Antibacterials Review

November 6, 2009

Cell-wall active agents

• Penicillins– Narrow spectrum:

• penicillinase susceptible• penicillinase resistant

– Broader spectrum

• Cephalosporins– Narrow spectrum (1° generation)– Broader spectrum (2-4° generations)

• Carbapenems• Aztreonam• Vancomycin

Penicillins

• All derived from 6-aminopenicillanic acid and have -lactam ring

• Vary in resistance to stomach acid, polar, not metabolized easily

• usually excreted unchanged in urine both via glomerular filtration and tubular secretion (latter is inhibited by Probenicid)

• Ampicillin and nafcillin also excreted in bile• Procaine/benzathine forms of penicillin G injected i.m. to

give long half-life, otherwise plasma half life is short (30-60 min)

• Most only cross blood brain barrier when meninges are inflamed.

Penicillins• Bactericidal• Targets (peptidoglycan synthesis)

– Penicillin binding proteins (PBPs)– Transpeptidase– Activate some autolytic enzymes

• Resistance usually due to -lactamases – (esp. Staph and many Gram-negatives)

• Resistance also known via changing PBPs– (methicillin-resistance in Staph – (PenG resistance in pneumococcus)

• Porins mutations in Pseudomonas may allow resistance

Clinical use of penicillinsNarrow spectrum, penicillinase-susceptible drugs

penicillin G (parenteral – unstable in stomach acid)

penicillin V (given orally)

Used for streptococci, meningococcus, Gram-positive bacilli (Bacillus), Spirochetes (Treponema)

Resistance reported for

most Staph aureus,

many Neisseria gonorrhoeae

many Strep pneumoniae

Clinical use of penicillins (cont.)Very narrow spectrum, penicillinase-resistant agents

(methicillin)

nafcillin

oxacillin

Primarily used for infections by Staph. aureus and Staph. epidermidis

Resistance seen with MRSA and with some organisms making ESBLs

Clinical use of penicillins (cont.)

Broader spectrum, penicillinase-susceptible agents

Ampicillin and amoxicillin

Used for PenG susceptible agents

and for

enterococci, Listeria, E. coli, Proteus, Haemophilus influenzae, Moraxella catarrhalis

Used in combination with penicillinase inhibitors (e.g. clavulanic acid)

Synergy shown with aminoglycosides for Listeria and enterococci

Clinical useBroader spectrum, penicillinase-susceptible agents (cont.)

Piperacillin and ticarcillin

Active against several Gram-negative rods Pseudomonas, Enterobacter, some Klebsiella

Synergistic with main glycosides

Often used with penicillinase inhibitors

Clinical use of penicillins (cont.)

Toxicity of penicillins

Nausea, diarrhea are fairly common, especially with oral penicillins

Allergy (including anaphylaxis or induction of Type II and III reactions). Persons with allergy may be desensitized if necessary using a ~3-4 h rapid desensitization protocol

Methicillin may cause nephritisNafcillin may cause neutropeniaAmpicillin often causes a maculopapular rash. This can be

very pronounced if ampicillin is given to someone with mononucleosis (EBV) when this reaction is almost diagnostic for infective mononucleosis.

Cephalosporins

• Most administered parenterally• Many partly metabolized by liver but still usually

excreted in urine (like penicillins)• But cefoperazone & ceftriaxone (mainly via bile)• Most 1° and 2 ° generation do not enter CSF (even

if meninges inflamed)• Targets same as penicillins – i.e, bactericidal drugs• Tendency to be more resistant than penicillins to

-lactamases, but not to all. • Note: MRSA is resistant to cephalosporins

1st generation cephalosporins

Cefazolin (parenteral) and cephalexin (oral)– Used for Gram-positive cocci– Many E. coli and Klebsiella pneumoniae

NOT for – Gram-neg cocci– enterococci– MRSA, – most Gram-neg rods

Second generation cephalosporins

Extended coverage of Gram-negatives

Less coverage of Gram-positives

Diverse activity shown by different members

Cefotetan, cefotoxin (Bacteroides fragilis - anaerobe)

often resistant to ESBLs

Cefomandole, cefuroxime, cefaclor

(H. influenzae. M. cattharalis)

Third generation cephalosporins

Extended coverage of Gram-negatives

Enter CSF (except cefoperazone and cefiximine)

