) are very similar for aerobic gram positive microorganisms. Benzyl penicillin is the drug of choice against many gram positive cocci (streptococci, penicillin-sensitive staphylococci), gram negative cocci ( Neisseria meningitidis and Neisseria gonorrhoeae ), gram positive bacilli ( Bacillus anthracis , Corynebacterium diphtheriae ), anaerobes (peptostreptococcus, Actinomyces israelii , Clostridium and some Bacteroides ), Pasteurella multocida and Treponema pallidum. Phenoxymethyl penicillin is an acceptable alternative for Streptococcus pneumoniae , Streptococcus pyogenes (A) and Actinomyces israelii .

The sole virtue of benzylpenicillin compared to phenoxymethyl penicillin is that it is more stable in an acid medium and therefore much better absorbed from the gastrointestinal tract. Benzylpenicillin is administered parenterally but has a half-life of only 30 minutes. Accordingly, repository preparations (penicillin G procaine, penicillin G benzathine) are often used, and probenecid may be administered concurrently to block the renal tubular secretion of the drug. Once absorbed, both penicillins are distributed widely throughout the body. Significant amounts appear in the liver, bile, kidney, semen, joint fluid, lymph and intestine. Importantly, penicillin does not readily enter the cerebrospinal fluid (CSF) when the meninges are normal. However, when the meninges are acutely inflamed, penicillin penetrates into the CSF more easily. Under normal circumstances, penicillin is eliminated unchanged by the kidney, mainly by tubular secretion.

The penicillinase-resistant penicillins

These drugs remain the agents of choice for most staphylococcal disease. Methicillin is a penicillin resistant to staphylococcal β-lactamase, although the increasing incidence of isolates of methicillin-resistant microorganisms is cause for concern. MRSA contain a high molecular weight PBP with a very low affinity for β-lactam antibiotics. From 40% to 60% of strains of Staphylococcus epidermidis are also resistant to penicillinase-resistant penicillins by the same mechanism. As bacterial sensitivities are usually not known in the ED, methicillin is rarely administered in this setting.

The isoxazolyl penicillins (oxacillin, cloxacillin, dicloxacillin and flucloxacillin) are congeneric semisynthetic penicillins that are pharmacologically similar. All are relatively stable in an acid medium and are adequately absorbed after oral administration. These penicillins undergo some metabolism but are excreted primarily by the kidney with some biliary excretion. All are remarkably resistant to cleavage by penicillinase and inhibit both penicillin-sensitive and some penicillin-resistant staphylococci. Methicillin-resistant staphylococci are resistant to these penicillins. Isoxazolyl penicillins inhibit streptococci and pneumococci but are virtually inactive against gram negative bacilli.

The aminopenicillins

Ampicillin is the prototypical agent in this group. It is stable in acid medium and, although well absorbed orally, is often administered parenterally. Amoxicillin is a close chemical and pharmacological relative of ampicillin. The drug is stable in acid and was designed for oral use. It is more rapidly and completely absorbed from the gastrointestinal tract than is ampicillin. The antimicrobial spectra of these agents are essentially identical, with the important exception that amoxicillin appears to be less effective for shigellosis. Ampicillin is the penicillin of choice for many gram negative bacilli ( Haemophilus influenzae , Escherichia coli , Proteus mirabilis , Salmonella typhi and Salmonella spp.), some gram positive bacilli (Listeria monocytogenes) and some gram positive cocci (Enterococcus faecalis) . It also has activity against Pneumococcus spp., Neisseria spp., Peptostreptococcus , Fusobacterium , Clostridium and Erysipelothrix.

Bacterial resistance to these drugs is becoming an increasing problem. Many pneumococcal isolates have varying levels of resistance to ampicillin. H. influenzae and the viridans group of streptococci are usually inhibited by very low concentrations of ampicillin. However, strains of H. influenzae (type b) that are highly resistant to ampicillin have been recovered from children with meningitis. It is estimated that 30% or more cases of H. influenzae meningitis are now caused by ampicillin-resistant strains. Similarly, ampicillin-resistant strains of H. influenzae have been increasingly isolated from cases of acute otitis media. An increasing percentage of N. gonorrhoeae , E. coli , P. mirabilis , Salmonella and Shigella are now resistant to ampicillin and practically all species of Enterobacter are now insensitive.

β-Lactamase inhibitors have been introduced to combat many penicillin-resistant microorganisms. These molecules bind to β-lactamases and inactivate them, thereby preventing the destruction of β-lactamase antibiotics. Clavulanic acid binds to the β-lactamases produced by a wide range of gram positive and gram negative microorganisms. It is well absorbed orally and can be given parenterally. It has been combined with amoxicillin as an oral preparation (Augmentin) and with ticarcillin (a carboxypenicillin) as a parenteral preparation (Timentin). Augmentin is effective for β-lactamase-producing strains of staphylococci, H. influenzae , gonococci and E. coli . Sulbactam is another β-lactamase inhibitor, which also can be administered orally or parenterally. In combination with ampicillin (Unasyn), good coverage is provided for gram positive cocci (including β-lactamase-producing strains of Staph. aureus ), gram negative anaerobes (but not Pseudomonas ) and anaerobes.

