With few exceptions, bacteria may be classified as Gram-positive or Gram-negative, according to a staining technique used in laboratory identification. Generally, Gram-positive bacteria are able to withstand desiccation better than can Gram-negative bacteria, and many form spores that resist drying. Gram-negative species multiply rapidly in the presence of moisture even when provided with minimal nourishment. Several Gram-positive and Gram-negative bacteria have had a long association with hospital infection and, because they can be carried on the hands, may be spread by cross-infection in any health care setting (Table 23.1).

**Table 23.1** Gram-positive and Gram-negative organisms in hospitals
Gram-positive	Gram-negative
Staphylococcus aureus	Haemophilus influenzae
Streptococcus pyogenes	Neisseria gonorrhoeae (Gonococcus)
Streptococcus viridans	Neisseria meningitides (Meningococcus)
Streptococcus pneumoniae (Pneumococcus)	E. coliProteusPseudomonasKlebsiella

Anaerobes

This term refers to bacteria that can live and multiply in the absence of free oxygen. In the laboratory they require special conditions before they will grow in culture, but they are able to cause severe infections given the correct circumstances. Anaerobic bacteria naturally inhabiting the gut may cause severe sepsis following abdominal surgery. If Clostridium tetani gains access to a penetrating wound that is free of oxygen the organism multiplies and produces a toxin that causes tetanus.

Choosing an antibiotic

When faced with a patient with an infectious disease, the first consideration is whether an antibiotic is required. Many infections (e.g. a mild sore throat) get better quickly without specific treatment. If antibiotic treatment is needed, the following points should be considered:

• The infecting organism: this is often suspected from the nature of the disease, and initial treatment is usually based on this guess. If possible, the nature of the organism should be confirmed by culture of blood, sputum, urine, etc., although in practice this is not always possible.

• The correct antibiotic to eradicate the infection.

• The ability of the antibiotic to penetrate the site of infection (for example, in meningitis not all drugs enter the cerebrospinal fluid).

• The route of administration: some antibiotics are ineffective orally and injection may also be required for rapid action.

• A drug history is essential (as always) to ensure that the patient has not previously had an adverse reaction to the chosen antibiotic, or that the antibiotic will not compromise any other drug being used, e.g. rifampicin and the Pill (see below).

• Possible complicating factors such as pregnancy, and renal or hepatic failure.

• In these difficult times, the cost of the drug, although this decision should not jeopardize the patient’s safety or return to health.

Note that antibiotic is a term used to describe any substance produced by or derived from an organism which inhibits the growth of or destroys another organism, usually a bacterial or fungal infection.

Case History 23.1 gives an example of the procedures used.

Case History 23.1

Miss B, aged 27, developed a cough which produced phlegm and she bought a proprietary cough mixture, which did not stop the cough. She also became troubled by shortness of breath, especially when she lay on her back, and a severe headache; therefore, she decided to visit her GP. The GP, who listened to her chest and said there was nothing untoward except a slight sound on one side, diagnosed a bacterial infection. A sputum specimen was taken and sent away for analysis. There was indeed a bacterial infection and a course of clarithromycin was prescribed to treat the chest infection; Miss B was told to complete the full course of treatment. Salbutamol, an α ₂ agonist, was prescribed for the shortness of breath, together with a spacer to help deliver the full dose of salbutamol. It was also recommended that Miss B take aspirin for the headache.

The sulphonamides

This is one of the oldest groups of antibacterial agents. They differ to some extent in the range of organisms they attack, but most of their pharmacological properties are similar. They have been largely replaced because of the development of bacterial resistance and adverse side-effects, and most have disappeared from use. They are, with few exceptions, well and rapidly absorbed from the intestinal tract. They circulate widely in the body fluids and cross the meningeal barrier to enter the cerebrospinal fluid (CSF).

After absorption, the liver begins to acetylate the sulphonamides. The acetylated drugs together with unaltered sulphonamide are excreted in the urine. The acetylated sulphonamides are very poorly soluble and therefore there is a danger that they will precipitate in the urine unless an adequate flow is maintained. Most of the sulphonamides are effective against a fairly wide range of bacteria. Unfortunately, certain of these bacteria have become resistant. Table 23.2 gives a number of available sulphonamides.

