DRUGS USED IN BACTERIAL INFECTIONS - A BRIEF REVIEW

Antiinfectives should never be given casually for mild infections. Ideally, a culture & sensitivity should be done before administering the antiinfective of choice. Antibiotics are ineffective against viruses. The product labeling should be consulted for specific information about organism sensitivity and resistance and for detailed microbiological indications. Advise patients to continue taking medication until course of treatment is finished (usually 7–10 days) unless severe allergic reactions occur. When selecting antibiotics for the prevention of bacterial endocarditis, the physician or dentist should read the full joint statement of the American Heart Association and the American Dental Association. Treatment of strep infections usually requires at least 10 days of therapy.

Interactions: Antibiotics may reduce efficacy of oral contraceptives. Bactericidal drugs are primarily active against actively dividing cells. Therefore, bacteriostatic antibiotics (eg, tetracyclines) may interfere with the action of bactericidal antibiotics (eg, penicillins).

Adverse Reactions: Pseudomembranous colitis may occur following the administration of antibacterial agents. This may range in severity from mild to life-threatening. This diagnosis should be considered in patients who present with diarrhea subsequent to antibiotic therapy. Mild cases usually respond to discontinuing the drug; more severe cases may need supportive care and/or therapy with an agent effective against Clostridium difficile. Anti-motility drugs should be avoided since they may precipitate toxic megacolon. Also, overgrowth of nonsusceptible organisms, including fungal overgrowth (superinfection) may occur with the prolonged use of antibiotics.

AMINOGLYCOSIDES: The aminoglycosides (eg, gentamycin, tobramycin, streptomycin, amikacin) bind to the 30S ribosomal subunit of bacteria resulting in decreased protein synthesis and misreading of mRNA. These agents exert concentration-dependent bactericidal effects and demonstrate a post-antibiotic effect to persistently suppress bacterial growth after concentrations fall below the MIC. Aminoglycosides are active against gram-negative aerobic and facultative bacilli, including Pseudomonas aeruginosa. Aminoglycosides have limited activity against gram-positive organisms when used alone; however, when combined with a cell wall-active agent (eg, penicillins, vancomycin), in vitro synergistic bactericidal activity against enterococci and staphylococci is observed. Aminoglycosides are not active against anaerobes or atypicals.

β-LACTAMS: β-lactam antibiotics inhibit bacterial cell wall synthesis by binding to and inactivating penicillin-binding proteins to exert time-dependent bactericidal activity. The β-lactam antibiotics can be divided into penicillins, cephalosporins, carbapenems, and monobactams, which are further divided into different groups according to spectra of activity.

Penicillins are primarily active against gram-positive cocci and some gram-negative bacilli. These agents can be subdivided into 5 distinct groups: natural penicillins, penicillinase-resistant penicillins, aminopenicillins, carboxypenicillins, and ureidopenicillins. β-lactamase inhibitors (eg, clavulanic acid, sulbactam sodium) may be formulated in combination with penicillins to restore the spectrum of activity of the corresponding β-lactam to include pathogens that were resistant due to their production of β-lactamases. 

Natural penicillins (eg, penicillin G, penicillin V) are active against non-β-lactamase-producing gram-positive bacteria, anaerobes, and select gram-negative cocci. Penicillinase-resistant penicillins (eg, nafcillin, oxacillin) are semi-synthetic penicillins stable against staphylococcal penicillinase. 

Aminopenicillins (eg, ampicillin, amoxicillin) have a spectrum of activity similar to penicillin G with added activity against gram-negative cocci and Enterobacteriaceae that do not produce β-lactamase. 

Carboxypenicillins (eg, ticarcillin) have an expanded spectrum of activity against non-β lactamase-producing gram-negative aerobic bacilli. 

Ureidopenicillins (eg, piperacillin) have a broader spectrum of activity compared to carboxypenicillins. Relative to carboxypenicillins, piperacillin offers activity against Enterococcus faecalis and Klebsiella and has greater efficacy against Pseudomonas. In addition, piperacillin has excellent activity against non-β-lactamase-producing anaerobic cocci and bacilli.