Adverse reactions to penicillin

Hypersensitivity reactions are the major adverse effects of penicillins. Penicillins are capable of acting as haptens to combine with proteins contaminating the solution or with human protein after the penicillin has been administered. Penicilloyl and penicillanic derivatives are the major determinants of penicillin allergy. All acute hypersensitivity reactions to penicillin are mediated by the immunoglobulin (Ig)E antibody and range in severity from rash to anaphylaxis. Anaphylactic reactions are uncommon, occurring in only 0.2% of 1000 courses of treatment, with 0.001% out of 100,000 courses resulting in death. Morbilliform eruptions that develop after penicillin therapy are likely to be mediated by IgM antibodies and the uncommon serum sickness is likely to be mediated by IgG antibodies. All forms of penicillin are best avoided in patients with a history of penicillin allergy.

Otherwise, the penicillins are generally well tolerated. Central nervous system (CNS) toxicity, in the form of myoclonic seizures, can follow the administration of massive doses of benzylpenicillin (penicillin G), ampicillin or methicillin. Massive doses have also been associated with hypokalaemia. Haematological toxicity—usually neutropaenia—and nephrotoxicity have also been reported. Gastrointestinal disturbances have followed the use of all oral penicillins, but have been most pronounced with ampicillin. Enterocolitis due to the overgrowth of Clostridium difficile is well documented, and abnormalities in liver function have been reported, especially with flucloxacillin.

Cephalosporins

The antimicrobial activity of cephalosporins, like that of other β-lactam antibiotics, results at least in part from their ability to interfere with the synthesis of the peptidoglycan component of the bacterial cell wall. However, the exact bactericidal and lytic effects of cephalosporins are not completely understood.

Classification and uses

The first-generation compounds (cephalothin, cefazolin, cefalexin) have a relatively narrow spectrum of activity focused primarily on the gram positive cocci, especially penicillin-sensitive streptococci and methicillin-sensitive Staph. aureus. These compounds have modest activity against gram negative organisms, including E. coli and Klebsiella spp. Cefaclor has extended gram negative activity and is active against H. influenzae and M. catarrhalis.

The second generation of cephalosporins (cefuroxime, cefamandole) are more stable against gram negative β-lactamases. They have variable activity against gram positive cocci, but have increased activity against gram negative bacteria ( E. coli , Proteus , Klebsiella ). In spite of relatively increased potency against gram negative aerobic and anaerobic bacilli (Bacteroides fragilis) , the cephamycins (cefoxitin, cefotetan) are included in this generation.

The third-generation cephalosporins (cefotaxime, ceftriaxone, ceftazidime, cefpirome) have very marked activity against gram negative bacteria. Most are useful against Ps. aeruginosa , Serratia and Neisseria species and some Enterobacteriaceae. Some of these compounds have limited activity against gram positive cocci, particularly methicillin-sensitive Staph. aureus. This generation of cephalosporins is particularly effective in meningitis because of their better penetration into the CSF and higher intrinsic activity. However, as these third-generation drugs are more expensive and have a wide antimicrobial spectrum, their use should be based on established guidelines.

Recently, several compounds have been considered as possibly meriting classification as a fourth generation. Cefepime has activity against gram positive cocci and a broad array of gram negative bacteria, including Ps. aeruginosa and many of the Enterobacteriaceae with inducible chromosomal β-lactamases.

Adverse reactions

Hypersensitivity reactions are the most common side effects of the cephalosporins and all compounds have been implicated. The reactions appear to be identical to those caused by the penicillins. Immediate reactions, such as anaphylaxis, bronchospasm, angio-oedema and urticaria, have been reported. More commonly, a maculopapular rash develops, usually after several days of therapy. Because of the similarity in structure between the penicillins and the cephalosporins, patients allergic to one class of agents may manifest cross-reactivity when a member of the other class is administered. Studies indicate that about 0.5% of patients allergic to penicillin will demonstrate a clinically apparent reaction when a first-generation cephalosporin is administered (0% for second- and third-generation cephalosporins). Patients with a mild or temporarily distant reaction to penicillin appear to be at low risk of rash or other allergic reactions following the administration of a cephalosporin. However, subjects with a recent history of an immediate reaction to penicillin should not be given a cephalosporin. Other reactions to cephalosporins are uncommon and include diarrhoea, nephrotoxicity, intolerance of alcohol and bleeding disorders.

Penicillin allergy cross-reactivity with cephalosporins is significantly overstated. Cross-reactivity between penicillins and cephalosporins is much less than the 10% commonly cited. Cephalothin, cephalexin, cefadroxil and cefazolin confer an increased risk of allergic reaction among patients with penicillin allergy.

Cefuroxime, cefpodoxime, ceftazidime and ceftriaxone do not increase risk of an allergic reaction.

No cross-reactivity exists between penicillins and third-generation cephalosporins. However, if a patient has known anaphylaxis to penicillin, caution with cephalosporin use is still warranted.

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