This slide categorises the commonly encountered pathogens and the spectra of antibiotic cover that is required to treat infections that they cause.
Past successes of being able to develop new drugs in time for resistant bacteria have lulled us into a false sense of security. Between 1970 and 2000 no new classes of antibiotics were brought to the market. Lots of me too drugs with cross resistance. There are no gram negative antibiotics in development at the moment. Very alarming that in the near future we may have infections that we have no antibiotics against. This will take us back to pre-antibiotics era.
Antibiotic use inevitably leads antimicrobials resistance as bacteria mutate to develop resistance.
This slide shows the spectra of activity for penicillins. Green areas indicate organisms against which the penicillin is active i.e. the organism is sensitive. Benzylpenicillin and phenoxymethylpenicillin only have reliable activity against Streptococci. They have some activity against anaerobes. Flucloxacillin covers Streptococci and Staphylococci. Amoxicillin has broader spectrum with some activity against gram-negative organisms and anaerobes. The addition of clavulanic acid to amoxicillin strengthens this activity against anaerobes and gram-negatives by mopping up the betalactamase produced by these organisms resulting in a higher amoxicillin concentration at the site of infection.
Early cephalosporins have activity against gram-positives and limited activity against coliforms. Cefuroxime has greater activity against gram-negatives and some anaerobic activity. It was one of the first broad spectrum agents and was used widely in surgical prophylaxis and treatment of a variety of infections. Cefotaxime and later ceftriaxone were developed and these also gave cover against extended spectrum betalactamases (ESBLs). Ceftriaxone was widely used as it seemed the ideal antibiotic – broad spectrum and administered once daily. However widespread use has lead to resistance and cephalosporins now implicated in rise of C. difficile infections. Ceftazidime is also broad spectrum agent but with the addition of Pseudomonas cover. Pseudomonas is common causative organism of respiratory infections in cystic fibrosis and ventilator associated pneumonia.
MRSA is a resistant strain of Staph. aureus which is mainly seen in hospital patients. Agents used against MRSA have activity against most gram-positive organisms. Vancomycin is usually the first line agent for MRSA infections. It is given by IV infusion and requires monitoring of serum levels to ensure safe use. Teicoplanin is a similar agent but it can be given as a bolus injection and requires no monitoring. Until recently it was much more expensive than vancomycin but patent expiry has significantly reduced its cost. Linezolid has similar activity to the glycopeptides but is expensive. It has the advantage of being available in an oral formulation so patients do not require to be hospitalised for treatment. Use usually restricted to ‘on advice of Microbiologist’. Daptomycin is a relatively new gram-positive agent. It is reserved for infections or patients not suitable for other agents and on advice of a Microbiologist. Sodium fusidate is an old antibiotic, available as IV infusion (rarely used) or tablets. It is commonly used as an oral step-down agent in MRSA infections in but needs to be used in combination with another agent such as rifampicin or trimethoprim to prevent development of resistance.
Doxycycline is the most commonly used tetracycline for treatment of systemic infections. Other tetracyclines used in acne. Doxycycline is used in respiratory infections – COPD, CAP, sinusitis. Tigecycline is a new tetracycline with broader spectrum of activity. Reserved for treatment of serious abdominal and skin/soft tissue infections on advice of Microbiologist. Trimethoprim is first line agent for UTIs. Resistance may be a problem – rates of up to 20% reported in some areas. Co-trimoxazole combines trimethoprim with a sulphonamide to give greater gram-positive activity. Until early 1990s was widely used for UTI and other infections but problems with blood dyscrasias, particularly in the elderly and in some cases serious, were reported and its use has since been restricted. Its main indication is Pneumocystis carinii pneumonia (PCP) which is associted with HIV infection. Recently the use of co-trimoxazole has increased as an alternative to glycopeptides for surgical prophylaxis and treatment of MRSA.