Cephalosporins

Cephalosporins are divided into 4 different generations based on microbiologic activity. In general, gram-positive activity diminishes while gram-negative activity increases moving from the first- to third-generations. Fourth-generation cephalosporins demonstrate similar activity to first-generation agents against gram-positive cocci and are also active against most gram-negative bacilli (including Pseudomonas). All cephalosporins are considered inactive against methicillin-resistant staphylococci, enterococci, Listeria, Legionella, Chlamydia, Mycoplasma, and Acinetobacter species. 

First-generation cephalosporins (eg, cefazolin, cephalexin, cefadroxil, cephradine) are most often used as alternatives to penicillins for infections caused by methicillin-sensitive staphylococci and streptococci.

Second-generation cephalosporins can be further subdivided into true cephalosporins and the cephamycins. True cephalosporins (eg, cefuroxime, cefprozil, cefaclor) have similar activity against staphylococci and noneterococcal streptococci compared to first-generation agents but have increased activity against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria. The cephamycins (eg, cefotetan and cefoxitin) have reduced activity against gram-positive pathogens but enhanced activity against certain Enterobacteriaceae and are active against anaerobes, especially Bacteriodes fragilis. 

Third-generation cephalosporins (eg, ceftriaxone, cefotaxime, cefixime, cefdinir) have enhanced activity against gram-negative bacilli that are resistant to other β-lactams. 

Fourth-generation cephalosporins (eg, cefepime) have the widest activity spectrum. Cefepime has enhanced activity against Enterobacter, Citrobacter, and Serratia and is active against Pseudomonas while maintaining potency against gram-positive cocci.

Carbapenems

The carbapenems (eg, imipenem, meropenem, ertapenem, doripenem) are primarily active against gram-positive cocci, gram-negative bacilli, and anaerobes. These agents are not active against atypicals.

Monobactams

Aztreonam is active only against gram-negative aerobic bacilli. Because of structural differences, aztreonam can be safely given to patients with immediate hypersensitivity reactions to other β-lactams.

FLUOROQUINOLONES: Fluoroquinolones (eg, ciprofloxacin, levofloxacin, moxifloxacin) exert concentration-dependent bactericidal activity. These agents inhibit bacterial DNA synthesis and promote cleavage of DNA leading to bacterial cell death. These agents inhibit the activity of DNA gyrase and topoisomerase IV to prevent uncoiling of DNA strands and decatenation of daughter DNA strands during the replication process, respectively. In general, fluoroquinolones primarily inhibit DNA gyrase in gram-negative bacteria, whereas topoisomerase IV is the main target in gram-positive bacteria. Fluoroquinolones are most active against aerobic gram-negative bacilli and gram-negative cocci and have some activity against atypicals but provide poor anaerobic coverage.

FOLATE SYNTHESIS INHIBITORS: Sulfonamides (eg, sulfamethoxazole, sulfisoxazole), trimethoprim, and pyrimethamine are bacteriostatic agents that inhibit microbial synthesis of folate, a necessary component of bacterial nucleotide synthesis. Only bacteria which must self-synthesize folic acid are susceptible to these agents. Sulfonamides and trimethoprim/pyrimethamine exert their inhibitory effects at different stages of the folate synthesis pathway. Sulfonamides competitively inhibit dihydropteroate synthase which acts to incorporate para-aminobenzoic acid (PABA) into dihydropteroic acid, the precursor to folic acid. Trimethoprim and pyrimethamine inhibit dihydrofolate reductase, which is responsible for the conversion of dihydrofolic acid to the active tetrahydrafolic acid. Thus, the combination of sulfonamides with trimethoprim or pyrimethamine acts synergistically to reduce intracellular folate and subsequently inhibit nucleotide synthesis and bacterial cell growth.