Resistance associated with extended spectrum beta-lactamases (ESBLs in Klebsiella and E. coli especially)

Active against several Gram-neg including Neisseria

ceftriaxone parenteral and cefiximine oral for gonococcus)

cefoperazone & ceftazidime active against Pseudomonas

One injection of ceftriaxone (~ 8h half life) usually effective for acute otitis media

Fourth generation cephalosporins

Cefepime –Expands coverage of 3rd generation to include activity against Gram+ found in 1st generation cephalosporins

–Used for penicillin-resistant pneumococci and for several -lactamase producing Gram-negatives including Enterobacter

Cephalosporins - Toxicity

•Allergy (cross-reactivity within cephalosporins as group)

•Some cross-reaction with penicillins•Pain at injection site•Phlebitis after i.v. administration•May increase nephrotoxicity of aminoglycosides•Disulfuram reaction with some (e.g. cefoperaxzone, cefotetan, cefamandole)

Other -lactams

•Aztreonam (a monobactam. Acts on PBP3)

–No activity on Gram-positive bacteria or anaerobes–Resistant to -lactamases produced by many Gram-negative rods including Klebsiella and Pseudomonas but not resistant to ESBLs.

–Synergistic with aminoglycosides–Prolonged half-life in renal failure

–No significant cross-allerginicity with penicillin

Other -lactams

•Imipenem, meropenem (carbapenems)

–Wide activity against Gram positive cocci, Gram-negative rods, and anaerobes

–Used with aminoglycoside for Pseudomonas infection–Resistant to ESBLs

–Imipenem is administered with cilastin to prevent inactivation by renal dehydropeptidase

CNS toxicity at high concn

Vancomycin• Bactericidal glycoprotein inhibiting cell wall formation• Binds D-Ala-D-Ala pentapeptide side chain to prevent

transpeptidation in growing peptidoglycan• Resistance in VRE and VRSA is due to change of one D-

ala to D-lactate• Narrow spectrum of use

– Mainly for MRSA, penicillin-resistant pneumococcus and C. difficile

• Eliminated unchanged in urine. Not absorbed from gut so only used orally for C. difficile

• Nephrotoxic, ototoxic, RED MAN syndrome with rapid infusion

P AmRNA

30S

50S

tRNA

aa-tRNA

X

Tetracyclines: Mode of ActionReversible binding to 30S ribosome subunit blocking aminoacyl-tRNA access to acceptor site (A site)

Tetracyclines• Drugs usually given orally and absorbed from small intestine

– BUT Interference of uptake by food, divalent and trivalent cations (Ca++, Mg+

+, Fe++, Bi +++, Al+++ ) in antacids, dairy products.

• Active against many Gram + and Gram – bacteria including anaerobes, rickettsiae, chlamydiae, mycoplasmae.

• Tigecycline has wider range. – Must be given i.v.– MRSA included, but NOT Pseudomonas nor Proteus

• Some tetracyclines act against protozoa and those filarial nematodes that have endosymbiotic bacteria– (e.g. doxycyline: Entamoeba and Plasmodium falciparum)

Tetracyclines

• Enter all body fluids well except CSF – (~10-20% plasma level)

• Actively excreted in bile and into feces– some enterohepatic circulation

• Also excreted in urine – But NOT doxycycline nor tigecycline

Tetracyclines toxicity

• Allergies• Minor effects on liver• Vestibular toxicity• Occasional photosensitivity• Kidney excretion means doses need to be watched in

renal failure

• Special effect on growing bones • Enter breast milk and cross placenta• Chelation with calcium causes binding to growing

bones/teeth - damage

23

Tigecycline (Tygacil)

• Became available 2005• Has very broad spectrum of activity including

– MRSA, VRSA, VISA, and coagulase-neg Staph– Penicillin resistant and susceptible streptococci– Enterococci (including VRE)– Gram-positive rods– Enterobacteriaceae – Acinetobacter (multidrug resistant)– Anaerobes (Gram + and -)– Chlamydiae, rickettsiae, Legionella, – fast growing mycobacteria

• NOT effective against Pseudomonas or Proteus where the efflux pump is effective at removing it thereby causing intrinsic resistance.