Macrolides are used for treatment of atypical infections. Erythromycin use has declined due to poor compliance and GI side effects. The newer macrolides have a greater spectrum of activity and require less frequent dosing. Clarithromycin is used in respiratory infections – COPD and CAP. Azithromycin used in Chlamydia and sometimes in children for respiratory infections. Clindamycin is an old antibiotic which is now used mainly for serious skin and soft tissue infections. Previous more widespread use lead to problems with C. difficile.
Ciprofloxacin and ofloxacin are active against gram-negatives and are used to treat UTIs. They are considered second line agents and should only be used if urine culture results show resistance to first line agents. The exception is UTI in men where ciprofloxacin is used first line. Widespread inappropriate use of ciprofloxacin for UTIs and respiratory tract infections in primary care has lead to emergence of resistance. Its use should be restricted to specific indications such as UTI in men, pyelonephritis, pseudomonal infections. Levofloxacin and moxifloxacin have increased activity against gram-negative organisms. They are both second line agents for respiratory infections. Moxifloxacin has been associated with hepatotoxicity so should only be used if no other treatment is suitable. Quinolones are associated with a high risk of predisposing patients to C. difficile so their use should be limited. Aminglycosides are used for IV treatment of gram negative infections. Gentamicin is the main one used, tobramycin in cystic fibrosis. Dosage requirements calculated on an individual patient basis and serum level monitoring required. Once daily gentamicin is generally used except for endocarditis.
Metronidazole is used against anaerobes and is often combined with another antibiotic for broad spectrum cover. It is used in surgical prophylaxis for abdominal procedures and treatment of abdominal infections. Nitrofurantoin has a broad spectrum of activity but its main use is in UTI. It is an alternative first line agent to trimethoprim. Rifampicin is an antitubercular agent which also has activity against gram-positive organisms. It is used in combination with another agent for oral treatment of MRSA infections. Chloramphenicol was one of the first broad spectrum agents but problems with toxicity have limited its use. It is used in treatment of meningitis in penicillin-sensitive patients.
Antibiotics are one of the most widely used group of medicines and a wide range of side effects have been reported. Most antibiotics can cause GI upset due to disturbance of the normal gut flora. Many can also cause rash which may or may not be a hypersensitivity reaction. Many side effects can be prevented by avoidance of certain agents in certain patient groups – check cautions and contraindications in BNF. Careful dosing and administration can prevent toxicity with aminoglycosides and vancomycin.
Interactions are common particulary with macrolides and quinolones which are metabolised by the P450 enzymes.
A summary of pharmaceutical microbiology part 2 - drugs
Part 2 <ul><li>Drugs </li></ul>
Antibiotic spectrum MRSA and Coagulase- negative Staph. Enterococcus faecalis & Enterococcus faecium Gut bacteria e.g. E. coli Anaerobic Streptococci & Clostridia Streptococcus pneumoniae & Group A, B, C, G Respiratory Gram -ve e.g. Haemophilus influenzae & Moraxella catarrhalis Extended-spectrum beta-lactamase producers & other resistant Gram negatives Pseudomonas aeruginosa Legionella, Chlamydia & Mycoplasma pneumoniae Bacteroides fragilis Green = Generally Sensitive; Orange = Unreliable; Red = Generally Resistant
New Antibiotics <ul><li>New antibiotics are always becoming available to fight resistance – right? </li></ul>1930 1940 1950 1960 1970 1980 1990 2000 2009 Sulphonamides Penicillin Aminoglycosides Chloramphenicol Tetracyclines Macrolides Glycopeptides Quinolones Streptogramins Lipopeptides Oxazolidinones Oritavancin Televancin Dalbavancin Ceftobiprole Ceftaurolin Iclaprim Phase III trials
Antimicrobial Resistance <ul><li>Antibiotic use causes resistance through selective pressure. </li></ul><ul><li>Broad spectrum antibiotics select for resistant pathogens by eradicating natural flora. </li></ul><ul><li>Current problems with resistant organisms </li></ul><ul><li>MRSA - methicillin resistant Staphylococcus aureus </li></ul><ul><li>VRE - vancomycin resistant enterococci </li></ul><ul><li>ESBL - extended spectrum betalactamase </li></ul>