Sulfonamides and trimethoprim are active against gram-positive and gram-negative bacteria, Actinomyces, Nocardia spp., Chlamydia, Plasmodium, and Toxoplasma. Trimethoprim is 20100 times greater in potency than a sulfonamide, making the synergistic combination of sulfisoxazole/trimethoprim more effective therapy than a sulfonamide alone. Pyrimethamine is highly selective against Plasmodium and Toxoplasma gondii; its activity against Toxoplasma is enhanced when combined with a sulfonamide.

GLYCOPEPTIDES: Vancomycin exerts time-dependent bactericidal activity by inhibiting cell wall synthesis. Vancomycin forms stable complexes with cell wall precursor units to prevent polymerization (transglycosylaton) of precursor units for the formation of a functional cell wall. Vancomycin is active only against gram-positive organisms. Vancomycin is not absorbed when given orally and is not appropriate for treatment of systemic infections. However, it achieves high concentration within the gastrointestinal tract and therefore is used for the treatment of pseudomembranous colitis caused by C. difficile or pseudomembranous enterocolitis caused by Staphylococcus aureus.

GLYCYLCYCLINES: Glycylcyclines (eg, tigecycline) are derivatives of minocycline that bind to the 30S subunit of bacterial ribosome to inhibit bacterial protein synthesis to exert bacteriostatic activity against gram-positive and gram-negative organisms, atypicals, and anaerobes.

KETOLIDES: Ketolides (eg, telithromycin) are derivatives of erythromycin that bind to the 50S subunit of bacterial ribosome and inhibit RNA-dependent protein synthesis of susceptible bacteria, similarly to macrolides. Telithromycin differs from macrolides in that it is more acid stable and demonstrates a higher binding affinity for the ribosome, which may contribute to its improved activity against macrolide-resistant pathogens. Telithromycin is bacteriostatic and has improved activity against gram-positive aerobic bacteria compared to macrolides. It is also active against gram-positive and gram-negative bacteria, atypicals, and some anaerobes.

LICOPEPTIDES: Daptomycin is a lipopeptide antibiotic that exerts concentration-dependent bactericidal activity. Daptomycin binds to the cell membrane of gram-positive bacteria in a calcium-dependent manner, resulting in loss of cell membrane depolarization. This action results in inhibition of protein, DNA, and RNA synthesis, leading to cell death. Daptomycin has a spectrum of activity that resembles that of vancomycin while maintaining activity against pathogens with reduced susceptibility to vancomycin (eg, vancomycin intermediate S. aureus and vancomycin-resistant enterococci).

LINCOSAMIDES: Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis through interactions with the 50S bacterial ribosomal subunit. Clindamycin primarily exhibits bacteriostatic activity against anaerobes and gram-positive organisms; it has been shown to be bactericidal against Streptococcus pneumoniae, Streptococcus pyogenes, and S. aureus.

MACROLIDES: Macrolides (eg, erythromycin, clarithromycin, azithromycin) bind to the 50S subunit of the prokaryotic bacterial ribosome and inhibit RNA-dependent protein synthesis of susceptible bacteria to exert bacteriostatic effects. Macrolides are active against gram-positive cocci and bacilli and atypicals and have some activity against gram-negative bacteria.

NITROIMIDAZOLES: Nitroimidazoles (eg, metronidazole) are prodrugs that exert their antibacterial actions by interfering with DNA synthesis to induce apoptosis; they are amebacidal, bactericidal, and trichomonacidal. By passive diffusion, these agents cross bacterial cell membranes and undergo nitro reduction to form free radicals. These reactive intermediates exert their cytotoxic effects via damage to nucleic acids and proteins. Metronidazole is active against anaerobic cocci, anaerobic gram-negative bacilli, anaerobic spore-forming gram-positive bacilli and microaerophilic pathogens. Due to its excellent penetration, metronidazole is used for the treatment of brain abscess or other central nervous system infections, as well as anaerobic infections involving the bones and joints, soft tissues, oral cavity, head and neck. 