Macrolides – block transpeptidylation

Macrolides

• Erythromycin, azithromycin, clarithromycinOral bioavailability

Active against Campylobacter, Mycoplasma, Legionella, Gram-pos cocci, some Gram-negs

Erythromycin widely used for community acquired pneumonia

Macrolides

• Azithromycin – Concn in tissues and phagocytes higher than plasma.

Slow release allows once a week dosing (half life 2-4 days). Especially useful for chlamydial infections

• Clarithromycin – Used for Mycobacterium avium

Aminoglycosides

• Broad spectrum

Gentamicin

Amikacin

Tobramycin

Netilmicin

• Those with limited clinical application

Streptomycin

Neomycin

Kanamycin

Do not work alone on serious infections by enterococci orstreptococci but can increase antimicrobial activity of other drugs when used in combination for these infections

Mistranslation – one effect of aminoglycosides

puglisi.stanford.edu/research.html

Gentamicin in major groove of RNAat site where aa-tRNA interacts with mRNA. Distortion of ribosomal site by antibiotic causes misreading of codons.

Interaction is within the 30S subunit

Aminoglycosides

• Highly charged (polycations) and poor lipid solubility • Do not penetrate human cell cytoplasm well.• Generally given by i.v. or i.m. injection.• Mainly excreted in urine• Action independent of microbial concentration so very

useful for intrabdominal infections• Persistent suppression of microbial growth after dropping

to non-lethal level (post antibiotic effect)• High dose once a day is more effective and less toxic

than same amount split and administered in 3 doses per day

• Toxicity largely depends on time the drug remains above a toxic concentration

Aminoglycosides - Toxicity

• Neuromuscular blockade – binding calcium in presynaptic region – reversible with

calcium gluconate

• Nephrotoxicity – interference with tubular function including excess

loss of Mg and Ca: increased toxicity in combination with vancomycin, amphotericin B, diuretics, several others. Generally reversible

• Ototoxicity (auditory and vestibular) – non-reversible

Novel uses in the works for aminoglycosides

• Treatment of genetic disease in humans when caused by premature stop codon in gene.

Spectinomycin

• Similar structure to aminoglycosides

• Target is on 30S ribosome

• Used to treat penicillin-resistant Neisseria gonorrhoeae

Others (all act on 50S subunit)Chloramphenicol

Wide spectrum of activity. Significant toxicities. Inactivated by liver (liver action has low activity in newborn)Aplastic anemia (gray baby syndrome)Restricted uses (e.g. serious rickettsial infections)

Clindamycin (a lincomycin) MLSB resistance knownWorks like macrolidesBacteroides, several anaerobesIncreased danger of Clostridum difficile colitis

Quinupristin-dalfopristin MLSB resistance known Mixture of streptogramins VRE if Enterococcus faecium (but not E. faecalis)

LinezolidVRSA, MRSA, VRE (both E. faecium and E.faecalis)May cause mild thrombocytopenia and bone marrow suppression

Drugs affecting nucleic acid synthesis

• Folate inhibitors– Sulfonamides (derivatives of sulfanilamide

structural analog of p-aminobenzoic acid)– Trimethoprim, pyrimethamine

• DNA gyrase inhibitors– Quinolones

35

Purine and pyrimidine synthesis

Spectrum of sulfonamides

Gram-positives and gram-negatives

Nocardia

Chlamydia

Some protozoa

Note: Sulfonamides stimulate rickettsial growth.

Poor activity against anaerobes

Adverse reactions of sulfonamides• Allergies• Photosensitivity• Nausea and diarrhea• Fever and skin rashes, exfoliative dermatitis• Steven-Johnson syndrome (<1% treatment courses)• Inactivation in part in liver• Crystalluria, hematuria (drugs and inactivated forms excreted in

urine and precipitate at acid pH)• Hematopoietic reactions

– Hemolytic anemia or aplastic anemia– Granulocytopenia, thrombocytopenia, leukemoid– Glucose-6-DH deficiency – enhanced hemolytic reactions

• If given in late pregnancy– Kernicterus (brain damage due to excess jaundice)

Trimethoprim (TMP)• Mainly excreted in urine• Good absorption orally. Lipid solubility enhances

distribution (more than sulfamethoxazole - SMX) including into CSF

• Extended use gives similar side effects to sulfonamides• Reduces length of sulfonamide treatment time when

used in combination with the sulfonamide• E.g. TMP-SMX for UTIs and Pneumocystis prophylaxis

• Pyrimethamine-sulfadiazine for Toxoplasma

Quinolones

• Interfere with DNA gyrase and DNA topoisomerase IV

http://www.web.virginia.edu/Heidi/chapter30/chp30.htm

Activity of fluoroquinolones

• Excellent activity against Gram-negatives• Lesser activity against Gram-positives but some

newer agents better– (e.g. ciprofloxacin maintained for anthrax)

• Bactericidal and have a post antibiotic effect

• Oral agents– Uptake inhibited up to 80% by coadministration

with Al and Mg-containing antacids. Some inhibition by calcium and ferrous ions.