**Table 23.2** Available sulphonamides
Drug	Important features
Sulfadimidine	Well absorbed orally
Sulfasalazine	Used in ulcerative colitis. It is particularly useful for long-term maintenance treatment
Silver sulfadiazine	Applied locally as a cream to prevent infection in severe burns

Therapeutic use of sulphonamides

Sulfadimidine and sulfasalazine

Sulfadimidine is still used occasionally in urinary infections provided that the infecting organism is susceptible. Sulfasalazine is given in the long-term treatment of ulcerative colitis and Crohn’s disease (see p. 151). Sulfasalazine can also be used in the treatment of rheumatoid arthritis.

Adverse effects

• Nausea can be troublesome and with sulfasalazine may be relieved by giving small and more frequent doses.

• Rashes of various types, sometimes with fever.

• Blood dyscrasias: polyarteritis nodosa is a rare, but dangerous, complication.

• The sperm count is reduced by sulfasalazine, but recovers on stopping the drug.

• Precipitation in the urinary tract causing obstruction; the patient should be given 2–3 litres of fluid daily to maintain a good urinary flow when receiving sulfadimidine.

Co-trimoxazole (trimethoprim+sulfamethoxazole)

Mechanism of action

Sulphonamides affect bacteria by interfering with their use of para-aminobenzoic acid (PABA), a precursor of folic acid, which is ultimately essential in cell division (see Fig. 23.1). Trimethoprim interferes with folic acid metabolism at the phase when folic acid is changed to folinic acid to build up the cell nucleus. This requires the action of an enzyme, and, by combining with that enzyme, trimethoprim stops the reaction and the cell dies. The combination of a sulphonamide with trimethoprim is particularly effective in preventing bacterial cell division and is also bactericidal. Co-trimoxazole is effective against Streptococcus pyogenes, Streptococcus pneumoniae, E. coli, Haemophilus (H.) influenzae, Salmonella and Pneumocystis carinii (in large doses).

Therapeutic use

The combined tablet of trimethoprim plus sulfamethoxazole, co-trimoxazole, has been widely and successfully used in exacerbations of chronic bronchitis and in urinary infections. It also has a place in the treatment of the more severe salmonella and other infections. Unfortunately, its adverse-effect profile has led to its use being largely confined to pneumocystis pneumonia. In large doses it is used to treat pneumocystis infection of the lung, a disease which occurs in patients whose immunity has been suppressed, often as a result of cancer chemotherapy or HIV.

Adverse effects

These are largely those of the sulphonamides, namely nausea and vomiting, and occasionally blood disorders. More serious is the occasional development of the Stevens–Johnson syndrome with a bullous rash, mouth ulceration and fever, which can be fatal.

Trimethoprim

Trimethoprim can also be used alone. At present it is largely used to treat urinary infection. It can also be used to treat bronchitis.

Adverse effects

These include nausea, rashes and, rarely, depression of the blood count.

Contraindication

It should not be used in the first 3 months of pregnancy.

The nitrofurans

This group of chemotherapeutic agents has been investigated sporadically for over 30 years. The only one currently used is nitrofurantoin.

Nitrofurantoin has a fairly wide antibacterial spectrum and is considerably concentrated in the urine. It is used in the treatment of urinary tract infections, or as a prophylactic. Nausea sometimes occurs but can be minimized by giving the drug after food. Other adverse effects include rashes and fever. It should not be used in patients with renal failure, as accumulation will occur.

The quinolones

The quinolones comprise:

• ciprofloxacin

• levofloxacin

• nalidixic acid

• norfloxacin

• ofloxacin.

This group of antibacterial drugs is increasingly important; several are available already and more will probably be introduced in the next few years. They interfere with an enzyme necessary for the cell division of bacteria.

Ciprofloxacin

Therapeutic use

Ciprofloxacin acts against a wide range of organisms, but is not very effective against some Gram-positive organisms, particularly pneumococci. It is given orally twice daily or by infusion, which is very expensive. At present, its use should be confined to patients for whom older antibacterial drugs are unsatisfactory, particularly for typhoid, urinary infection and gonorrhoea. It is the preferred drug in adults as a prophylactic for close contact with meningococcal meningitis. There has been a large increase in resistance to ciprofloxacin in recent years.

β-Lactam antibiotics

The β-lactam antibiotics can be divided into:

• the penicillins

• the cephalosporins

• others.

The β-lactam antibiotics all contain the β-lactam ring, which is a chemical structure essential for their antibacterial activity. The family of β-lactams is summarized in Figure 23.2.

Figure 23.2

The β-lactam family of antibiotics.

The penicillins

The penicillins comprise:

• amoxicillin

• ampicillin

• azlocillin

• benzylpenicillin

• co-amoxiclav

• flucloxacillin

• phenoxymethylpenicillin

• piperacillin

• pivampicillin

• ticarcillin.