OXAZOLIDINONE: Linezolid is an oxazolidinone that binds to the 50S ribosomal subunit of the 30S unit to prevent the formation of the 70S initiation complex. Linezolid is generally bacteriostatic, however it is bactericidal against some strains of S. pneumoniae and S. pyogenes. It is active against gram-positive pathogens including gram-positive anaerobic cocci, as well as mycobacteria. Linezolid lacks activity against most gram-negative aerobes and anaerobes. In addition to its antibiotic effects, linezolid is also a weak monoamine oxidase inhibitor, thus concomitant use with adrenergics, serotonergics, or consumption of tyramine-rich foods may lead to palpitations, headache, hypertensive crisis, fever, and mental status changes.

RIFAMYCINS: Rifamycins (eg, rifampin and rifaximin) are broad-spectrum antibacterials. These agents bind to DNA-dependent RNA polymerase, resulting in a drug-enzyme complex. Formation of this complex inhibits activity of the RNA polymerase, preventing the initiation of chain formation in the synthesis of RNA, but not chain elongation. Rifamycins are most active against gram-positive organisms, but are also active against gram-negative pathogens. Additionally, rifampin is moderately active against slow-growing mycobacteria and has some activity against Legionella.

STREPTOGRAMINS: Quinupristin and dalfopristin are streptogramins that bind to the 50S ribosomal subunit of the 70S unit in the elongation phase of protein synthesis. Quinupristin acts at the same site as macrolides and causes protein synthesis termination at a later phase, whereas dalfopristin directly blocks the addition of amino acids into the peptide chain to inhibit early polypeptide elongation. The streptogramins are active against most gram-positive aerobic pathogens. Available as combination therapy, the synergistic activity of quinupristin/dalfopristin accounts for its bactericidal activity; it is bacteriostatic against Enterococcus faecium.

TETRACYCLINES: Tetracyclines (eg, tetracycline, doxycyline, minocycline) are bacteriostatic antibiotics that bind to the 30S subunit of bacterial ribosome to inhibit bacterial protein synthesis. Tetracyclines primarily exhibit activity against atypicals and have some activity against gram-positive and gram-negative bacteria.

OTHER CLASSES: Fosfomycin exerts its antibacterial effect by inhibiting the enzyme enolpyruvyl transferase to irreversibly block an initial step in bacterial cell wall synthesis and, additionally, decreasing bacteria adherence to uroepithelial cells. Fosfomycin has a broad spectrum of activity against gram-positive and gram-negative pathogens.

Nitrofurantoin is used exclusively for prophylaxis against recurrent urinary tract infections (UTI); and treatment of uncomplicated cystitis or uncomplicated UTIs. Nitrofurantoin is rapidly eliminated and thus only achieves adequate concentrations in the urine. Reduction of nitrofurantoin by bacteria in the urine leads to formation of reactive intermediates that subsequently damage bacterial DNA; the antibacterial activity of nitrofurantoin is enhanced in the presence of acidic urine. Macrocrystalline preparations of nitrofurantoin (eg, Macrodantin, Macrobid) are absorbed and excreted more slowly than microcrystalline preparations (eg, Furadantin).

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by

Akshaya Srikanth, 

Pharm.D Intern,

Hyderabad, India.

The drugs don't work - so what will?

Antibiotics have been one of the greatest success stories in medicine.

But there is growing concern that the drugs' usefulness is coming to an end.

It has been reported that antibiotic resistance has reached "unprecedented levels". Last year in Europe more than 25,000 people died of bacterial infections that were resistant to antibiotics.

source: http://www.bbc.co.uk/news/health-13005739

As the director general of the World Health Organisation, Dr Margaret Chan, put it: "The world is heading towards a post-antibiotic era in which many common infections will no longer have a cure and, once again, kill unabated."

During the last decade, MRSA became one of the most feared words in hospitals.

The latest concern is NDM-1. It is resistant to one of the more powerful groups of drugs, carbapenem antibiotics, and has been detected in UK patients.

Why not produce more antibiotics?

One solution to antibiotic resistance is to develop new drugs.