• Most also available for i.v. administration

• Excreted in urine – except ciprofloxacin with 50% bile and 50% urine

Uptake of Quinolones

Indications for fluoroquinolones

lactam-resistant gonococcus Cystitis (where trimethoprim-sulfamethoxazole not useful)

Complicated ascending UTIs (ureter/kidney) Prostatitis (drugs concentrate in prostatic tissue) Single dose for gonorrhea (but resistance developing)

Pelvic inflammatory disease

Indications for quinolones

• Respiratory tract infectionsMany uses but may be need in combination with -lactams for severe pneumococcal pneumonia or with other drugs when Pseudomonas is likely (e.g. ventilators)

• Gastrointestinal infection– Very useful for Shigella (1 dose), Salmonella

(including typhoid), E. coli, cholera, Campylobacter (3-5 days). Resistance a concern

Adverse reactions of quinolones

• Nausea – vomiting - diarrhea• Some cause Q-T interval prolongation• May damage growing cartilage (not

recommended in under 18 year olds) but the damage appears reversible and the drugs are likely safe for some uses

• Tendinitis (rare in adults – main >50 years) Usually starts in Achilles tendon - can lead to tendon rupture

• Probably should be avoided during pregnancy since safety not shown

45

Metronidazole (Flagyl®)H3C

No net charge at physiological pH. Small molecule enters cells. Very good bioavailability, can be given orally

Effective on most obligate anaerobic bacteria including Clostridium difficile, and Gardnerella vaginalis but NOT useful for most Actinomyces spp. and all Propionibacteria (e.g. P. acnes).

Effective against anaerobic protozoa (Trichomonas, Giardia, Entamoeba)

Activated after being reduced by ferredoxin

Redox potential produced by aerobically growing bacteria not low enough to activate the drug.

46

Ferredoxinred

Ferredoxinox

Metronidazole

Short-lived intermediates

R-NO2 + e- → R-NO2-●

R-NO2-● + H+ → R-NO2H●

2R-NO2H● → R-NO2 + R-N(OH)2

R-N(OH)2 → R-NO + H2OR-NO + e- → R-NO-●

R-NO-● + H+ → R-NOH●

R-NOH● + R-NO2H● → R-NHOH + R-NO2

R-NHOH + 2e- + 2H+ → R-NH2 + H2O

Free radicals (●) fragment DNA.

The intermediatesproduced by reduction of the –NO2 group are the active form of the drug

AntimycobacterialsDetecting resistance

Probiotics

Antimicrobials Part II

47

Treatment of mycobacterial diseases

• Problems

• Waxy cell walls (inhibiting drug diffusion)

• Bacteria live both extracellular and intracellular

• Slow growth (drugs must be used for long periods)

• Many drugs only work for one or a few species

Active disease should be treated using combination therapy with multiple drugs

48

Tuberculosis

• All first line agents except ethambutol are all hepatotoxic and when used together have heightened hepatotoxicity

• Streptomycin (no longer first line because resistance is fairly common) is not hepatotoxic

• Treatment using first line agents becomes modified based on:– Pre-existing hepatitis– Pre-existing drug resistance

49

First line agents

• Isoniazid (INH) – Targets cell wall fatty acid synthesis– Only for Mtb (not used for other mycobacteria)– Requires activation by Mtb catalase-peroxidase– Used alone in treatment of PPD-positive persons with

latent TB infection (i.e., no active disease)– Resistance when Mtb that have lost catalase gene– Resistance shown by Mtb with altered INH targets– Liver toxicity increases with age– Other toxicities include peripheral neuropathy (often

reversible by vitamin B6), lupus-like syndrome (~1% of persons though 20% develop anti-DNA)

50

Other first line agents against Mtb• Rifampin (RIF)

– Good at inhibiting and killing bacteria – Used for other mycobacteria including M. leprae– Used for HIV-associated Mtb– Induces acetylating enzymes in liver thus reducing its

activity as treatment continues– Hepatotoxicity, itching, and orange staining of secretions

are most common side effects– Significant drug interactions (including cyclosporine,

contraceptives …) since it induces many cytochrome P450 isoforms.