The penicillins were the first antibiotics to be isolated. Over the years their structure has been repeatedly modified to deal with the problem of resistance and to extend their antibacterial range. They are still probably the most widely used family of antibiotics.

Benzylpenicillin

Benzylpenicillin was the first penicillin to be used clinically. It is usually given by deep intramuscular injection, which is painful; if a large single dose is needed, it should be given intravenously. It enters the circulation rapidly and spreads through the body; it does not, however, cross into the CSF in any great quantity, although this may be increased if the meninges are inflamed.

Elimination of penicillins

All penicillins are excreted by the kidneys, partially through the glomeruli but the major part via the renal tubules. The excretion is rapid and blood levels fall nearly to zero 4 hours after injection. If benzylpenicillin is given orally, it is partially broken down by the gastric acid, and is not now given by this route.

Range of benzylpenicillin

Benzylpenicillin is effective against a fairly wide range of organisms. Table 23.3 lists the most common.

**Table 23.3** Main uses of benzylpenicillin
Organisms	Disease
^*Note that a high proportion of staphylococci found in hospital are now resistant to benzylpenicillin.

Streptococcus pyogenes	Tonsillitis, scarlet fever, septicaemia
Streptococcus viridans	Subacute bacterial endocarditis
Staphylococcus aureus*	Carbuncles, osteomyelitis, septicaemia, boils
Streptococcus pneumoniae	Pneumonia
Neisseria gonorrhoeae	Gonorrhoea
Neisseria meningitidis	Meningococcal meningitis
Treponema pallidum	Syphilis
Clostridium perfringens	Gangrene
Clostridium tetani	Tetanus
Actinomyces	Actinomycosis

Penicillins are bacteriostatic and in higher doses are bactericidal. When treating infection it is ideal to maintain the blood level of penicillin continually at bactericidal levels, and this requires injections every 4 hours. In milder infections, however, it is often adequate to give less frequent injections. Even after the blood levels of penicillin have dropped below bactericidal or bacteriostatic levels, the organism may take some time to recover and by that time the blood level of penicillin has risen again following a further injection.

Procaine benzylpenicillin

Numerous attempts have been made to prolong the action of benzylpenicillin after injection by slowing down its release from the injection site. A successful method is to combine benzylpenicillin with procaine. The combination is called procaine benzylpenicillin and will maintain a satisfactory blood level for at least 12 hours. This preparation is, however, rather slow to produce a satisfactory blood level, so that if a rapid effect is required, benzylpenicillin should be given as well.

The action of penicillin can be augmented and prolonged by slowing down its excretion. This can be done by giving probenecid, a drug that blocks the tubular secretion of penicillin, thus allowing the drug to accumulate in the body.

Penicillin resistance: penicillinase and the β-lactam ring

Certain organisms develop resistance to the action of penicillin. Organisms which were originally sensitive appear to adapt themselves to the penicillin by producing an enzyme called penicillinase, which inactivates penicillin by attacking part of the penicillin molecule known as the β– lactam ring. This structure is an essential part of penicillins and cephalosporins, and the family of enzymes involved is sometimes known as the β-lactamases. This is particularly so in the case of staphylococci, and strains of this organism which are resistant to penicillin and other antibiotics are a serious clinical problem. There is now a considerable degree of alarm because of the rapidly reducing number of effective antibiotics, and there is growing realization that we may be in danger of entering a period analogous to that before antibiotics were originally introduced.

Other penicillins

These comprise:

• phenoxymethylpenicillin

• flucloxacillin

• broad-spectrum penicillins

• extended-spectrum penicillins (ureido penicillins).

There are a number of penicillins that are similar to benzylpenicillin but are effective by mouth. Some of the examples given below are not destroyed by the acid in the stomach and are fairly well absorbed from the intestinal tract.

Phenoxymethylpenicillin

Adequate absorption with a satisfactory therapeutic response usually occurs with oral penicillin but it is important that it is taken 30 minutes before a meal. The patient must be carefully observed in case the drug is ineffective due to vomiting or inadequate absorption. Penicillin must then be given by injection.

Flucloxacillin

The elucidation of the structure of the penicillin nucleus has made it possible to produce penicillins which are not broken down by penicillinase and are therefore effective against organisms, particularly staphylococci, which have become resistant to benzylpenicillin. Flucloxacillin is a commonly used example. It is used almost exclusively for treating staphylococcal infections.