The eminent microbiologist Professor Hugh Pennington told the BBC: "There are no new antibiotics coming along and we've run out of easy targets.

"Pessimism is the order of the day, we're holding the line, but we're not gaining."

However, Professor Chris Thomas, molecular geneticist at the University of Birmingham, says that while a degree of complacency did set in: "There is a pipeline of new antibiotics from the evidence I've seen. There are new ways of developing drugs and new drugs have come through."

Drug manufacture almost inevitably depends on the pharmaceutical industry and unfortunately there are problems with the present business model.

To take a drug from discovery to market is estimated to cost £700m.

Colin McKay, from the European Federation of the Pharmaceutical Industries and Associations, said: "It is very difficult to make economically viable models for antibiotics."

"With heart medication or anti-depressants a lot of people take them for a long time so you can make money back. An antibiotic that works is unlikely to be used for more than a couple of weeks."

He added: "A new way to promote research is needed and there is an ongoing debate into how to do it."

Virus vs Bacteria

Viruses have long been touted as a solution to antibiotic resistance.

Bacteriophage are a group of viruses which infect and kill bacteria. They were discovered in 1915 in the former Soviet republic of Georgia and have remained part of medical practice there.

However, research on them was largely abandoned in the West due to the success of antibiotics.

Clinical trials on phage are taking place, but the subject area has attracted some critics who say the field has not delivered.

Dr Martha Clokie, a microbiologist at the University of Leicester working on phage for Clostridium difficile, said: "That criticism is fair, there has been a lot of talk and hyperbole about phage, but recently there is increasing evidence that they do work."

"It's an exciting time to be in this area, I hope the criticism won't be accurate soon. I'm very optimistic that phage have a future."

Vaccines

Vaccination has also attracted a lot of publicity.

Just like for seasonal flu, a vaccine would be developed for superbugs.

This could be taken before going into hospital for surgery.

In 2008, the then chief medical officer for England, Sir Liam Donaldson, said vaccines for MRSA and C. difficile should be ready within a decade.

Surveillance and hygiene

Monitoring antibiotic resistance in the UK is the responsibility of the Health Protection Agency.

Its executive director of microbiology services, Christine McCartney, said: "The emergence of antibiotic resistance, especially against carbapenems, is a major public health concern.

"Antibiotic resistance makes infections much harder to treat and its spread underscores the need for good infection control in hospitals."

Prof Pennington said: "We need to stop patients passing bugs on. It needs very strict rules with patients kept in isolation and barrier nursing. We need to sharpen infection control practices."

Prof Thomas argues that "hygiene appears to be responsible for the reduction in MRSA cases" and that "we need to get back to careful nursing."

He concluded: "We need to pursue every possible link, having one strategy is like having all your eggs in one basket."

Source: BBC News UK

by Akshaya Srikanth, Pharm.D Candidate

Breakpoints to MICs Help Hone Pseudomonas aeruginosa Therapy

Selecting the most appropriate antibiotic therapy can be a challenge when it comes to empirical treatment for severe, multidrug-resistant infections, such as those caused byPseudomonas aeruginosa.

At the University of Pittsburgh Medical Center, clinical pharmacists bolstered the odds of success against likely P. aeruginosa infections by devising a combination antibiogram that applied pharmacodynamic (PD) breakpoints to minimum inhibitory concentration (MIC) distributions for a range of commonly used antibiotics.

Inclusion of PD breakpoints led to “substantial changes” in antibiotic treatment recommendations, according to the pharmacist-researchers, who presented the results of their investigation at the American College of Clinical Pharmacy annual meeting (abstract 135). The study was based on 376 P. aeruginosa isolates identified from blood or bronchoalveolar lavage cultures at three ICUs from January 2009 to December 2010.

“There were some striking findings,” said Brian A. Potoski, PharmD, BCPS (AQ-ID), associate director of the medical center’s Antibiotic Management Program and one of the authors. For example, he said, although cefepime has been used extensively as monotherapy at the medical center, “we found that we should probably not be [using] cefepime in the empiric setting, at least by itself, based on the PD breakpoint.”