– Can’t be used with AZT (zidovudine) since it upregulates the glucuronyl transferase that inactivates AZT.

– Also used for prophylaxis of contacts of children with active H. influenzae type b disease

51

• Pyrazinamide– Most hepatotoxic of first line agents– Good killing within macrophages and in caseous lesions– Not effective at alkaline or neutral pH– Deaminated in bacteria to make inhibitor of fatty acid

synthase. – M. bovis is resistant (amino acid substitution in deaminase)– Polyarthraligia and hyperuricemia are main side effects

• Ethambutol– Inhibits cell wall arabinogalactan formation– No liver toxicity– Significant toxicities include retrobulbar neuritis affecting

visual acuity and severe skin reactions52

Other first line agents against Mtb

Streptomycin

• One of numerous second line agents

• Aminoglycoside works extracellularly only

• Toxicities include ototoxicity, circumoral parathesias

• Toxicity noted especially for Cranial nerve VIII

• Not hepatotoxic

53

Other mycobacteria

• Dapsone – sulfonamide-like inhibits folate synthesis

– Used in Multiple Drug Therapy to prevent resistance arising.

– Typically dapsone is used with rifampin and clofazimine in leprosy

54

Other mycobacteria

• Azithromycin or clarithromycin (macrolides)– Prophylaxis for M. avium when CD4<75/l– Azithromycin has elimination half life ~3 days

(i.e. once-a week dosing is possible)

55

56

ANTIMICROBIAL SUSCEPTIBILITY TESTING

57

Resistance limits usefulness of antimicrobials Need to identify isolates and also test for resistance

1. Intrinsic resistance in some species (no target)

2. Development of resistance• Blocking entry of antibiotic or upregulating export pumps• Mutation or enzymatic modification of target• Overexpressing target or upregulating alternative pathway

bypassing target• Modifying antibiotic directly to inactivate it• Failing to activate antibiotic.

58

MIC – a quantitative measure of susceptibility

Minimum inhibitory concentration (MIC) Measures concentration of drug that prevents growth in vitro (does not necessarily kill bacterium) when tested over a set period, usually 1 day.

MIC is an intrinsic property of the bacterium. It stays the same regardless of site of infection (unless strain develops resistance).

Therapy should be chosen to so the concentration of drug in the areas of infection exceeds the MIC

59

Significance of MIC for clinical practice

• When the MIC for an antimicrobial is greater than safe therapeutic concentration, bacteria are resistant

• When the MIC is below the safe therapeutic level, bacteria are susceptible

• An increase in MIC points to resistance developing

60

MIC determination - Tube dilution assay Bacterium, growth medium and drug added to each tube

incubated 24 h

16 8 4 2 1 0.5 0 Concentration of drug in tube (g/ml)

MIC = 1 g/m

l

Susceptible isolate (Drug only toxic above 6 g/ml)

61

Tube dilution assay - resistant isolateIsolate is resistant because drug is toxic above 6 g/ml)

16 8 4 2 1 0.5 0 Concentration of drug in tube (g/ml)

MIC = 8 g/m

l

62

MIC from antibiotic diffusion in agar

Kirby-BauerInoculation of plate with clinical isolate. Antibacterialdisks are placed on surface. Plates incubated~24 h to allow bacteria to form a lawn

AB

C

Zone around antibiotic disc showing no bacterial growth due to presence of antibacterial diffusing out of disk. Antimicrobial is most concentrated at disk

63

64

E-TEST® agar diffusion MIC determination

Continuous scale - not just doubling dilutions.

Expensive

Surrogate tests

• Numerous types: tests with one drug to predict response to another

– E.g. 30 g cefoxitin disk for oxacillin-resistant Staph. aureus (i.e. MRSA)

– Cefoxitin induces mecA (PBP2a) more effectively than oxacillin in those MRSA that are not constitutive producers of PBP2a

65

66

Macrolide - Lincosamide - Streptogramin B resistance

• Staphylococcus aureus – Erythromycin R– Clindamycin S

• This result could hide potential to express clindamycin resistance (MLSB pattern) due to methylase.