Drawing on the medical center’s susceptibility and MIC data, the researchers also found that the optimal PD-based combination therapy for P. aeruginosa involved the use of a β-lactam antibiotic with an aminoglycoside. The top selection reported in their study was piperacillin-tazobactam plus tobramycin, followed closely by meropenem plus tobramycin. “We think that’s important,” Dr. Potoski said, “because there seems to be this reflex to use just a quinolone along with a β-lactam backbone. That doesn’t give you the best chance for appropriate therapy.”

Dr. Potoski noted that susceptibility patterns can vary greatly from institution to institution, even between those in the same locality. “It might be worthwhile,” he said, “for other institutions to take a look at using these methods because they might find something very different and yet very appropriate and important for their populations.”

The PD breakpoints recommended by the Pittsburgh researchers were at least 50% lower than those published by the Clinical and Laboratory Standards Institute (CLSI). “We know that there are certain MICs for particular antibiotics that are extremely unattractive,” Dr. Potoski explained, adding that outcomes at those MICs “are poorer” than those attained at lower MICs, even if the organism has been shown to be susceptible.

PD breakpoints recommended in the Pittsburgh P. aeruginosa antibiogram included cefepime no greater than 4 mcg/mL (vs. the CLSI standard of up to 8 mcg/mL); piperacillin-tazobactam no greater than 16 mcg/mL (vs. up to 64 mcg/mL); meropenem 2 mcg/mL or less (vs. 4 mcg/mL); and tobramycin 2 mcg/mL or less (vs. up to 4 mcg/mL).

Getting the Complete Picture

David P. Nicolau, PharmD, FCCP, FIDSA, director of the Center for Anti-Infective Research & Development at Hartford Hospital, Hartford, Conn., said, “Certainly we understand as a collective that there are some inadequacies from simply presenting susceptibility as defined by the laboratory. It works for a great many patients, but it doesn’t give the complete picture. So the [pharmacodynamic] approach is an opportunity to not only try to pick the right drug but also the right dose, dosing interval and infusion technique to optimize exposures.

“What these folks basically said was, ‘Hey, at the end of the day we can’t get there with one drug. So we’re going to take a PD-optimized drug A and ... PD-optimized drug B, and if we put them together, do we have a greater probability of success?’ And the answer is yes.”

Dr. Nicolau said the same approach could be used for other “drug–bug combinations, and we have done that both nationally and with international databases. We have a global program called Passport, [which] tries to take local resistances in South America, North America, Europe and the Asia-Pacific region and link them with drug exposures and dosing and optimization” (Int J Antimicrob Agent.)

The Pittsburgh researchers, he said, are taking the same concept and “bringing it home. What [they] have done is take their local Pseudomonas and asked, ‘What’s the best combination for our bugs?’ I think it makes a great deal of sense. It is something that could be done at many institutions if people took a little bit of time.”

Debra A. Goff, PharmD, FCCP, clinical associate professor at Ohio State University (OSU) College of Pharmacy and infectious disease specialist at the OSU Medical Center in Columbus, said the Pittsburgh Medical Center study was “an excellent example of how important pharmacodynamic modeling is in selecting optimal antibiograms. It also demonstrates how stewardship programs need to go beyond the antibiograms to make drug therapy selections for multidrug-resistant gram-negatives such as P. aeruginosa.”

The study, she added, “drives the point home with cefepime. We did a similar analysis at The Ohio State University Medical Center in partnership with Dr. Nicolau’s research lab. We found it necessary to increase the dose of cefepime to 2 g every eight hours infused over three hours to achieve the optimal pharmacodynamic target, despite the antibiogram reporting a 91% susceptibility. We are running out of options so we must learn how to get the most out of the agents we have. If we continue prescribing the same dose and the same drug to treat multidrug-resistant P. aeruginosa, we cannot expect a different response.”

by

Akshaya Srikanth

Pharm.D Internee

P.R.R.M.College of Pharmacy,

Kadapa