• Erythromycin far better inducer of methylase than is clindamycin

• If resistance to clindamycin induced by erythromycin (D-test), this points to MLSB resistance

67

Measuring bactericidal activity

• MBC (minimum bactericidal concentration) – concentration needed to ensure all bacteria killed

• Specialty test, only occasionally used when patients lack residual immunity, or when infection may require bactericidal levels such as in endocarditis/osteomyelitis

68

Extended spectrum -lactamases ESBLs

Over 340 different -lactamases in Gram-negative rods.

Some have very limited substrate activity

e.g. the plasmid-mediated penicillinases with little activity against cephalosporins

SHV-1- ~ 100% Klebsiella pneumoniae isolates (confers R to ampicillin+ticarcillin)

TEM-1 - ~ 50% (currently ) E. coli isolates (confers R to ampicillin).

Mutations in the genes for SHV-1 and TEM-1 → extended-spectrum -lactamases (ESBLs)

ESBLs have activity against ALL the penicillins, most cephalosporins, and aztreonam.

Most common in Klebsiella pneumoniae, K. oxytoca, E. coli but also in other Gram-negatives

Many microbes exist in complex communitiesTherapeutic alterations to “microbiota”

• Antibiotics Chemicals directly targeting (inhibiting/killing) microbes

• PrebioticsNon–digested ingredients that selectively stimulate one or

a group of bacteria in the colon: e.g. lactulose used to reduce ammonia

• ProbioticsLive organisms, which when administered in adequate

amounts, confer a health benefit on the host

69

Targeted antibiotics

Bacteriophages

Increasing interest in bacteriophages to attack biofilms and at other sites.

Many are highly species-specific

Many bacteria attacked by a large number of different bacteriophages suggesting several targets

Rapid lysis of cell wall bright about by murein (peptidoglycan) hydrolases produced during infection (similar structures to bacterial peptidoglycan hydrolases)

70

Lysins produced during intracellular growth by bacteriophages

Hermoso et al., Current Opinion in Microbiology 2007, 10:461-472

Lysins transferred to wall via pores (holins) produced by phage during infection.Pure lysins can act at outside of bacterial cell

71

Potential problems of bacteriophage therapy

1. Narrow host range of most lytic phages

2. Bacteria can become resistant

3. Antibody responses may neutralize activity

4. Pharmacokinetics not easy

5. Potential to mobilize and transfer genes

Use of phage lytic enzymes appears to avoid most of these problems. Resistance does not seem to develop

72

Probiotics

“Live organisms, which when administered in adequate amounts, confer a health benefit on the host.”

Bacteria must be able to adhere and colonize and work within context of a biofilm

Indications suggest usefulness in halitosis and maybe caries (tooth decay)

Strong evidence for value in pouchitis following ileal pouch-anal anastomosis

73

Fecal flora therapy in relapsing Clostridium difficile colitis

• 5% of C. difficile colitis do not respond permanently to treatment with metronidazole or vancomycin and develop a relapse

• Fecal flora replacement with non-C. difficile donor has been reported effective– More research needed

74

Microbial intestinal flora may prime for allergic responses

• Antibiotic-treated and Candida colonized mice

•Noverr et al. Infect. Immun. 2005;73:30-38

Cefoperazone5 days

± Candida albicans orally

antigen/spore lung challenge for 2-3 weeks

75

Candida in intestinal flora may prime for allergic responses in lung (response is IL-13 dependent)

Mice treated with cefoperazone Mice treated with cefoperazone for

for 5 days No Candida 5 days and colonized with C. albicans

•Noverr et al. Infect. Immun. 2005;73:30-38

Challenge with

Aspergillus spores4 times in 12 daysafter Candida

Ovalbumin6 times in 21 daysafter Candida

increased IgE, goblet cell metaplasialung eosinophils 76

Antibiotics and asthma in humans

• Antibiotic usage changes microbial flora in intestine and changes stay for significant time –– More clostridia and Candida (stimulatory lipids)– Less lactobacilli (butyrate, anti-inflammatory)

• Possibly allows increased chances of developing asthma

• Several papers suggest antibiotic use early in life is a risk factor for asthma

• Suggestion that probiotics given infant may reduce tendency to develop asthma (some data)

77